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UndergraduateJ ournalofNeurosci ence

Vol 5| 2011


Call for Submission! cornell Synapse 2013

For more information email us at synapse.submisson@gmail.com


cornell

synapse Volume 5 2011

Editor-in-Chief Chong Guo ‘13

Managing Editor Yoshiko Toyoda ‘14 Jonathan Lin ‘14

Graduate Peer Editors

Design Editors

James Golden Loren Law Hsien-Wei Meng Spencer Park Shane Peace

Louis Hopkins ‘14 Trianna Lutchman ‘14 Lindsay Rappa ‘14

Undergraduate Peer Editors

Staff Writers

Daniel Acker ‘13 Jeanie Gribben ‘15 Shayra Kamal ‘14 Alexandra Mattei ‘14 Brian Morris ‘14 Tracy Netemeyer ‘14 Samantha Olyha ‘14 Camille Shaw ‘14 Ryan Woolley ‘14

Daniel Acker ‘13 Emily Acton ‘13 Peter Cohn ‘14 Daniel Lee ‘14 Brian Morris ‘14 Ethan Romano ‘14

CUSN President Chong Guo ‘13 Bina Bansinath ‘14

Faculty Advisor Bruce Johnson The publication of this journal was made possible with funding from the Cornell University Student Assembly Finance Commission (SAFC). Views expressed in this publication may not necessarily reflect those of the SAFC or Cornell University.


Dear Readers of Synapse,

EDITOR’S LETTER

I have recently encountered a book written by X on mathematics in nature. In the introduction to the chapter on fractals, the author wrote something to the effect of “caution, do not proceed if you wish to preserve your childhood perception of clouds, you will never see them quite the same way again at the end of this chapter.” In a way, this facetious (or maybe totally serious) statement captures well what neurobiologists had accomplished in advancing our scientific understanding of the nervous system. From the epoch-setting doctrinal debate between Golgi and Remon y Cajal to the ingenious formulation of the Hodgkin-Huxley model, neuroscience had indeed come a long way in dispelling many of our ancient dogmas about how the mind works. While it is reassuring to know that we do not see via tentacle-like threads originating from the pupils as Greek philosophers once believed or that hydraulic affects of the ventricular system formed the basis of all cognitive functions, neuroscience as it stands today is still an on-going endeavor, one which involves researchers, clinicians and educators alike. To that end, Synapse exists as a window for students to get a glimpse of this enterprise and to share their own works and ideas via an open platform with the rest of the Cornell community. In this issue of Synapse, we will explore some interesting topics such as the relationship between mirror neurons and social behaviors, the efficacy of Omega 3 supplements, the growth of new neurons in adult brain and neurological diseases such as epilepsy, migraine, and Parkinson’s. We have strived to find a good balance between basic science and translational research during the editing process. So we hope that this final collection may interest as wide an audience as possible. Having said that, as much as those of us here at Synapse would like to share with you our passions and curiosities about the brain, there is a limit to what a group of twenty or so undergraduate students can modestly accomplish with a 40 page publication. We wish that we could caution our readers with the boldness of the aforementioned author that “a reading of Synapse shall forever shatter your existing belief about clouds” or, failing to do that, “how you can perceive them at all.” Nevertheless, we hope that you may walk away with a few amusing tidbits about the brain, some nerdy conversation starters that may or may not work with that girl from BIONB 2220 and ,if you are lucky, finally discovering what you do or do not want to do with the rest of your life. The familiar readers of Synapse will note some key changes in the publication’s structure. Two entirely new sections have been added to the magazine, namely the Featured Articles section and Neuro-in-the-News. While the rigorousness with which Synapse selects and publishes literature review and original research from Cornell undergraduate has been our biggest strength since the very inception of this journal, we wish to engage a wider audience as well as to provide opportunities for students to write about neuroscience in a more open and expressive format. In an effort to diversify our publication in terms of its style and content, we have created a brand new publication which we are very excited to share with you. Last but not the least, I want to extend my sincerest appreciation to our staff writers, undergraduate/graduate editors and the layout designers for all the work they have put into this issue of Synapse. I am very grateful also for having the opportunity to work with our two amazing managing editors Yoshiko Toyoda and Jonathan Lin. The publication process wouldn’t have gone nearly as smoothly without their help. Sincerely, <signature> Chong Guo Biometry and Statistic ‘13


Vol 5 | 2011

Cornell Synapse

TABLE OF CONTENTS Feature Articles Progeria: We’re Not All Dying Slowly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 by Daniel Acker The Elusive Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 by Ethan Romano

News. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Stimulation of Entorhinal Cortex Improves Memory in Epileptic Patients by Emily Acton Single Cell Endoscope Opens Door To Nanoscale Interaction With Neurons by Daniel W. Acker The Effects of Methamphetamine Use on Memory in Snails by Peter Cohn

Research Articles Anti-Epileptic Drugs and Seizure Severity. . . . . . . . . . . . . . . . . . . . . . . . . . . 7 by Kaitlin Hardy

Review Articles Omega-3 or Omega-6? Breastmilk or Formula? . . . . . . . . . . . . . . . . . . . . . .12 by Jonathan C. Lin and Yoshiko Toyoda Migraine Prevention: Neuromodulation for the Hyperexcitable Brain . . .19 by Bryanna Gulotta There is More to Parkinson’s Disease than Motor Dysfunctions. . . . . . . . .25 by Diana Hong Hippocampal Neurogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 by Rachel Bavley

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ?

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Progeria: Weâ&#x20AC;&#x2122;re Not All Dying Slowly Daniel W. Acker Agriculture and Life Sciences â&#x20AC;&#x2DC;13 Biological Sciences and Animal Science

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Aging is a fact of mammalian life. The basic life cycle of birth, growth, maintenance, decrepitude, and death is universal. Humans can even be considered lucky because we enjoy a particularly long lifespan compared to some of our closest relatives. Humans at retirement age can often expect to live for another twenty years, enjoying a period of relative leisure. Because of this, old age has become somewhat glamorized. Many suburbanites dream of retiring one day and spending their sunset years living in Florida, playing golf and absorbing the sunlight. Nevertheless, few would give up their young life to instantly become old. Youth is a time of discovery and selfdefinition, not to mention peak physical health accompanied by great stamina, strength, and regenerative capability. Youth is quintessential to the human experience, and this may be why progeria is so thoroughly unsettling. Progeria is a disease that affects young children. Sufferers experience symptoms such as a lack of hair and teeth, a diminished stature, a narrow and wrinkled face, thin, dry skin, and an impeded range of motion. Nearly all of those affected die in their early to mid teens because of heart attacks or strokes. One of the longest-lived individuals with a verified case of progeria was an artist and musician named Leon Botha who died in June of 2011 at the age of 26. In short, progeria mimics the decay portion of the aging process, turning children into seniors. To add to the tragedy, progeria is untreatable. Those who receive the diagnosis can, at best, expect to live into their early twenties. All that their doctors can do at the moment is prescribe aspirin in hopes of delaying heart failure. Cornell University

Because of its unsettling effects and the similarity of these symptoms to the normal aging process, a great deal of research has been focused on identifying the mechanisms that underlie progeria. As a result, we now know a lot about why progeria occurs. Discoveries have also led to the testing of potential treatments, although none have made it to market as of yet. The fundamental cause of progeria was identified as genetic in 2003 by a team of scientists working at the New York State Institute for Basic Research in Developmental Disabilities. They found that, in 19 out of 20 subjects, there was a single base pair substitution in the DNA coding for the protein lamin A. The researchers went on to find that this substitution resulted in a 50 base pair long deletion when the DNA was transcribed into RNA. This deletion was found to lead to the production of a defective version of lamin A. Later work has shown that many different mutants of lamin A can lead to progeria-like symptoms. A group of French scientists found in 2003 that some of these mutations led to the formation of a mutant protein called progerin. Progerin is similar to lamin A, but has an extra farnesyl group. Such groups often confer membrane-anchoring tendencies on the proteins to which they are bound. This tendency was observed in progerin, which associates with the nuclear membrane that surrounds the nucleus. These discoveries led to experimentation with farnesyltransferase inhibitors. Farnesyltransferase inhibitors disable the farnesyltransferase molecules that are responsible for attaching the extra farnesyl group to progerin.

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|Progeria: We’re Not All Dying Slowly|

2008collaborative collaborativestudy studybetween betweenscientists scientists AA2008 EmoryUniversity, University,New NewYork YorkUniversity, University,the the atatEmory NationalHuman HumanGenome GenomeResearch ResearchInstitute, Institute,and and National theNational NationalHeart, Heart,Lung, Lung,and andBlood BloodInstitute Institutefound found the thatadministering administeringfarnesyltransferase farnesyltransferaseinhibitors inhibitors that could prevent heart disease in mice with progeria could prevent heart disease in mice with progeria symptoms.Furthermore, Furthermore,a a2010 2010study studybybyresearchers researchers symptoms. UCLAand andthe theUniversity UniversityofofKentucky KentuckyatatLexington Lexington atatUCLA foundthat thatwhen whenmice micewere wereengineered engineeredtotoexpress express found unfarnesylatedprogerin, progerin,they theyshowed showednonosymptoms symptomsofof unfarnesylated progeria. progeria. Thefarnesyl farnesylgroup groupononprogerin progerinwas was The wellimplicated implicatedasasa acause causeofofprogeria, progeria,and and sosowell preventingitsitsattachment attachmentwas wassosowell wellimplicated implicated preventing withprogeria progeriatreatment, treatment,that thata ahuman humantrial trialwith with with the farnesyltransferase inhibiting drug lonafarnib the farnesyltransferase inhibiting drug lonafarnib wasapproved approvedinin2007. 2007.The Thestudy studywas wasconducted conductedatat was Children’sHospital HospitalBoston. Boston.Unfortunately, Unfortunately,although although Children’s thestudy studywas wassaid saidtotohave haveconcluded concludedinin2009, 2009,nono the resultshave havebeen beenpublished publishedtotodate. date. results Hopefully, the conductors thisstudy studywill will Hopefully, the conductors ofofthis publishtheir theirresults resultssoon, soon,because becausefinding findingananeffective effective publish treatmentwould wouldbebea avictory victoryfor foranyone anyoneinterested interested treatment alleviatinghuman humansuffering. suffering.However, However,the thehealth health ininalleviating implicationsofofprogeria progeriaresearch researchextend extendbeyond beyondthe the implications obvious. Scientists at the National Human Genome obvious. Scientists at the National Human Genome ResearchInstitute InstituteininBethesda Bethesdafound foundinin2007 2007that that Research elevatedlevels levelsofofprogerin progerinlead leadtotodefects defectsininmitosis mitosis elevated thatare aresimilar similartotowhat whatcould couldbebeobserved observedinincells cells that afternormal normalaging. aging.This Thisconnection connectionwas wasreinforced reinforced after by research from the National Cancer Institute by research from the National Cancer Institute inin Bethesdathat thatshowed showedthat thatthe theelderly elderlyoften oftenexhibited exhibited Bethesda thesame samelamin laminAAmutation mutationthat thatcauses causesprogeria. progeria. the seemsthat, that,totoa acertain certainextent, extent,everyone everyone ItItseems dyingfrom fromthe thesame samedisease. disease.The Theonly onlydifference difference isisdying between those who are deemed healthy and those between those who are deemed healthy and those withprogeria progeriaseems seemstotobebethe therate rateofofitsitsprogression. progression. with progeriacure curecould couldhave havea apotentially potentiallymonumental monumental AAprogeria effectononhow howold oldage ageisisthought thoughtof.of.ItItmay maybebe effect audacioustotothink thinkthat thata acure curewould wouldcompletely completelyhalt halt audacious the aging process, but it’s reasonable to assume that the aging process, but it’s reasonable to assume that wouldlead leadtototreatments treatmentsfor foratatleast leastsome someofofthe the it itwould undesirablesymptoms symptomsassociated associatedwith withold oldage. age. undesirable

References

Vol 5 | 2011

Aboobaker, S (2011, June, 7). Cape DJ dies of Progeria. Independent Online. Retrieved 2011, December, 17 from iol.co.za/ Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely KN, Qu X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani R, Nabel EG, Collins FS. 2008. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc Natl Acad Sci U S A. 106 (31):13143. Eriksson M, Brown WT, Gordon LB, et al. 2003. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423 (6937): 293–8. Makar, AB; McMartin, KE; Palese, M; Tephly, TR 1975. Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria. Biochemical medicine 13 (2): 117–26. McClintock D, Ratner D, Lokuge M, et al. 2007. Lewin, Alfred. ed. The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin. PLoS ONE 2 (12): e1269 Progeria: Treatment. MayoClinic. Retrieved 2011, December, 17 from MayoClinic.com/ Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart C, Munnich A, Merrer M, Levy N. 2003. Lamin A Truncation in Hutchinson-Gilford Progeria. Science 27, Vol. 300 no. 5628 p. 2055 Yang S, Chang S, Ren S, Wang Y, Andres D, Spielmann H, Fong L, Young S. 2010. Absence of progeria-like disease phenotypes in knock-in mice expressing a nonfarnesylated version of progerin. Hum. Mol. Genet. 10.1093

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Vol 5 | 2011

The Elusive Vision Ethan Romano Chemistry, Art and Sciences ‘14 Higher cognition seems to be the hallmark of being human, but there is an immense amount of cognition that churns below our awareness and thankfully so. For example, it may come as a surprise to you that the world we are seeing is the one we are creating. The light reflected off objects in our universe hits the retina as a two dimensional image, yet we see in three dimensions. This reality is known as the fundamental problem of vision. We are constructing the three dimensional world around us. How this happens is still nebulous, but there has been some important strides in uncovering the rules our mind may follow. For example, optical illusions break rules. The Necker Cube is a three dimensional drawing of a cube that has one side shaded, which causes the viewer to perceive one perspective of a cube and then another, but never simultaneously. The Devil’s Triangle is another illusion since, from our perspective, it should not exist. Both of these illusions highlight the importance of a generic view point in our visual processing. When viewing the Devil’s Triangle, our visual systems does not perceive that the object can actual exist since this object requires an unusual change in perspective. Our mind is operating under the probability that small perturbations in perspective will not drastically change the conformation of the object. This contributes to the unsettling and aggravating reality of optical illusions. No matter how aware we are that the Devil’s triangle has a shape that can exist in reality, we can not help but to see a shape that visually can not exist. Although this rule may seem very inconvenient in the face of optical

illusions, it most likely has arisen because in most cases because it is accurate. Such heuristics are important in all types of mental processing since it greatly narrows down the probability of certain images or steps in processing. Objects could be perceived from a variety of perspectives and angles, composed of different shapes and lines, which could cause astronomical possibilities of what the object could look like. However, we only see one object because our mind follows heuristics that say determine how probable an image actually is. Luckily, such computations occur without out attention. Imagine having to consciously assemble every object you saw into possible three dimensional images! Since all humans see in three dimensions with out conscious awareness, such heuristics are probably the result of selective evolution. Just as a computer programmer can directly tell the computer certain heuristics, evolution has painstakingly, through trial and error over billions of years, programmed human vision. The humbling creation and capacity of human vision becomes more apparent compared to computers. Algorithms have been created so that computers can “see” very simplified three dimensional images, such as blocks. The enormity and complexity of such programs to just see simple shapes can really make one stand in awe at the incredibly intricate world we see and the enormously complicated algorithms that allow our mind to compute objects. If looking at blocks is hard, imagine how elaborate the process for seeing the rushing, turbulent water of the gorges must be!

Cornell University Synapse

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| What You are Thinking when You don’t know You are Thinking|

Vol 5 | 2011

Another incredible and maybe uniquely more human characteristic is language. There is an unbelievable amount of processing that occurs without your attention as you read these very words. Every word you read causes your brain to search for associated words within its memory. This becomes more clear in experiments with ambiguous words. For example, when subjects heard or read the word “palm” and were then presented with related words, such as “hand” or “tree” along with unrelated words and nonexistent words, subjects reacted faster in deciding whether a word was English if it was semantically related to “palm.” Thus, not only is the mind primed to expect certain meanings but also accesses these possible meanings in parallel, it considers all possible definitions simultaneously. Vision and language may be two of many modules that support high cognition. Modules are a concept of the mind in which processes can be divided into separate domains, one for speech, one for vision, etc., that are fast and involuntary. These modules may feed into our higher thinking, which can access all modules.

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News Stimulation of Entorhinal Cortex Improves Memory in Epileptic Patients

mice supported the results of this study, with the mice demonstrating improved brain cell growth, increased memory for locations and spatial knowledge upon stimulation. While the study’s authors clearly seek to depict extensive supplemental research is necessary to verify and better qualify these results, this study pres ents an exciting new pathway of exploration for the Emily Acton, Agriculture and Life Sciences ‘13, future treatment of human memory disorders.

Food Sciences

“Memory Gets Jolt in Brain Research,” a recent article published in the Wall Street Journal, chronicles the implications of a study presenting a “new spark” in research on memory disorders. The referenced study by Nanthia et al. (2012) recently published in the New England Journal of Medicine presented preliminary data suggesting that deep brain stimulation in specific areas of the brain may have future significance for the treatment of memory disorders including Alzheimer’s disease. Deep brain stimulation already has notable use as medical treatment, including approval for the treatment of Parkinson’s disease, dystonia and utilities in the treatment of chronic pain and severe depression.1 This study tested the effects of deep brain stimulation in seven epilepsy patients whose baseline memory capacity varied from normal to severely limited. The researchers applied deep brain stimulation, undetectable bursts of electricity through depth electrodes, to different regions of the brain. When the researchers tested the patients’ spatial memory through a location-recollection game, it was found that stimulation of the entorhinal cortex yielded improved memory in six of the patients implanted with electrodes in this region, regardless of their baseline memory capability. The entorhinal cortex is central in the transformation of experiences into memory, and is one of the first sections of the brain to be altered by Alzheimer’s disease. Prior data in human models from studies published in 2008 and 2010 provide limited support of the potential for a correlation between brain stimulation and improved memory. Further, animal models examining the impact of stimulating the entorhinal cortex in

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Single Cell Endoscope Opens Door To Nanoscale Interaction With Neurons Daniel W. Acker, Agriculture and Life Sciences ‘13, Biological Sciences and Animal Science

Researchers at Berkeley National Laboratory developed a nanoscale endoscope, called a nanoscope, that can emit or detect light within a single cell. They built the remarkable instrument by attaching a nanowire waveguide to the tip of an optical fiber. They were then able to focus laser light through the optical fiber, and control its emission within a HeLa cell. They were also able to record wavelength information from within the cell by attaching a spectrometer to the device. This type of endoscope is remarkable because it breaks the diffraction barrier. The diffraction barrier is a problem encountered when using lensed microscopes. It constitutes the difficulty met when trying to examine an object smaller than the wavelength of light being used as illumination. The nanoscope circumvents this issue with its nanowire component, which can transmit subwavelength light through fluid media. The researchers have already demonstrated


News several uses for their nanoscope. In addition to imaging and illumination, they have shown that it can be used in the directed delivery of a payload to a specified intracellular area. They attached quantum dots to the tip of the nanowire, and were able to release these particles into targeted regions by cleaving their link to the nanowire with low intensity ultraviolet stimulation. In addition to its spatial accuracy, this delivery method was shown to have unheard of temporal specificity, as the release time of the quantum dots could be controlled to within a minute.

riod, the researchers observed the snails in order to determine how long this memory persisted. Snails that had not been exposed to methamphetamine generally forgot the training after 24 hours, where as snails that had been “drugged” retained this memory for longer, even though the drug was no longer in their system. These results indicate that the presence of methamphetamine helped the snails to create more persistent, or longer lasting, memories. This finding may help to explain why so many people who have overcome their addiction in treatment facilities relapse after returning to their normal lives. When addicts return to their normal environment, the re-exposure to the visual, environmental, and olfactory stimuli that they had experienced while on drugs may prompt them to have cravings and potentially relapse. Therefore, understanding how memories formed while on methamphetamine are remembered and Peter Cohn, Arts and Sciences ‘14, Psychology forgotten may help with the development of successful treatment strategies. While scientists have a partial understand- Recent studies by Professor Kenneth Luing of the mechanisms of drug addiction, there is kowiak of the University of Calgary, indicate that still much unknown about the specific processes the cell which is critical to learning and memory that result in this condition. In a recent article in pond snails is dopaminergic, and therefore from the Journal of Experimental Biology, Dr. similar to the neural circuits associated with adBarbara Sorg of Washington State University, diction in humans. These studies also point to explored the effects of an addictive drug, methchanges at the level of the neuron’s DNA that are amphetamine, on pond snails. caused by the drug. If we can learn more about Pond snails, which normally live in wahow these memories are learned – and more imter, breathe through their skin most of the time. portantly unlearned – we might be able to make When the water gets low in oxygen, however, they advances in the treatment of drug addiction in will surface and open up a breathing tube. In humans. this study, the researchers utilized this behavior References: in order to study how methamphetamine affects memory by poking the snails in their breathing Wang, S.S. “Memory Gets Jolt in Brain Research.” Wall Street tube when they attempted to surface. Through Journal. (February 9, 2012.) Web. this procedure, the experimenters taught the Yan R., Park J. H., Choi Y., Heo C. J., Yang S. M., Lee L. P., Yang P. (2011) Nanowire-based single-cell endoscopy. Nature nanotechsnails not to surface, or, in other words, caused nology (1748-3387) them to form a memory. After this training pe-

The Effects of Methamphetamine Use on Memory in Snails

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REVIEW

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Anti-Epileptic Drugs and Seizure Severity in Bss1 and Sda Drosophila

Kaitlin Hardy, Agriculture and Life Sciences â&#x20AC;&#x2DC;12, Biological Sciences Abstract

FACES; Facts, Advocacy, and Control of Epileptic Seizures began as a non-profit organization dedicated to epilepsy outreach with the goal of erasing any negative misconceptions surrounding seizure disorders and providing direct assistance to people of all ages living with epilepsy. The FACES lab at Cornell is the only research lab entirely run by undergraduates in the history of the university. Through the use of two bang sensitive Drosophila Melanogaster mutants bang senseless (bss1) and slamdance (sda), the FACES lab is investigating the neural mechanisms of commonly prescribed anti-epileptic drugs (AEDs) with a focus on the commonly prescribed brand name drugs Lamictal (Lamotrigine) and Keppra XR (Levitracetam). Each AED is administered to Drosophila at different dosages beginning at 0.015 mg/ml and increasing until a maximum dosage of 0.4 mg/ml is reached. Flies are exposed to the AED for five days, during which they are tested once for seizure sensitivity through vortex at intervals of ten seconds. Both bss1 and sda Drosophila displayed the most significant reduction in each measure of seizure behavior and severity when tested after three days on 0.15 mg/ml Keppra XR. Both bss1 and sda fly mutants showed reduction across all measures of seizure behavior after three days of exposure to 0.15 mg/ml Lamictal as well, though to a lesser degree. Both bss1 and sda flies respond positively to the human AEDs Keppra and Lamictal when administered at specific dosages and within a narrow margin of time elapsed since initial exposure.

Future tests will include administration of alternate anti-epileptic drugs.

Methods

Twelve hours after eclosion wild type flies and both bss1 and sda fly mutants were placed on one of six feeding conditions for each AED: Keppra XR and Lamictal. Only the brand name forms of each AED were used; no substitutions were made with Lamotrigine (the generic form of Lamictal) or Levitracetam (the generic form of Keppra XR). Furthermore, Keppra was never substituted for Keppra XR, the extended release version. The six feeding conditions included each of the following concentrations of AED dissolved in water and added to yeast based agar: 0 mg/ml, 0.05 mg/ml, 0.1 mg/ml, 0.15 mg/ml, 0.3 mg/ ml, and 0.4 mg/ml. The 0 mg/ml condition was used as a control as the severity of seizure behavior differed amongst individual flies when seizures were induced as a result of individual tolerance to stimulating activity. The 0 mg/ml condition was achieved through adding only distilled water to the pre-made agar mix. The same base agar mix was used for each feeding condition and included Quaker Yellow Cornmeal, Agar Type II, Tate and Lyle corn syrup solids, Lynside Nutri Inactive Nutritional Yeast, and ADM soy flower. The food that contained AEDs did not include excess water as a result of the addition of dissolved AEDs, and all AEDs were ground into a uniform fine powder before dissolved in distilled water. As a result, all food plates had the same overall consistency. A total sample size of 50 - 60 flies of each genotype, and for each of the five days of testing,

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Vol 5 | 2012

| Anti-epileptic Drugs|

was exposed to either 1 of the 5 days of testing, was exposed to either one of the five AED containing food environments or the control non-AED food environment. In total, data for at least 50 flies of each genotype (150 total) was obtained each day over a five day testing period for each of the six feeding conditions. In total, slightly more than 4,500 flies were tested over a period of four months (50 flies of each genotype*3 genotypes*5 days of testing*six feeding conditions). The entire sample size of flies of each genotype and for each of the feeding conditions was spread out over several vials with no more than 25 flies in each vial so as to limit overcrowding and ensuring ample access to food. Care was taken to include an approximately even number of both male and female flies in each vial. Wild type, Bss1, and sda flies were kept separate through the duration of the experiment. As a result, it was not for flies of different genotypes to reproduce. All samples were kept incubated at 20째 C (68째 F) throughout the duration of the experiment and only removed from the incubator for routine maintenance (which included making sure all vials were clean and free of any kind of mold) and behavioral testing. In total, time spent outside of the incubated environment never exceeded one hour per day. Exactly 24 hours after exposure to each feeding condition, seizure behavior is tested and recorded as day one data. AED effectiveness was tested through inducing seizure behavior in groups of ten flies at a time by the use of vortex. Flies are transferred from their feeding environment to an empty test tube and then allowed to recover from this transfer for 30 minutes. The 30 minute rest period allowed individuals to recover from any trauma resulting from the transfer from the food containing vials to the empty experimental vials. Transfer procedure included exposing flies on their feeding environment to a minimal amount of CO2. With each transfer, the goal was to only administer enough CO2 to stop fly activity for less than two minutes, as prolonged exposure to CO2 has the capability to induce seizures in the most sensitive individuals. After 30 minutes the test tube containing a sample of ten flies was placed on a vortex set at maximum power (2500 rpm) for ten seconds. After ten seconds flies were removed from the vortex and observed. The following quantitative observations were made: number of flies initially paralyzed, duration of paralysis for each individual fly

as measured immediately from the time that the flies were removed from the vortex, number of flies displaying seizure behavior, duration of seizure for each individual fly, and recovery time for each individual fly, which was also measured immediately from the time that the flies were removed from the vortex. Complete recovery was defined as resuming negative geotaxis behavior. No more than ten flies were studied at a time to improve accuracy in data collection. After one trial the flies were disposed of in order to control for any long-term damage caused by repeated seizures. The procedure was repeated for each genotype and each feeding condition after flies had been exposed to their assigned food for 48, 72, 96, and 110 hours. In total, data was retrieved for five days of exposure. For each day of testing in the experimental cycle, every individual fly was tested one time before being disposed of.

Results Keppra XR was successful in eliminating seizure activity when ingested by adult flies for a total of 72 hours. This group performed the best overall when subjected to the vortex test as measured across all five parameters: number of individuals initially paralyzed, duration of paralysis for each individual, number of individuals displaying seizure behavior, duration of seizure for each individual, and recovery time for each individual. Flies tested after 96 hours of exposure to 0.15 mg/ml Keppra XR food performed slightly worse than the 72 hour exposure group in two of the five measurement categories: number of individuals initially paralyzed and duration of paralysis for each individual. Differences across the other three categories were small and statistically insignificant. Overall recovery rates for flies exposed to AED food for 96 hours matched the performance of the 72 hour exposure group after 200 seconds, an improvement from the non-AED control flies. Flies exposed to Keppra XR food for 110 hours performed worse than the flies in both the 72 and 96 hour exposure groups in the same two categories where the 72 and 96 hour exposure groups differed most significantly: number of individuals initially paralyzed and duration of paralysis for each individual. All other categories of measurement did not differ significantly. The 72 hour, 96 hour, and 110 hour exposure groups all displayed

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Figure 1. Therapeutic dose of Keppra XR and its ability to control seizures in bss1 Drosophila. N = 150 for each group. Individuals were introduced to food as adults, 12 hours after eclosion. Non-AED agar groups observed two and three days after introduction to food serve as a control variable to measure baseline sensitivity of flies to seizures induced through vortexing at 2500 rpm for 10 seconds. 10% of the individuals studied across all groups, both those that were exposed to AED food and those who were exposed to non-AED food and recorded 48 and 72 hours after exposure, did not display any seizure behavior and immediately resumed negative geotaxis behavior upon removal from the vortex. These results display both the most effective dose of AED and the least possible duration of exposure to AED until a significant improvement in seizure control is observed. This figure compares the duration of paralysis immediately after vortex and until flies resume negative geotaxis behavior, which was the easiest measurement to record most accurately, and a score of 0 seconds for this parameter means that no seizure activity occurred at all. Each group represented on this figure is comprised of 50 bss1 mutant Drosophila. 0.15 mg/ml of Keppra XR ingested for a minimum of 72 hours significantly decreases overall paralysis time and eliminates all measurable seizure activity for over 70% of flies subjected to induce seizure through vortex.

REVIEW better resistance to seizures than the 24 and 48 hour groups and the non-AED exposed groups. 0.15 mg/ml was the most effective dose of Keppra XR in controlling seizures in bss1 Drosophila mutants. The 0.05 mg/ml and 0.1 mg/ml feeding groups did not significantly control seizure activity across each of the five categories measured. The 0.3 mg/ ml and 0.4 mg/ml feeding groups did not significantly control seizure activity across each of the five categories measured. The 0.4 mg/ml Keppra XR dosage food was lethal for a small percentage of flies in both the 96 and 110 hour exposure groups with significantly less flies surviving than any of the other groups. Lamictal was nearly as effective in suppressing seizures as Keppra XR measured across the dimensions of number of individuals paralyzed immediately after vortex and total recovery time for individuals. Identical to the Keppra XR data, 0.15 mg/ml was the most effective dose in controlling seizures. Trials with the lower dosage feeding conditions, 0.05 mg/ml and 0.1 mg/ml, did not have a significant

Figure 2. Therapeutic does of Lamictal and its ability to control seizures in bss1 Drosophila. N = 150 for each group. Procedures for the testing of Lamictal in seizure control were identical to the procedures followed when testing Keppra XR. Like the Keppra XR groups, 10% of the individuals studied across all groups, both those that were exposed to AED food and those who were exposed to non-AED food and recorded 48,72,and 96 hours after exposure, did not display any seizure behavior and immediately resumed negative geotaxis behavior upon removal from the vortex. Data for the 96 hour exposure group is included in this figure due to illustrate its improvement over the non-AED exposed group and almost identical results to the 48 hour group.

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effect on controlling susceptibility. The higher dosages, 0.3 mg/ml and 0.4 mg/ml, were lethal to a greater percentage of flies than the same dosage of Keppra XR. Also identical to the Keppra XR exposed flies, the 72 hour exposure group displayed the most control of seizure activity across all five categories measured. The performance of the 24 and 48 hour exposure groups was similar to the 96 and 110 hour exposure groups, with the 48 and 96 hour exposure groups presenting almost identical data in both the number of individuals initially paralyzed and the time of total recovery and resumption of negative geotaxis behavior. In contrast to Keppra XR, all groups exposed to Lamictal AED food displayed nearly identical overall recovery curves at every interval of exposure time. 200 seconds after removal from the vortex all groups reached the same number of individuals recovered and the remainder of individuals recovered at nearly identical rates regardless of the dosage of AED that they were exposed to and the duration of exposure. Sda Drosophila mutants were not as susceptible to seizures through vortex as Bss1 Drosophila mutants. In contrast to Bss1 flies, a slight minority of a flies displayed paralysis and seizure behavior instead of a majority. The control groups exposed to non-AED food did not perform significantly different from flies exposed to both Keppra XR and Lamictal at identical dosages that bss1 Drosophila mutants were tested at. There was no statistically significant duration of exposure to AED difference for either medication at any 24 hour time interval at which tests were conducted over the course of 110 hours.

Discussion

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It is estimated that 61% of known human disease genes and have a recognizable match in the genetic code of fruit flies, and 50% of fly protein sequences have mammalian matches (NASA radio broadcast, 2/2004). Fruit flies are therefore an appropriate model for testing differences in human AEDs and exploring mechanisms of current drugs in which the mechanism is still unknown. Bss1 Drosophila mutants are susceptible to seizure through physical trauma, such as that induced by the vortex, being abruptly jarred in

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some kind of vial, or slammed against a hard surface, due to a sodium channel mutation. Lamictal is known to control seizures in humans through blockage of sodium channels. The active ingredient in Lamictal is Lamotrigine (the name that generic Lamictal is sold under) which works by preventing sodium ions from entering nerve cells when they begin irregular rapid firing and repetitive electrical signals. By blocking sodium ions from nerve cells, irregular activity is preventing from spreading through nerve cells in the brain. It was expected that Lamictal, a drug that targets sodium channel activity, would be successful in controlling seizures in Bss1 mutants, a strain that is susceptible to seizures as a result of a sodium channel mutation caused by an allele of the paralytic voltage-gated sodium channel gene. The mechanism of Keppra XR is currently unknown, but was successful in seizure suppression in a majority of bss1 flies tested, most notably when administered a dose of 0.15 mg/ml for 72 hours. The results for total flies paralyzed after 72 hours of exposure to a 0.15 mg/ml AED agar mixture of each medication were statistically identical with 70% of the total flies tested resuming negative geotaxis behavior immediately. Recovery time after paralysis was also extremely similar for each AED. Data for Lamictal was more consistent across the 48, 72, and 96 hour time intervals, however for the most effective dose and duration of exposure (0.15 mg/ml for 72 hours) bss1 mutants on Keppra had a slightly faster average recovery time. On average, 80% of flies in this group recovered by 225 seconds after vortexing. The same experimental group in terms of dosage administered and time of exposure that was administered Lamictal instead of Keppra XR reached an 80% recovery rate after an average of 240 seconds. While this difference is slight, it does fall within the range of statistical significance. This suggests that a possible mechanism of Keppra XR includes some form of positive intervention in sodium channel function, a possibility is an ion blocking mechanism similar to that utilized by Lamictal. It is also possible that sodium channel intervention is one of several methods through which Keppra XR suppresses seizure activity. It was expected that bss1 mutants would display greater phenotypic differences than sda mutants when exposed to the vortex test as bss are the most severe of the bang-sensitive Drosophila mutants

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and past studies have never consistently achieved 100% success in seizure suppression. Statistical analysis of data collected in this study was focused on immediate paralysis after vortexing. Number of individuals paralyzed is representative of flies that avoided seizures altogether, and is therefore most analogous to AED controlled seizure activity in humans. In order for AEDs to be considered successful in treatment for people with epilepsy, they would experience no paralysis or seizure activity at all. This measure of fly activity matches the guidelines for successful AED use in humans.

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Omega-3 or Omega-6? Breastmilk or Formula?

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The Controversy Over the Effectiveness of ‘Essential’ Fatty Acids in Infants and Their Mothers on Brain Function and Development Jonathan C. Lin, Human Ecology ‘14, Human Biology, Health & Society Yoshiko Toyoda, Arts and Sciences ‘14, Biological Sciences and History Abstract

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The chemical anatomy of Omega-3 and Omega-6 differ only by the placement of a carbon-carbon double bond, yet these two distinct macronutrients have drastically different effects on nutrition and cognitive development in pregnant and pediatric populations. Both macronutrients can be ingested naturally through the diet or taken in supplements and formulas. Today, our society consumes a disproportionate amount of n-6 fatty acids (Omega 6) compared to Omega-3. We have attempted to make up for this deficiency by consuming more fish, a principal source for Omega-3, but environmentalists warn us of the potential dangers of mercury poisoning. As the consequences of poor nutrition have become increasingly more evident, some of us have heeded to warnings of potential dangers in fish and turned to supplements. This review seeks to explore whether Omega 3 consumption will make children smarter by comparing the two macronutrients. By weighing the strengths and weaknesses of several articles assessing the two fatty acids and their modes of administration, we found that despite the risk of toxicant ingestion in fish, maternal n-3 polyunsaturated fatty acid (n-3 PUFA/Omega-3) consumption increases a child’s intelligence quotient (IQ) at least through four years of life. After birth, long chain-PUFA supplementation, which includes both Omega-3 and Omega-6, in infant formula improves neural development among infants and the critical period of supplements extends beyond the first six weeks of life. Although only a handful of articles are exmined, there are still insights drawn from

this research that may be applied towards the adult population with regards to dietary choices and the often controversial need for supplements.

Introduction With global industrialization, our diets have dramatically shifted away from traditional plant-based diets to processed food diets. Over the past 100-150 years, consumption of n-6 fatty acids has gone up due to the increased intake of vegetable oils, principally found in corn and corn-based products.1 N-6 fatty acids or Omega-6 fatty acids simply refer to the carbon-carbon double bond in the n-6 position of the polyunsaturated fatty acid (PUFA). The n-6 counterpart, n-3 or Omega-3 PUFAs, which are found most prominently in fish and fish-based products, come from the same family of fatty acids but have their carbon=carbon double bond located at the n-3 position. This subtle difference affects our diet and health and plays an important role in our cognitive development. Both n-3 and n-6 PUFAs are long chain-PUFAs (LC-PUFAs) and are essential nutrients.2 We once were a plant-based society that lived on diets with a healthy ratio of n-6 to n-3 fatty acids. However, in Western diets today the ratio of n-6 to n-3 fatty acids ranges from 20-30:1 instead of the traditional range of 1:1 or 2:1.1 It is important to consider that in the past the life expectancy was also lower. There are many factors that might explain this trend of increasing life expectancy, namely our advanced medical knowledge and ability to fight disease. However, technology must not overshadow good nutritional care, a 23 necessary preventative line of defense against disease.

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The PUFA docosahexaenoic acid (DHA) is a potent neurobiological agent that affects neuronal membrane structure, synaptogenesis, and myelination. It can be thought of as a macronutrient that is important in preventing cognitive abnormalities. Studies in preterm humans indicate important benefits in retinal and cognitive development after DHA supplementation.3 Today, PUFAs such as DHA are marketed as ‘miracle workers’ that make people ‘smarter,’ and as a result, dietary supplements of fish oil have become popular among health-conscious Americans. As seen in Figure 1, total fats, including saturated, trans, and n-6 fats increased during the transition to an industrial society while n-3 PUFAs decreased moderately.

cones during neuronal development,7,8,9 enhances synaptic function,10 and regulates nerve growth factor,11 among other functions. The effects of PUFAs on brain development have been experimentally studied extensively during the early years of life when the growing infant relies heavily on fatty acids for cognitive development. Normally, an infant acquires enough nutrients from the mother’s breastmilk. However, some mothers are unable to produce milk, others are undernourished, and some mothers prefer not to breastfeed. All of these reasons result in the need for some babies to be fed formula. Formulas are often supplemented to include the essential fatty acids for cognitive development that we have discussed thus far. But are the formulas necessary, sufficient, or even more effective than breastmilk? We reviewed the literature that discusses the potent benefits of n-3 PUFAs compared to n-6 PUFAs and weigh in on these findings. We will focus on the effects of dietary intake of PUFA during prenatal infancy and infancy, and use the context of PUFAs to examine the effectiveness of supplemented formulas compared to breastmilk.

The popularity of PUFAs derived from fish oils is backed by scientific data. PUFAs are generally the ‘healthier’ fats compared to saturated fats and trans fats. They are also important for cognitive functions. According to Kitajika, et al., PUFAs are essential structural components of the central nervous system.2 Arachidonic acid (AA), a n-6 PUFA, and DHA, a n-3 PUFA, have been shown to be essential for brain growth and cognitive development because they accumulate rapidly in the brain of a developing child in the later part of gestation and early postnatal life.4 On the one hand, n-6 PUFA is over-consumed by western society to the point where its excessive consumption may be damaging to our health. On the other hand, DHA (n-3 PUFA) is under-consumed by some populations and its potentially beneficial effects are still being explored. Mammals obtain DHA either as DHA itself or as the precursor alphe-linolenic acid (ALA), and intermediates between ALA and DHA, including eicosapentaenoic acid (EPA),5 DHA protects neural cells from apoptotic death,6 induces synaptic growth

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Omega-3 vs. Omega-6 and Maternal Intake of these PUFAs

Neural tissues in the brain show progressive enrichment of phospholipids with LC-PUFAs, especially during the last trimester of fetal development and the first 3-6 months after birth, suggesting that the availability of LC-PUFAs is critical for neural development.12 Animal studies have shown that a deficiency of n-3 PUFA may lead to cognitive deficits later in life.13 This leads many to believe that maternal seafood and specifically, n-3 PUFA consumption by mothers during pregnancy and lactation will make their kids ‘smarter.’ However, in another study, infants who received breast milk formula with n-3 PUFAs but not n-6 PUFAs scored lower than infants fed both kinds of PUFAs on cognitive assessments.14 These seemingly contradictory results reveal that a controversy exists over whether or not maternal intake of seafood and n-3 PUFAs can in fact increase a child’s IQ, an indicator of cognitive development. However, with increased consumption of potentially beneficial n-3 PUFA, risk and exposure of mothers and children to toxic contaminants found in fish, such as mercury,

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increases. Furthermore, comparisons between the effects of n-3 and n-6 PUFAs need to be made and the timing of consumption and its effects assessed. Upon discussion and interpretation of the following studies, we can state with greater confidence that despite the risk of toxicant ingestion, maternal n-3 PUFA consumption during later stages of pregnancy increases a child’s IQ at least through four years. Much progress has been made on this controversy since the turn of the century. In 2003, Helland et al. examined the effect of n-3 PUFA supplements on mental development of children of pregnant and lactating women, compared with that of n-6 PUFA supplements. A control group of pregnant and lactating mothers on the same diet without supplements was used. The two supplements—one enriched with n-3 PUFA from cod liver oil and the other with n-6 PUFA from corn oil—contained the same amount by mass of either fatty acid. At four years of age, 90 of 135 randomly selected children took the Kaufman Assessment Battery for Children (K-ABC). In the K-ABC, a mental processing composite was used to assess intelligence.14 The notable inclusion criteria for the women in the study included being age 19 to 35 and having an intention to breastfeed. Self-administered food frequency questionnaires were filled out by the mothers for dietary intake information. At four years of age, children in the n-3 PUFA group had higher K-ABC scores than children in the n-6 PUFA group on the mental processing composite (106.4 vs. 102.3, p = 0.049). This composite correlated positively with DHA found in n-3 PUFA supplements(r = 0.28, p = 0.01). The results of this study showed that four-year-old children whose mothers took n-3 PUFA supplements during pregnancy had higher mental processing scores than children whose mothers took n-6 PUFA supplements.14 Thus, maternal intake of DHA and n-3 PUFA supplementation during pregnancy may be important for mental development. The study did have weaknesses, such as self-administered food frequency questionnaires filled out by the mothers for their children and a geographic scope limited to the Oslo, Norway area. However, the strengths, such as the double-blind nature of the study and the widerange of inclusion/exclusion criteria, outweighed the limitations. Therefore, evidence supports the \ argument that n-3 PUFAs consumed by pregnant

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mothers increases a child’s full-scale intelligence. Three years later, Helland et al. conducted a follow-up study from the previously discussed 2003 study to assess if n-3 PUFA still had beneficial effects over n-6 PUFA on children’s intelligence at seven years of age. No additional fatty acid supplements were given; 143 children, some of which were from the 2003 study, were invited back and reassessed with the K-ABC. No statistical differences in the K-ABC scores at seven years of age between the two groups of children were found (p>0.05). The researchers also did not find any significant differences between the two groups at either four or seven years of age (p>0.05). However, both groups did improve their scores from four to seven years of age (p<0.05).4 Overall, the authors concluded that there were no differences in IQ scores at seven years of age between children of mothers of the two groups. Therefore, Helland et al. argued that n-3 PUFA consumption by pregnant mothers does not increase a child’s fullscale intelligence and specified that it does not have a beneficial effect on seven year old children. The same cognitive tests as those used in 2003 were used in the follow-up study, which allowed for comparisons. However, the validity of the author’s conclusion is reduced because of the inconsistency of study samples, subjectivity of data collected, and weak control for confounding factors. In a different study examining varying levels of maternal seafood intake during pregnancy, Hibbeln et al., in 2007, used the Avon Longitudinal Study of Parents and Children (ALSPAC) to verify the U.S. Advisory Board’s 2004 recommendation that pregnant women limit their seafood intake during pregnancy to 340 grams per week. Eighty-five percent of 13,988 children and their mothers elected to participate. To obtain data about diet and other variable factors, mothers answered questionnaires four times during pregnancy and four times after birth. At 32 weeks gestation, a self-completed food frequency questionnaire asked for the number of times daily that white fish, dark or oily fish, and shellfish was consumed and was used to obtain n-3 PUFA intake values. Each child’s IQ was measured at age eight using the Weschler Intelligence Scale for Children III. The estimated n-3 PUFA intake ranged from 0 to 15.6 g/week (mean: 1.06, SD: 1.05). Children of

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mothers who reported no seafood intake had the greatest risk of adverse or suboptimum outcomes. When seafood intake was moderate (1-340 g per week), the risk of suboptimum outcome in the children was between the two extremes of seafood consumption. The results of this study—in contrast to the U.S. Advisory Board’s recommendation—show that maternal consumption of more than 340 g of seafood per week is actually beneficial for a child’s cognitive development. The advice to limit seafood intake to reduce levels of methyl-mercury found in fish might reduce the intake of nutrients necessary for optimum neurological development. Based on the data, the authors concluded that the risk of losing the potential intellectual benefits of n-3 nutrients exceeds the risk of exposure to trace amounts of contaminants.15 Though the observed cohort is studied with limited geographic samples, the researchers note the fact that the U.K. population had a higher mean consumption of mercury (0.05μg/kg bodyweight) than the U.S. population (0.02μg/kg bodyweight).15 This statistic lends more validity to the conclusion that there are benefits of seafood consumption. Thus, there is strong support that maternal consumption, and even overconsumption, of n-3 PUFAs during pregnancy may increase a child’s intelligence. In order to examine fish intake in different stages of pregnancy and its effects in post-infancy, Gale et al. (2008) used the Wechsler Abbreviated Scale of Intelligence (WASI) to assess intelligence and its association with maternal oily fish intake during early and late gestation in a sample of 217 nine-yearold children. A questionnaire asked for the frequency of white fish, fish in sauces, oily fish, and shellfish consumption—which was then recorded into eight categories representing different durations of time. Behavioral data was skewed so it was dichotomized to have a reference category containing 80-90% of the data and an upper tail representing adverse behaviors.13 After adjusting for confounding variables such as IQ and age, the infants’ cognitive function scores were not statistically significant between mothers who never ate fish and those who ate fish 1-2 times a week. The analyses were repeated looking at oily fish intake only and significant association was not found between intake and higher total difficulties scores (p<0.05). Thus, the results of this study found no significant associations between intake of oily fish in early or late pregnancy and intelligence

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subcategories.13 It must be noted that there was no significant association between frequency of eating fish in early pregnancy and children’s full scale IQ, but “there was a significant association when eating fish in late pregnancy.”13 While the inclusion and exclusion criteria are strong, they are overshadowed by the lack of an upper age limit for eligibility in the study, which may have led to variability. In addition, the parameters of the results were changed after collection of data, which decreases validity. Therefore, their conclusion that n-3 PUFA consumption during late pregnancy does not increase a child’s full-scale intelligence is weak. Considering the results and weighing the strengths and weaknesses of the previous four articles discussed, it seems that despite the risk of toxicant ingestion, maternal n-3 PUFA consumption during later stages of pregnancy increases a child’s IQ through at least four years of life.

Breastmilk or Formula? Infant Intake of Long-Chain PUFAs In addition to maternal intake of PUFAs, direct consumption of PUFAs by infants may also affect their brain development. As an example, Fujimoto, et al. showed that dietary supplementation of DHA improves learning skills.16,17 These ‘essential’ fatty acids have been added to infant formula18 which benefits infants who do not have access to naturally supplemented breast milk. Studies have been conducted to assess the effects of supplemented formula. Here, we will review studies that compare breastmilk, supplemented formula, and unsupplemented formula, and their respective effects on neural development, in order to determine which feeding pattern is best for neural growth in infants. To assess the effects of the three different diets on neural development, Agostoni, et al. studied the influence of increased LC-PUFAs on neural development and fatty acid status in infants in a randomized control trial.19 The authors attempted to directly connect the psychomotor performance of full-term infants at four months of age with LC-PUFA integrated in a formula regimen. 90 infants were fed one of three different diets (breast-fed, LC-PUFA supplemented formula, or standard formula lacking LC-PUFA but containing precursors LA and ALA) for four months after birth and their blood DHA

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concentrations and performance on the Brunet-Lezine test, which measures motor function, social reactions, and language, were recorded.19 The scores were then used to calculate the developmental quotient (DQ) of the child. At four months, infants who were fed the enriched formula scored significantly higher on the Brunet-Lezine test than those fed the standard formula (DQ=105.3 ± 9.4 vs. 96.5 ± 10.9, p<0.01). Breast-fed infants also scored higher than those on standard formula (DQ=102.2 ± 11.5). In addition, among the infants who underwent blood sampling, breast-fed infants (AA=8.5 ± 2.4, DHA=2.7 ± 0.8) and supplemented formula-fed groups (AA=7.0 ± 1.5, DHA=2.1 ± 0.6) had higher AA and DHA levels in their blood than those fed the standard formula (AA=4.4 ± 1.1, DHA=0.6 ± 0.1). The results of this experiment therefore support the supplementation of infant formula with AA and DHA, as it correlates significantly with higher DQ scores and higher blood levels of AA and DHA. A strength of this experiment was that the tests were carried out by the same monitor, which allowed each infant’s performance to be standardized and judged equally. In addition, quantitative data of blood lipid concentrations strengthened the performance results’ validity. Considering the strong design and high validity of this study and weighing it with the inherent variability of breastmilk composition, there is sufficient support for the authors’ conclusion that LC-PUFA supplementation in infant formula improves neural development in four-month old infants. In another study, however, a different conclusion was reached. Auestad, et al. conducted a double-blind study in which researchers observed the cognitive development of 157 infants at 39 months. This study was a follow-up of a previous 2001 study in which 80 infants of 12 and 14 months were exclusively breastfed for three months. 196 infants were randomized within one week after birth into three groups: control formula containing no AA or DHA (n=65), formula with just DHA (n=65), and formula with both DHA and AA (n=66). Standard tests of IQ, receptive vocabulary, expressive vocabulary, visual-motor function, and visual acuity were then administered. At 12 months, no difference was found between the three formula groups or between the breastfed and formula-fed infants in terms of growth, visual acuity, or mental and motor

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development. However, at 14 months, infants fed DHA but no AA had lower vocabulary production and comprehension scores than infants who were fed the unsupplemented formula or who were breastfed. In the follow-up study at 39 months, no difference was seen among the three randomized formula groups or between breastfed and formula groups in their neural developmental performance, growth, or AA and DHA levels in blood. The 14-month observation of lower vocabulary score as a result of supplementing formula with only DHA and no AA may have been a transient effect of DHA on early development. However, the lack of differences in neural development, growth, and blood LC-PUFA levels at 39 months suggests that DHA with or without AA supports normal growth in full-term infants, though no improved performance was seen. Thus, the authors concluded that adding both DHA and AA are not deleterious to infants, yet these macronutrients do not seem to provide increased benefits through 39 months of age.20 This study’s strengths included a large sample group and supplementation of its qualitative data with quantitative data from the growth and blood level measurements. Also, the follow-up design allowed the authors to follow and compare data from the same cohort of participants at varying time intervals. However, while the exclusion criteria were relatively strict, there was no upper limit to gestational age. In addition, the comparison group of breastfed infants was only exclusively breastfed for three months and consumed whatever they wished for the rest of the study, increasing variability of the infants’ diet and potentially reducing the effect of breast milk. Finally, only 80% of the infants from the 2001 study participated in the follow-up. Perhaps bias in the selection criteria occurred, as is the case when parents who see a poor vocabulary score at 12 or 14 months elect to discontinue their children in the study. In our opinion, the weaknesses of this study seem to outweigh the strengths and thus, the authors’ conclusion—that DHA and AA are relatively neutral in their effects—is not strongly upheld. Scientists hypothesize that there is a critical period during which dietary supply of LC-PUFAs may influence the maturation of cortical function in term infants. Previous research suggests that neural tissues in the brain show progressive enrichment of phospholipids with LC-PUFAs, especially during the last trimester of fetal development and the first 3-6 months after birth.21-25 Birch et al. conducted a study

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to determine the importance of LC-PUFAs at different stages of infancy for the maturation of cortical function. The study compared relative importance in the first six weeks of life with that of week 7 through the end of year one. If the critical period for accretion of LC-PUFAs by the brain extends beyond 6 weeks, one would expect that dietary LC-PUFA supplements in infant formula would improve cortical function in term infants weaned from breast-feeding at 6 weeks of age. In a randomized control trial, 65 healthy term infants were randomized into two diet groups, the control group with commercially available infant formula and the other with the same commercial formula supplemented with 0.36% DHA and 0.72% AA. The infants were fed their respective assigned diets from weeks 7 to year one. Throughout the year, the infants were assessed for acuity (keenness of vision), stereoacuity (the ability to detect differences in distance), growth, and blood samples at various time points. Despite a dietary supply of LC-PUFAs from breastmilk during the first 6 weeks of life, infants who were weaned to the control formula had significantly poorer visual acuity at 17, 26, and 52 weeks and significantly poorer stereoacuity at 17 weeks compared to infants who were weaned to LCPUFA-supplemented formula.12 Better acuity and stereoacuity at 17 weeks was correlated with higher DHA concentration in blood samples at 52 weeks. In addition, a significant reduction in the unsaturation index, which can influence function of membranerelated enzymes, receptors, and nutrient transport systems, was found in the control formula group throughout the study period. The control formula group also had a higher Mead acid (suggestive of essential fatty acid deficiency) to AA ratio than did the supplemented formula group. Overall, the average difference between the LC-PUFA supplemented and control formula groups was equivalent to one line on an eye examination chart. The authors therefore concluded that the critical period during which dietary LC-PUFA can influence the maturation of cortical function extends beyond 6 weeks of age, and that such supplemented formulas are well tolerated and beneficial to the maturation of the visual cortex in term infants weaned at 6 weeks. The researchers followed the same infants for a full year (52 weeks) and made assessments at numerous points in time, allowing them to draw

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comparative data. Because the measurements were quantitative, there was less variability in the data. However, this study drew its cohort from a specific geographic region and obtained infants from two separate hospitals. While the authors attempted to increase ethnic and socioeconomic variability by taking the infants from two different hospitals, they may have unintentionally subjected their subjects to different qualities of care and thus potentially skewed results. However, the strengths in the design outweigh the weaknesses seen in the variability of the cohort. Therefore, the conclusion that the critical period extends beyond 6 weeks and that LC-PUFAs are beneficial to the infants’ visual system is likely upheld. From the previous three studies, which assess the benefits of LC-PUFA supplementation of infant formula and the length of its effects, we have reached the conclusion that LC-PUFA supplementation in infant formulas improve neural development in fourmonth old infants and that the critical period of these supplements and their benefits, specifically on the visual system, extends past the first six weeks of life.

Conclusion From the seven articles discussed above, we have reached an overarching conclusion that despite the risk of mercury ingestion, maternal n-3 PUFA consumption increases a child’s IQ at least through four years of life. After birth, LC-PUFA supplementation in infant formula improves neural development in infants and the critical period of supplements extends beyond the first six weeks of life. While we were only able to analyze a handful of articles out of the myriad available in scientific literature, we have attempted to weigh the strengths and weaknesses of each article’s experimental design to better appreciate the reasoning behind each conclusion and to develop our own overall conclusion. Based on our conclusion that PUFAs, specifically n-3 PUFAs, have positive effects on human neural development, we deduced that we should incorporate these healthy fats into our diet by eating oily fishes or perhaps by taking supplements. Future relevant work in this area may include analyzing the effects of n-3 PUFAs on adult neural development and the effect of supplements on adult diets compared to natural ingestion. Supplements not only for n-3 PUFAs but for a variety of other nutrients, such as vitamins

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and minerals, are widespread in American healthconscious diets, but are these really effective? Further research and analysis is required to answer these integral questions.

References

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1.Simopoulos, AP. Essential Fatty Acids in Health and Chronic Disease. The American Journal of Clinical Nutrition. (1999). 70:560S-9S. 2.Kitajika, K., Sinclair, A., Weisinger, R., Weisinger, H., Mathal, M., Jayasooriya, A., Halver, J., Puskas, L. (2004). Effects of Dietary Omega-3 Polyunsaturated Fatty Acids on Brain Gene Expression. Proceedings of the National Academy of Science of the United States of America, 101(30), 10931-10936. 3.Uauy R., Dangour A. Nutrition in Brain Development and Aging: Role of Essential Fatty Acids. Nutrition Review. (2006). 64:S24-33. 4.Helland, I., Smith, L., Blomén, B., Saarem, K., Saugstad, O., Drevon, C. (2008). Effect of Supplementing Pregnant and Lactating Mothers with n-3 Very-Long-Chain Fatty Acids on Children’s IQ and Body Mass Index at 7 Years of Age. Pediatrics, 122(2), 472-479. 5.Innis, SM. (2007). Dietary (n-3) Fatty Acids and Brain Development. American Society for Nutrition. Journal of Nutrition, 137, 855-859. 6.Akbar, M. & Kim, H.-Y. (2002) J. Neurochem. 82, 655– 665. 7.Huettner, J. E. (2003) Prog. Neurobiol. 70, 387–407. 8.Auestad, N. & Innis, S. M. (2000) Am. J. Clin. Nutr. 71, 312S–314S. 9.Bazan, N. G. & Rodriguez de Turco, E. B. (1994) J. Ocul. Pharmacol. 10, 591–604. 10.McGahon, B. M., Martin, D. S. D., Horrobin, D. F. & Lynch, M. A. (1999). Neurocsiences 94, 305–314. 11.Ikemoto, A., Nitta, A., Furukawa., Ohishi, M., Nakamura, A., Fujii, Y. & Okuyama, H. (2000) Neurosci. Lett. 285, 99–102. 12.Birch, E., Hoffman, D., Castaneda, Y., Fawcett, S., Birch, D., Uauy, R. (2002). A Randomized Controlled Trial of Long-Chain Polyunsaturated Fatty Acid Supplementation of Formula in Term Infants After Weaning at 6 wk of Age. American Journal of Clinical Nutrition, 75, 570-580. 13.Gale, C., Robinson, S., Godfrey, K., Law, C., Schlotz, W., O’Callaghan, F.J. (2008). Oily Fish Intake During Pregnancy – Association with Lower Hyperactivity but not with Higher Full-Scale IQ in Offspring. The Journal of Child Psychology and Psychiatry, 49(10), 1061-1068. 14.Helland, I., Smith, L., Saarem, K., Saugstad, O., Drevon, C. (2003). Maternal Supplementation With Very-Long-Chain n-3 Fatty Acids During Pregnancy

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and Lactation Augments Children’s IQ at 4 Years of Age. Pediatrics, 111(1), 39-44. 15.Hibbeln, J., Davis, J., Steer, C., Emmett, P. (2007). Maternal Seafood Consumption in Pregnancy and Neurodevelopmental Outcomes in Childhood (ALSPAC study): an Observational Cohort Study. The Lancet, 369(9561), 578-585. 16.Fujimoto, K., Yao, K., Miyazawa, T., Hirono, H., Nishikawa, M., Kimura, S., Maruyama K., Nonaka, M. (1989). The Effect of Dietary Docosahexaenoate on the Learning Ability of Rats. In: Chandra RK (ed) Health Effects of Fish and Fish Oils. ARTS Biomedical Publishers, St. John’s, newfoundland, pp 275-284. 17.Wainwright, PE, Huang YS, Bul-man-Fleming, B., Mils DE, Redden P., McCutcheon, D. (1991). The Role of n-3 Essential Fatty Acids in Brain and Behavioral Development: a Cross-Fostering Study in the Mouse. Lipids, 26, 37-45. 18.Jensen RG. Lipids in Human Milk. (1999). Lipids, 34, 1243-1271. 19.Agostoni, C., Trojan, S., Bellu, R., Riva, E., Giovannini, M. (1995). Neurodevelopmental Quotient of Healthy Term Infants at 4 Months and Feeding Practice: The Role of Long-Chain Polyunsaturated Fatty Acids. Pediatric Research, 38(2), 262-266. 20.Auestad, N., Scott, D.T., Janowsky, J.S., Jacobsen, C., Carroll, R.E., Montalto, M.B., Halter, R., Qiu, W., Jacobs, J.R., Connor, W.E., Connor, S.L., Taylor, J.A., Neuringer, M., Fitzgerald, K.M., Hall, R.T. (2003). Visual, Cognitive, and Language Assessments at 39 Months: A Follow-up Study of Children Fed Formulas Containing Long-Chain Polyunsaturated Fatty Acids to 1 Year of Age. Pediatrics, 112(3), 177-183. 21.Svennerholm L. Distribution and Fatty Acid Composition of Phosphoglycerides in Normal Human Brain. (1968). Journal of Lipid Research, 9, 570-579. 22.Svennerholm L, Vanier M. The Distribution of Lipids in the Human Nervous System. III. Fatty Acid Composition of Phosphoglycerides of Human Foetal and Infant Brain. (1973). Brain Research, 50, 341-351. 23.Martinez M. Tissue Levels of Polyunsaturated Fatty Acids During Early Human Development. (1992). Journal of Pediatrics, 120 (suppl), S129-138. 24.Martinez M, Conde C, Ballabriga A. Some Chemical Aspects of Human Brain Development. (1974). Pediatric Research, 8, 91-102. 25.Martinez M, Mougan I. Fatty Acid Composition of Human Brain Phospholipids During Normal Development. (1998). Journal of Neurochemistry, 71, 2528-2533.

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REVIEW Migraine Prevention: Neuromodulation for the Hyperexcitable Brain Vol 5 | 2012

Bryanna Gulotta, Agriculture and Sciences â&#x20AC;&#x2DC;13, Biological Sciences Abstract

Migraines associated and unassociated with auras are linked to excitation in the neural network. Cortical spreading depression (CSD) is a phenomenon characterized by sudden excitatory potentials followed by an extended period of inhibition that moves in waves across the brain. CSD may underlie the presentation of aura in migraine sufferers and is used to model aura in mice. Although the exact mechanisms governing migraine headaches are currently unknown, the presentation of neural excitation and aura during migraines and CSD makes CSD an ideal system to study neural activity potentially influencing migraine occurrence. Simply studying neural excitation exhibited during CSD is not enough, however. Lamotrigine is a medication that inhibits neural excitation; it is particularly effective as suppressing CSD and migraine with aura. Its mechanisms of action are well investigated. Examining how lamotrigine obstructs generation and propagation of neural excitation offers insight into how detrimental neural excitation occurs. Exploring how neural activity is altered in CSD patterns and migraine events and how lamotrigine impedes such altered activity illuminates mechanisms of migraine pathogenesis, inhibition, and prophylaxis.

Neural Hyperexcitation

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Migraines are the result of hyperexcited neural networks in the brain.1 Understanding the root cause of hyperexcitability could help neurobiologists and physicians prevent and treat migraines as well as other disorders caused by neural excitation, such as epilepsy.2 Over 10% of the United States population suffers from migraines.3 Generally, the debilitating condition manifests as a throbbing headache localized to one side of the brain.4,5 Nausea, vomiting, dizziness, visual distortion, and sensitivity to light, sound, and smell may accompany the pain. These secondary symp-

toms, called auras, precede migraine headaches about 20% of the time. Auras are caused by a condi tion called Cortical Spreading Depression (CSD), which is known to begin with excessive, or hyper-, excitation of neurons.6 Although they may be seen as separate occurrences, both CSD, presenting as auras, and migraines are caused by hyperexcitability in the neural network. Additionally, CSD has been noted in some migraine patients without aura presentation, which strengthens the link between the two conditions.6 While migraine genesis is still a mystery, CSD can be experimentally induced in mice.7 CSD also has a characteristic pattern of activity as it travels through groups of neurons.6 For this reason, examining CSD is an ideal way to investigate hyper-excitability and ways to stop or prevent it.

The Model: CSD Although CSD has been somewhat difficult to detect and study in humans, ample evidence of CSD in animals and some evidence about CSD in humans have been garnered. CSD is usually localized to a particular lobe, generally in the occipital lobe in humans.6 It is characterized by an initial depolarization and a resulting action potential in a group of neurons, followed by an extended (inhibitory) refractory period.6 During this refractory period, the neurons cannot depolarize for further firing. CSD moves in slow waves through the brain, traveling at a rate of approximately three millimeters per minute.8 The waves spread from their origin in one lobe to other groups of neurons in other parts of the brain. A sudden decrease of extracellular calcium that is presumably a result of the initial depolarization distinguishes CSD.9 Overall, CSD prevents communication among neurons. Thus, sufferers usually experience sensory deficits during CSD episodes that are perceived as auras.6 Although successful treatments for migraine and CSD separately are not always cross effective, recent research has demonstrated that if they are used

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| Migraine Prevention: Neuromodulation for the Hyperexcitable Brain |

long-term, some migraine medications can reduce the frequency of CSD episodes.6,7

Medicating Hyperexcitation

A medication called lamotrigine has beenvery successful in treating CSD. In a recent trial, lamotrigine reduced CSD occurring in the anterior and posterior sections of the brain in rats most successfully when compared with other migraine medications.10 It also demonstrated the best treatment outcome when compared with carbamazepine, gabapentin, oxcarbazepine, and topiramate in treatment of partial onset seizures in epileptic patients; epilepsy is another disorder of neural excitation.11 Other works demonstrate a neuromodulatory function of lamotrigine in the neurons. Studies in rats have shown that lamotrigine decreases the frequency of spontaneous excitatory postsynaptic potentials by decreasing the release frequency of glutamate, an excitatory neurotransmitter.12 Lamotrigine also increased the amplitude and frequency of spontaneous inhibitory postsynaptic potentials by increasing the release of GABA, an inhibitory neurotransmitter.12 In humans, lamotrigine has demonstrated the ability to suppress aura and the potential to suppress migraines in patients with comorbid, or multiple simultaneous, aura.13 Overall, lamotrigine may suppress hyperexcitability at both the neuronal and neural network levels. This makes lamotrigine an excellent candidate to study the pathogenesis of migraines. The following review aims to expound upon this research and discuss means of neuromodulating excitatory and inhibitory postsynaptic potentials in order to influence migraine pathogenesis. Presented investigations of CSD will illustrate mechanisms of neural excitation. Next, discussion on the function of lamotrigine will confirm how neural excitation might arise and propagate, and how it may be stopped or presented. The goal of this review is to provide evidence that simultaneous modulation to decrease excitation and increase inhibition in neurons and neural networks at different levels of excitation is an effective way to alleviate CSD and, if not migraines in general, at least migraines in the portion of patients that experience comorbid aura. From Neural Excitation to Migraines Initial depolarization or excitation of neurons

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in CSD is marked by a decrease in extracellular calcium levels. In a recent experiment by Richter et al, a blockade of high threshold voltage gated calcium channels (VGCCs) translated into decreased CSD wave propagation.14 Their experiment explicitly demonstrates that CSD and excitation can be inhibited by blocking calcium flow from the extracellular space into neurons. The link between calcium and neural excitation rests in calciumâ&#x20AC;&#x2122;s function in individual neurons. Intracellular calcium is involved in presynaptic cell signalling. High threshold VGCCâ&#x20AC;&#x2122;s, known as N or P/Q type channels, regulate the entry of calcium into presynaptic terminals, and consequently are at least partially responsible for the amounts of the neurotransmitters glutamate and GABA that are released into the synaptic cleft.12,15,16,17 Specifically, the blockade of N and P/Q type channels resulted in decreased repetition of CSD waves across the rat brain in the presence of a known CSD generator, potassium chloride crystals.14 Since CSD is dependent upon excitatory activity followed by inhibitory activity, that changes in calcium conductance alter CSD patterns implies an alteration in excitatory and inhibitory potentials is occurring. Another indicator that calcium conductance is a factor in CSD activity is that a mutation in the Îą1A subunit of presynaptic P/Q type VGCCs in mice in vivo resulted in a resistance to chemically induced CSD waves, and once established, a slower wave propagation speed. In this particular experiment, the glutamate release pattern via microdialysis in these mice indicated a greater than two-fold attenuation of the calcium current and a decreased probability ofopen P and Q channels compared with the control mice. The glutamate measurements in this experiment indicated that the interruption in communication impeded the excitation of postsynaptic neurons.7 Malfunction or blockade of the P/Q type channels inhibits cell-to-cell communication via reductions in glutamate release - this may be the actual cause of disruption in neuronal communication. Generally, the evidence suggests that decreasing calcium conductance reduces the likelihood of hyperexcitation of neurons and of the neural network. Human genetic studies similarly find that calcium channel mutations affect neural excitation. The gene CACNL1A4 encodes for P/Q calcium channels. Members of several families with Familial Hemiplegic Migraine (FHM), which is 20

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suffering from Episodic Ataxia Type-2 (EA-2), causing uncoordinated movement and sometimes cerebellar atrophy, were determined to have either mutations or deletions in this same gene. In EA-2, the DNA changes possibly lead to the gain of function due to changes in the channel α1subunit. This would explain why in the mice described above α1A subunit mutations reduce the likelihood of CSD, but other P/Q channel mutations increase the likelihood of neural excitation.18 A caveat to work presented thus far is the unsuccessful treatment of migraines with the voltagegated calcium channel blocker Nifedipine.19 However, Nifedipine is an L-type calcium channel blocker. L-type calcium channels are also VGCCs, but are composed of different amino acid chains than the P/Q type channel; they have been shown to be largely unrelated to repetitive CSD waves and to the effects of lamotrigine.14,16

Figure 1. Map of the P/Q channel calcium channel

depicting mutations prevalent in Familial Hemiplegic Migraine, mouse Etaxia Type-2, and in two types of mice used by Ataya 1999, tg and tg1a. Mutations in the channel appear to influence calcium conductance and, subsequently, neural excitability (Terwindt 1998).

Medicating Hyperexcitation: Analysis

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It is interesting to note that the α1A subunit, which confers voltage sensitivity which confers voltage sensitivity in calcium channels, is a homologue to Lamotrigine appears to have multiple modes that found in sodium channels. This may explain why of action. Its first documented effect was reducing lamotrigine appears to affect conductance of both sodium conductance by blocking voltage gated 20 ions.15 Furthermore, the concentration of lamotrigine sodium channels. Lamotrigine halted sodium dependent sustained action potentials in mouse spinal used to evoke changes in sodium conductance and cord neurons.20 In a separate experiment, lamotrigine calcium conductance is similar, supporting the idea that lamotrigine is multimodal.17 The work inhibited the function of neuromodulator veratridine, presented above contradicts the work of Cunningham which opens voltage sensitive sodium channels, and colleagues, who found that lamotrigine’s and competed for binding locations with toxin [3H effect on spontaneous potentials does not depend batrachotoxininin A 20-α-benzoate, which prevents 20,21,22 voltage gated sodium channelinactivation. These on the activity of sodium and calcium channels.12 findings reveal that lamotrigine specifically acts on the They speculated that lamotrigine may function as a neuromodulator that interacts with the vesicular inactive forms of the voltage gated sodium channel system involved in releasing neurotransmitter into the and portrays the drug as a neuromodulator itself. It synaptic cleft.12 These findings may not, however, be is thought that by reducing sodium conductance and mutually exclusive. In one experiment, lamotrigine inhibiting depolarization of the presynaptic cell, demonstrated no effect on low threshold calcium lamotrigine decreases the release rate of glutamate channels in rat thalamocortical neurons, even though to the postsynaptic neuron, and thus the frequency of 21 it did suppress general absence seizures and tonicexcitatory postsynaptic potentials. clonic seizures modeled in these cells.23 Furthermore, Lamotrigine plays a similar neuromodulatory in the same experiment, identical volumes of role in calcium conductance, which, based on the chloride current entered the postsynaptic terminals CSD and migraine research, offers insight into how of lamotrigine treated cells and lamotrigine treated the drug could work to suppress these disorders. cells in solution containing magnesium ions. The Under lamotrigine treatment, the N and P/Q VGCCs 16 demonstrate decreased conductance of calcium. This magnesium solution induces cellular spiking in these treatment would also reduce the release of glutamate latter cells similar to that seen in generalized absence from the presynaptic terminal. Cornell University Synapse


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action has been discovered. Lamotrigine demonstrated the ability to globally decrease the ratio of excitation to inhibition in vitro in the rat ethorinal cortex.24 This poorly defined global pattern hints at a yet unknown and complex neuromodulatory function of lamotrigine. This is especially true in light of research demonstrating that lamotrigineâ&#x20AC;&#x2122;s full efficacy is not reached until several months after application.13

Figure 2. Lamotrigine reduces firing rate at high voltages (as the cell depolarizes), but has no effect when the cell is held in a hyperpolarized state; this suggests a neuromodulatory effect on voltage gated sodium channels.20

current is a marker of neuron inhibition, usually induced by GABA reception on the post-synaptic terminals of lamotrigine treated cells and lamotrigine treated cells in solution containing magnesium ions. The magnesium solution induces cellular spiking in these latter cells similar to that seen in generalized absence and general tonic-clonic seizures. Inward chloride current is a marker of neuron inhibition, usually induced by GABA reception on the postsynaptic cell. This result indicates no difference in the reception of GABA on postsynaptic cells in conditions of high excitation.23 If presynaptic cell calcium and sodium conductance does not change during periods of low neural excitation, and inhibitory neurotransmitter reachig postsynaptic cells in cultures treated with lamotrigine also do not change in high activity conditions, the activity of lamotrigine may differ according to the state of excitation in cells. The results from Cunningham et al and Gibbs et al both suggest that lamotrigine increases GABA release and decreases glutamate release in tandem. Thus, in instances of high voltage activity, lamotrigine may affect high threshold calcium and high threshold sodium channels and change the ionsâ&#x20AC;&#x2122; conductance, which decreases neurotransmitter release. In conditions of low excitation, lamotrigine may reduce both the frequency of glutamate release and increase frequency and concentration of GABA release by affecting presynaptic vesicular release

Fig. 3 Lamotrigine increased the time between spontaneous excitatory potentials (top) and decreased the time between spontaneous inhibitory potentials (bottom). Spontaneous potentials occur without activating high voltage calcium or high voltage sodium channels.12

Discussion Voltage gated calcium channel conductance play a central role in incidences of CSD. Furthermore, due to the effect of VGCCâ&#x20AC;&#x2122;s on neurotransmitter release, it appeared that glutamate levels were directly involved in neural excitation, as might be suspected from an excitatory neurotransmitter. These experiments on CSD events demonstrated clearly that changes in ion channel conductance were a key factor leading to neural excitation.Reports on lamotrigine

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Table 1, 2 Lamotrigine effectively suppressed tonic-clonic and generalized absence epileptic seizure activity in the rat thalamocrotical slices. cTBs and sTBs are neural wave models for general absence and tonic-clonic seizures respectively in rat neurons. This effect was seen despite no evidence of an effect of lamotrigine on calcium conductance during spontaneous potentials in Cunningham et al.

confirmed this finding, and strengthened the notion that neurotransmitter release was crux of the propagation of neural excitation. In addition, the studies on lamotrigine expose how neural excitation may actually have many progenitors. While periods of high activity, such as during hyperexcitation may be stopped or prevented by the use of VGCC blockers, events which precede hyperexcitation are not affected by such blockade. In the hyperexcitable brain, there may be an increased ratio of spontaneous excitatory to inhibitory potentials. Lamotrigine corrects this ratio, possibly by affecting vesicular release machinery. This discovery points to a possible mechanism by which sufferers are predisposed to migraines. It also proposes a direction for research on future medications. It is clearly important in patients with disorders of neural excitation to look at both brain activity during periods of hyperexcitability and when activity is supposedly normal in orderto tease out events whose inhibition or reversal could prevent neural excitation altogether. Hopefully, future research will determine how lamotrigine has its remarkable effect on cells and what can be done to correct hyperexcitability when it develops.

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References

1. Dâ&#x20AC;&#x2122;Andrea, G., & Leon, A. 2010. Pathogenesis of migraine:from neurotransmitters to neuromodulators and beyond. Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 31 : 1-7. 2. Bigal, M. E., Lipton, R. B., Cohen, J., & Silberstein, S. D. 2003. Epilepsy and migraine. Epilepsy and Behavior (4): 13-24. 3. Lipton, R. B., Scher, A. I., Kolodner, K., Liberman, J., Steiner, T. J., & Stewart, W. F. (January 01, 2002). Migraine in the United States: epidemiology and patterns of health care use. Neurology, 58, 6, 885-94 4. Osterhaus, J. T., Gutterman, D. L., & Plachetka, J. R. (July 01, 1992). Healthcare Resource and Lost Labour Costs of Migraine Headache in the US.Pharmacoeconomics, 2, 1, 67-76. 5. Selby, G., & Lance, J. W. (January 01, 1960). Observations on 500 cases of migraine and allied vascular headache. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 23-32. 6. Parsons, A. A. 2004. Cortical spreading depression: its role in migraine pathogenesis and possible therapeutic intervention strategies. Current Pain and Headache Reports, 8 ( 5) : 410-6. 7. Ayata, C., Shimizu-Sasamata, M., Lo, E. H., Noebels, J. L., & Moskowitz, M. A. 1999. Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the @Îą1AA subunit of P/Q type calcium channels. Neuroscience 95(3): 639-645. 8. Reid, K. H., Marrannes, R., & Wauquier, A. (January 01, 1988). Spreading depression and central nervous system pharmacology. Journal of Pharmacological Methods, 19, 1, 1-21 9. Lauritzen, M. (January 01, 1994). Pathophysiology of the migraine aura. The spreading depression theory. Brain : a Journal of Neurology, 117, 199-21 10. Bogdanov, V. B., Multon, S., Chauvel, V., Bogdanova, O. V., Prodanov, D., Schoenen, J., & Makarchuk, M. Y. 2011. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiology of Disease, 41 (2): 430-435. 11. Marson, A. G., Al-Kharusi, A. M., Alwaidh, M., Appleton, R., Baker, G. A., Chadwick, D. W., Cramp, C., Cockerell, O.C., Cooper, P.N., Doughty, J., Eaton, B., Gamble, C, Goulding, P.J., Howell, S.J., Hughes, A., Jackson, M., Jacoby, A., Kellet, M., Lawson, G.R., Leach, J.P., Nicolaides, P., Roberts, R., Shackley, P., Shen, J., Smith, D.F., Smith, P.E., Smith, C.T., Vanoli, A., Williamson, P. R. (March 24, 2007). The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised

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controlled trial. The Lancet, 369, 9566, 1000-1015. 12. Cunningham, M. O., & Jones, R. S. 2000. The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro. Neuropharmacology, 39 (11) : 2139-2146. 13. Lampl, C., Katsarava, Z., Diener, H. C., & Limmroth, V. 2005. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. Journal of Neurology, Neurosurgery, and Psychiatry, 76 (12) : 1730-2. 14. Richter, F., Ebersberger, A., & Schaible, H.-G. 2002. Blockade of voltage-gated calcium channels in rat inhibits repetitive cortical spreading depression. Neuroscience Letters, 334 (2): 123. 15. Kwan, P., Sills, G. J., & Brodie, M. J. 2001. The mechanisms of action of commonly used antiepileptic drugs. Pharmacology & Therapeutics 90(1): 21-34 16. Stefani, A., Spadoni, F., Siniscalchi, A., & Bernardi, G. 1996. Lamotrigine inhibits Ca2^+^ currents in cortical neurons: functional implications. European Journal of Pharmacology 307(1): 113-116. 17. Stefani, A., Spadoni, F., & Bernardi, G. 1997. Voltageactivated calcium channels: targets of antiepileptic drug therapy?. Epilepsia 38( 9): 959-65 18. Ophoff, R. A., Terwindt, G. M., Vergouwe, M. N., van, E. R., Oefner, P. J., Hoffman, S. M., Lamerdin, J. E., Mohrenweiser, H.W., Bulman, D.E., Ferrari, M., Haan, J., Lindhout, D., van Ommen, G. B., Hofker, M.H., Ferrari, M.D., Frants, R. R. 1996. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87(3): 543-52 19. Welch KM. 1993. Drug therapy of migraine. The New England Journal of Medicine. 329(20): 1476-83 20. Cheung, H., D. Kamp, E. Harris. 1992. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Research 13(2): 107 21. Brodie, M. J. 1992. Lamotrigine. Lancet 339(8806): 1397-400. 22. McNeal, E. T., Lewandowski, G. A., Daly, J. W., & Creveling, C. R. 1985. [3H]Batrachotoxinin A 20 alphabenzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs. Journal of Medicinal Chemistry 28(3): 381-8 23. Gibbs, J. W. ., Zhang, Y. F., Ahmed, H. S., & Coulter, D. A. 2002. Anticonvulsant actions of lamotrigine on spontaneous thalamocortical rhythms. Epilepsia 43 (4): 342-349. 24. Greenhill, S. D., & Jones, R. S. G. 2010. Diverse antiepileptic drugs increase the ratio of background synaptic inhibition to excitation and decrease neuronal excitability in neurones of the rat entorhinal cortex in vitro. Neuroscience 167 (2): 456-474.

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Parkinson’s Disease:

A review on both motor and non-motor symptoms

Diana Hong, Arts and Sciences ‘13, Biological Sciences Abstract

Parkinson’s disease (PD) is considered a motor system disorder caused by the degeneration of dopaminergic neurons in the substantia nigra. However, it is also associated with a wide range of non-motor symptoms. Some of these symptoms include sensory dysfunction, depression, and dementia. Because the exact biochemical pathways for these non-motor symptoms are not yet completely understood, current treatment options for PD focus primarily on relieving motor symptoms of the disease and leave the non-motor symptoms inadequately treated. It is important to better understand non-motor symptoms because not only are these symptoms associated with the rapid progression of PD, but many of these symptoms often also precede the more obvious motor symptoms such as bradykinesia, tremors, and rigidity, which could prove useful for early diagnosis of PD.

Introduction

Parkinson’s disease (PD) is an age-related neurodegenerative disease that affects approximately 2.0% of adults over the age of 65,1 and 1 in 300 in the general population.2 PD is most commonly linked with a degeneration of the dopamine synthesizing neurons in the substantia nigra that project to the striatum, which causes an overall loss in motor function, as presented by tremors and rigidity in movement.1, 3-8 Recent data pointed to the possibility of chronic inflammation and sustained immune responses in the brain in causing dopaminergic cell death in PD.4 25 However, PD affects more than the dopaminer-

gic systems,including areas of the brain that are not directly related to motor control, such as the amygdala and peripheral autonomic nervous system.1,6 Defects in these areas lead to the non-motor symptoms that affect many PD patients, such as pain, cognitive and sensory dysfunction,6 as well as depression and other mood disorders as seen in 20 – 40% of PD patients.1 Thus, the aim of this review is to examine both the motor and non-motor PD symptoms and review the current understanding of the associated biochemical pathways.

Motor Symptoms Parkinson’s disease (PD) is often associated with overt motor symptoms that include the asymmetric onset of bradykinesia, tremors, and rigidity due to the degeneration of dopaminergic nigrostriatal neurons of the basal ganglia.1-8 Bradykinesia, or a slowness of movement, is a trademark of basal ganglia disorders and is a clearly identifiable symptom of PD.8 With this symptom, PD patients experience a decrease in dexterity and fine motor control. Of all the motor symptoms, the rest tremor is the most well known and is the classic motor dysfunction associated with PD. This type of tremor occurs at rest but decreases with voluntary movement.3 Tremors can be observed in the hands, lip, chin, jaw and legs, but almost never involves the neck-head regions or the voice.8 Although the tremors usually remain asymmetric, it may manifest into bilateral tremors as PD progresses. The pathophysiology of the rest tremors are not fully understood, but it has been generally accepted to be caused by atypical synchronous oscillating neuronal activity within the

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basal ganglia.8 Tremors often accompany rigidity, or the resistance seen in the passive movement of a limb. Rigidity may also play a role in the recurrent pain afflicting PD patients. An early diagnosis of PD can be greatly supported when rigidity increases with reinforcing movements and is seen ipsilateral to the rest tremor. At later stages of PD, postural instability develops and can become one of the major devastating symptoms and a main cause of falls in PD patients. This symptom also contributes to gait abnormalities seen in patients with PD, who often shuffle with slow, narrow steps in a characteristically stooped posture.8

Neuronal Mechanisms Governing Motor Symptoms Smooth, well coordinated muscle movement is determined by the direct and indirect output pathways of the basal ganglia to the globus pallidus and the substantia nigra.7 While the direct pathways disinhibit the thalamocortical neurons, the indirect pathways inhibit these neurons. These neurons are influenced by excitatory inputs from the cortex and thalamus and by regulatory control of dopamine release from the nigrostriatal neurons. As seen in Figure 1, in PD, dopamine denervation occurs with the death of nigrostriatal neurons. Dopamine denervation causes an imbalance in the activity of the two basal ganglion pathways, which is thought to correlate with the motor symptoms seen in PD.2,7 Neuronal loss observed in brains of PD patients may be due to the presence of Lewy bodies, or a mass of fine fibers. Lewy bodies serve as defining histological characteristics of PD and have been found in various areas of the central and peripheral nervous systems in PD patients. The extensive distribution of these Lewy bodies may also be linked to the wide range of motor and non-motor symptoms seen in PD patients.9 In PD, Lewy bodies are mainly comprised of a presynaptic nerve terminal protein known as α-synuclein.9 In a healthy brain, α-synuclein is found in presynaptic terminals and is absent in the neuronal cytoplasm. In the normal aging process, α-synuclein non-pathologically accumulates in the substantia nigra, but not in other dopamine neuronal nuclei.5 However, in PD, this protein develops inside nerve cells as pale and diffuse cytoplasmic inclusions and displaces other components of the cell.2,5 The

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molecular components of α-synuclein are cytotoxic and as long as these toxins are made, Lewy bodies expand. This causes an excessive build-up of protein aggregates in the host cell and leads to cell death.

Early Non-motor Symptoms Non-motor symptoms afflicting patients with PD often precede the more obvious motor symptoms associated with the disease. One recent hypothesis suggests that the Lewy body pathology develops only after the olfactory system and lower brainstem areas have become affected. Recent data have been found to show a correlation between the decreased sensitivity to odors and the increased risk of developing PD. Olfactory dysfunction eventually effects up to 90% of patients with PD. Another common early symptom seen in PD patients is constipation. This may be one of the earliest symptoms of Lewy body degeneration as seen in PD. Lewy bodies found to effect the peripheral autonomic nervous system also affect the colonic sympathetic denervation which has been associated with a prolonged intestinal passage time leading to constipation. Constipation has been reported as one of the main complaints preceding the classic motor symptoms in about half of PD patients. In one longitudinal study following the bowel habits of 7,000 men over the course of 24 years, those with initial constipation were three times more likely of developing PD over a mean time period of 10 years. Therefore, the identification of early non-motor symptoms, such as the decrease in function of the olfactory system and the onset of constipation, could lead to an earlier diagnosis of PD.6,10

Neuropsychiatric Dysfunctions PD patients are not only affected by somatic non-motor symptoms but also neuropsychiatric nonmotor symptoms, including depression, anxiety, and apathy. Studies have indicated that depression, characterized by guilt, lack of confidence, sadness, and remorse, often occurs with anxiety in PD patients. Depression or panic attacks have been seen to antedate the onset of motor symptoms in up to 30% of patients with PD. Separate from the depression that is usually seen in PD patients, apathy has also been recognized as a unique symptom of PD. Apathy is defined as the presence of reduced motivation that is not related 26

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| Parkinson’s Disease|

to a decrease in conscious state or emotional distress and could be caused by the neuronal degeneration in the reward centers of the brain, such as the dopaminergic projections between the ventral tegmentum and nucleus accumbens. Anxiety and apathy are both commonly seen early on in PD and can be pre-clinical risk factors.1,6,10

Neuronal Mechanisms Governing Depression as seen in PD Damage to the limbic noradrenergic and dopaminergic mechanisms and to the serotoninergic neurotransmission as seen in PD patients may link depression to a more biological cause than to a reaction to the disease itself.10 Neurons in the ventral mesencephalon, located near the substantia nigra, project to limbic and cortical structures that control cognition, emotions, and reward-seeking behavior. There is a greater degeneration of dopaminergic neurons in this area in PD patients who have depression than those who do not. Depression associated with PD is also associated with a decrease in serotonin in the dorsal raphe nucleus and norepinephrine in the locus coeruleus. The locus coeruleus projects to the anterior cingulated gyrus, the hippocampus, the ventral striatum, and the amygdala. The amygdala, a region of the brain closely associated with motivation and emotional behavior, is atrophied and consists of Lewy bodies in PD patients with depression, which may link PD to depression. Therefore, the relatively weak correlation between depression and the severity of PD suggests that depression is not a psychological reaction to PD but part of PD itself.1

Cognitive Impairment

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Some hypotheses propose that depression antecedes dementia.1 Dementia, another non-motor symptom, is seen in up to 40% of PD patients – a rate that is about six times greater than that of healthy individuals. Dementia advances gradually but is associated with a rapid progression of disability, which often puts many PD patients at risk of nursing home placement. Dementia is clinically characterized by impairment to visuospatial abilities, memory, and the executive attention in the control of thoughts and emotions. Personality disorders, hallucinosis,

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and psychosis are also seen in PD patients afflicted with dementia.6,10

Neuronal Mechanisms Governing Dementia as seen in PD The underlying mechanisms of dementia in PD are not yet fully understood. There have been hypotheses that Lewy body degeneration is a main driving factor for the development of dementia in PD.6 There have been studies linking the presence of Alzheimer-type changes in the brain, such as senile plaques, with the α-synuclein of Lewy bodies.11 A decrease in hippocampal volume has also been seen in PD patients with dementia that is comparable in extent to the decrease seen in individuals afflicted with Alzheimer’s disease.10 Connections have also been made between the severity of motor symptoms and intellectual impairment.12 Using the Mini-Mental State examination to assess intellectual status (perhaps include a brief description of examination in case readers are not familiar with it), Huber et al. found a significant negative correlation between intellectual impairment and the severity of both rigidity and bradykinesia. This seemed to suggest that these motor symptoms were related to the increased intellectual impairment seen in patients with PD.

Discussion PD, a disease that is usually categorized as a motor system disorder, also has many non-motor symptoms. Neurodegeneration in PD affects the central nervous system as well as the peripheral nervous system, leading to a wide range of classic motor symptoms, such as bradykinesia, tremors, and rigidity,1,2,4-8 in addition to non-motor symptoms. Many non-motor symptoms, such as sensory dysfunction and depression, often precede the more obvious motor symptoms. Therefore, it is important to pay attention to and correctly identify the early non-motor symptoms, as they could lead to an earlier diagnosis of PD. Although many drugs are currently prescribed to relieve the classic motor system malfunctions seen in PD patients, these drugs often worsen non-motor symptoms and decrease the quality of life.2,7,8 While newer treatments are beginning to treat both motor and non-motor symptoms, there are currently

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no medications that stop the degeneration of dopaminergic neurons.3 Thus, future studies that aim to gain a better understanding of the relationship between the biochemical pathways of PD and the motor and non-motor symptoms are warranted. Furthermore, being able to pinpoint the neurons that are most susceptible to neurodegeneration could lead to more effective treatment options for relieving both motor and non-motor symptoms in PD.

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235 – 45. 11. Caballol N, Marti MJ, Tolosa E. 2007. Cognitive dysfunction and dementia in Parkinson Disease. Movement Disorders; 22 (S17): S358 – S366. 12. Huber SJ, Paulson GW, Shuttleworth EC. 1988. Relationship of motor symptoms, intellectual impairment, and depression in Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry. 51: 855 – 858.

References 1. Lieberman A. 2006. Depression in Parkinson’s disease – a review. Acta Neurol Scand; 113: 1 – 8. 2. Schapira AHC, Bezard E, Brotchie J, Frederic C, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novere N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G. 2006. Novel pharmacological targets for the treatment of Parkinson’s disease. Nature Reviews; 5: 845 – 854. 3. Dauer W, Przedborski S. 2003. Parkinson’s disease: mechanisms and models. Neuron; 39: 889 – 909. 4. McGeer PL, McGeer EG. 2004. Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism and Related Disorders; 10: S3 – S7. 5. Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O. 2008. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nature Medicine; 14(5); 507 – 509. 6. Poewe W. 2008. Non-motor symptoms in Parkinson’s disease. European Journal of Neurology; 15: 14 – 20. 7. Richardson PJ, Kase H, Jenner PG. 1997 Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson’s disease. Trends in Pharmacological Sciences; 18 (4): 338 – 344. 8. Shahed J, Jankovic J. 2007. Motor symptoms in Parkinson’s disease. Handbook of Clinical Neurology; 83: 329 – 342. 9. Wakabayashi, K, Kunikazu T, Fumiaki M, Takahashi H. 2007. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of α-synuclein aggregates. Neuropathology; 27: 494 – 506. 10. Chaudhuri KR, Healy DG, Schapira AHV. 2006. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurology; 5: Synapse

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Hippocampal Neurogenesis: A Role for Adult Neuroplasticity in New Learning and Memory Formation Rachel Bavley Psychology 13â&#x20AC;&#x2122; Abstract

The hippocampus is one of the few areas of the mammalian brain that continues to generate new neurons into adulthood, a process that is regulated at least in part by experiences that engage the hippocampus. However, the specific role that these new neurons play in the various learning and memory functions attributed to the hippocampus remains unclear, and more research is needed before the true purpose of adult hippocampal neurogenesis can be determined. Computational models suggest an important relationship between adult hippocampal neurogenesis, context processing, and cognitive flexibility, and can help explain the role of adult hippocampal neurogenesis in memory formation and the neurocognitive pathologies associated with mood disorders.

Introduction Ever since the discovery that brain regions such as the hippocampus continue to produce new neurons into adulthood, there has been a growing interest in the role that these new neurons play in brain function. An accumulating body of research has shown that new neurons generated in the hippocampus are involved in certain hippocampus-dependent learning tasks. Furthermore, learning such tasks can actually increase the survival rate of new hippocampal neurons, most of which would otherwise die within a few weeks. However, the primary role that newly-generated hippocampal neurons play in learning and memory processes has yet to be determined, and findings regarding which kinds of learning tasks require adult hippocampal neurogenesis have been inconclusive and often contradictory.The specific function of hippocampal neurogenesiswithin the adult brain is currently an open question, the answers of

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which promise to have widespread implications for our understanding of the brainâ&#x20AC;&#x2122;s lifelong ability to learn, remember, and adapt to the environment.

Mechanisms of Neurogenesis One of the hallmarks of the brain is its plasticity, or ability to change and adapt in response to the environment 1. Adult neurogenesis is one example of how the brain can continue to change throughout life by producing new neurons which can be integrated into the brainâ&#x20AC;&#x2122;s neural networks. However, perhaps because of the difficulties associated with successfully incorporating new neurons into existing neural networks 2, neurogenesis is generally limited to only two areas of the mammalian brain: the subgranular zone (SGZ) of the hippocampal formation, and the subventricular zone (SVZ) which provides new neurons to the olfactory bulbs 3. Adult neurogenesis can be studied in the brains of experimental animals using the chemical marker bromodeoxyuridine (BrdU), a synthetic thymidine analogue that acts by incorporating into replicating DNA and can be subsequently detected using immunohistochemistry to identify a specific generation of proliferating neurons 4. Using this technique, we now know that the SGZ produces about 9,000 new neurons each day in rats, many of which migrate to the dentate gyrus of the hippocampus and differentiate into granule neurons 5 . Furthermore, evidence suggests that these new neurons are capable of becoming synaptically integrated into existing neural networks in the hippocampus. They begin projecting axons to area CA3 of the hippocampus 4-10 days after mitosis 6 and eventually become capable of generating action potentials and producing functional synaptic inputs 7, 1. Adult-generated granule

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rons. Adult-generated hippocampal neurons seem to be particularly sensitive to environmental manipulations that occur during a critical period beginning about one week after they are produced 10, which corresponds to the time at which theyare beginning to extend axons into the CA3 region 11, 12 and therefore becoming synaptically integrated. This is evidenced by the fact that the survival rate is increased when environmental manipulations such as enrichment begin up to three weeks after BrdU administration, with the maximum survival rate occurring when environmental manipulations begin after one week 13.

Facilitative Effect of Neurogenesis on Hippocampus-Dependent Learning

FIGURE 1. (prev. page) Dividing cells in the adult mouse dentate gyrus express early neural markers at 48 h after virus injection. a, Confocal micrograph (a merged image of 15 1-microm optical sections) of GFP expression in the dentate gyrus in a section that was labelled for the neuronal marker NeuN (red). No co-labelling of GFP+ cells with NeuN was observed. b, Single confocal plane of a cluster of GFP+ cells labelled with the early neuronal marker Tuj1-beta (red). c, Single confocal plane of a GFP+ cell with immunoreactivity for the progenitor marker NG2 (red). In b and c, nuclei (DAPI) and GFAP are blue. 7

cells have been found to initially exhibit many of the same distinctive characteristics as neurons generated during development, including an excitatory response to GABA, a lower depolarization threshold, and heightened elicitation of LTP 8. This enhanced excitability suggests that newly generated hippocampal neurons may play a special role in learning-related plasticity by virtue of their unique electrophysiological properties. While a large percentage of these new cells will typically begin to die off about a week after DNA synthesis 9, the survival rate of new hippocampal neurons appears to be critically dependent on the experience and learning that occurs during the new neuronsâ&#x20AC;&#x2122; maturation. For example, one month after being injected with BrdU, rats that had lived in an enriched environment retained more BrdU-labeled neurons than rats that did not 2, indicating that the enriched environment increased the survival rate of proliferating neu-

Given that new hippocampal neurons can be integrated into existing hippocampal networks, it can be predicted that these neurons may participate in tasks in which the hippocampus plays a functional role. There is a wealth of indirect evidence that supports this view. For example, conditions such as stress 14, aging 15, and drug use including alcohol 16, nicotine 17, 18, and opiates 19, 20 have all been correlated with both decreases in hippocampal neurogenesis and learning impairments, while enriched environments 2, physical exercise 21, and estrogen 11, 12 have all been found to increase hippocampal neurogenesis and facilitate learning on hippocampus-dependent tasks 2. More direct evidence for a facilitative role of hippocampal neurogenesis in learning comes from experimental procedures in which neurogenesis is partially inhibited, and any resulting decrements in learning are measured. These methods have been used to test the effects of impaired hippocampal neurogenesis on several hippocampus-dependent and hippocampusâ&#x20AC;&#x201C;independent tasks.One approach to determine whether neurogenesis is involved in a certain type of learning is to inject the animal with an antimitotic agent which reduces neurogenesis. In one such experiment, Shors and colleagues (2001) administered the antimitotic toxin methylazoxymethanol (MAM) to one group of rats, and compared their performance on a trace eyeblink conditioning task to a control group that did not receive MAM. Trace eyeblink conditioning measures the ability of an animal to create trace memories by learning to associate two stimuli that are separated in time. Unlike other types of associative learning in which there is no temporal separation of stimuli, trace conditioning is

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impaired by hippocampal lesions 24, 25, and is therefore considereda hippocampus-dependent task. The two groups did not differ in their performance on a hippocampus-independent delay eyeblink conditioning task, suggesting that MAM treatment did not cause a universal learning impairment. However, the group with impaired neurogenesis performed significantly worse than controls on the trace eyeblink conditioning task 26. These findings provide evidence that the new cells produced by hippocampal neurogenesis play an important functional role in the formation of trace memories. This interpretation is strengthened by the fact that when rats who had received MAM and performed poorly on trace conditioning were allowed to recover and begin producing new hippocampal neurons again, their performance on the trace eyeblink conditioning task returned to the level of controls 26.

FIGURE 2. Graphs of the timing parameters of the CR. (A) A graph of the duration of the response. (B) A graph of the ratio of the percent of late CRs to the percent of other nonalpha CRs. The data range from 0.0 to 1.0, with 1.0 indicating that all responses included some significant activity during the 200 ms time period prior to US onset. h, Hippocampal lesion (complete and partial); n, neocortical lesion; s, sham lesion. 25

A similar effect has been found during trace fear conditioning, in which a tone (CS) is repeatedly paired with a footshock (US) after a delay, and learning is measured in terms of freezing behavior in response to the tone. MAM-treated rats with decreased hippocampal neurogenesis showed a significant learning impairment on this task compared to controls 27. However, rats treated with MAM did not show a decrement in all types of hippocampus-dependent learning. Their performance on two other hippocampus-dependent tasks, spatial navigation in the Morris water maze and contextual fear conditioning, was not impaired in rats treated with MAM relative to controls 27.

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Another technique that has been used to interrupt adult neurogenesis is focal or whole-brain irradiation, which avoids many of the potential side effects ofâ&#x20AC;&#x2039; MAM treatment while at the same time inhibiting neurogenesis in the treated area more completely 23. Using this technique, Madsen and colleagues (2003) found that irradiated rats performed worse than controls on a hippocampus-dependent place-recognition task, but did not show impairment on a hippocampus-independent object recognition task 28. Likewise, Winocur and colleagues (2006) found that irradiated rats performed worse than controls on a hippocampus-dependent water maze non-match-to-sample (NMTS) task with a long delay between sample and test trials, but not on a hippocampus-independent NMTS task with a short delay 29. However, a similar study by Hernandez-Rabaza and colleagues (2009) that used a regular t-maze instead of a water maze found no irradiation-induced impairment on a NMTS task during short or long delays 30, suggesting that the stressful nature of the water maze task may have contributed to the impairment. Interestingly, another study by Saxe and colleagues (2007) found that inhibition of hippocampal neurogenesis actually improved performance on a NMTS task on a radial arm maze in which the animals were required to disregard highly similar and often conflicting information from previous trials 31. While counterintuitive, this result is consistent with the idea that new hippocampal neurons play a role in linking together multiple contextual elements across time, and may therefore increase the interference related to having to remember distinct episodes within a continuous context. Also consistent with this idea, irradiation experiments have found significant impairments on a contextual fear conditioning task, in which the rats learn to associate a specific context with a footshock, even though their fear response itself was no different from controls 29, 30 . This task requires the subject to construct a multidimensional representation of the context and form an association between the context and a fear response, so irradiation-related impairments suggest that hippocampal neurogenesis may play a role in context processing and generalization across learning instances. Impairments have also been found in irradiated rats relative to controls for spatial navigation on the Morris water maze 32. However, this finding is far from conclusive given that several other studies have failed to show impairment on the Morris water maze task in irradiated rats 28, 33, 34. To make matters more confusing, strains of

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mice bred to exhibit higher levels of neurogenesis had a faster acquisition rate on a Morris water maze task than strains with lower rates of neurogenesis 35, yet there was no such correlation between strain and acquisition in a similar study done with rats instead of mice 36. This suggests that the role of hippocampal neurogenesis in spatial navigation, and probably other tasks as well, is complex and can show variation depending on the specific procedure used and species tested. There is still much debate over how adult-generated hippocampal neurons participate in learning. However, based on the research to date, it appears that adult hippocampal neurogenesis does play a role in some, but not all, forms of hippocampus-dependent learning. While most results remain inconsistent and inconclusive, the evidence appears to be strongest for tasks which require the animal to retain information across a delay (such as trace eyeblink conditioning and delayed NMTS), tasks that require context processing (such as contextual fear conditioning), and aversive learning tasks that cause stress to the animal (including fear conditioning and tasks that occur in a water maze). While some authors have suggested that hippocampal neurogenesis may only be necessary for more difficult tasks 28 or for more long-term memory formation 32, more research is needed before any conclusive characterization of the role of hippocampal/neurogenesis in facilitating hippocampus-dependent learning can be made 23.

Evidence for Learning-Induced Survival of New Hippocampal Neurons While it is clear that hippocampal neurogenesis can have an effect on learning, it has been suggested that the converse may also be true, namely that learning can have an effect on hippocampal neurogenesis. Specifically, it has been hypothesized that training on hippocampus-dependent tasks can facilitate the integration of new hippocampal neurons into functional circuits, thereby increasing their survival 37. Evidence for this hypothesis comes from a study by Gould et al. (1999) in which rats injected with BrdU were trained on either hippocampus-dependent tasks (trace eyeblink conditioning or spatial navigation in the Morris water maze) or hippocampus-independent tasks (classical eyeblink conditioning or cue training in the Morris water maze). They found that when training began one week after BrdU injections, which corresponds to the time when

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new cells begin to either sprout axons or die off, a higher percentage of cells survived in rats trained on hippocampus-dependent tasks than on hippocampusindependent tasks. Furthermore, they found that if rats were injected with BrdU during training, rather than a week before, there was no increase in cell survival in rats trained on hippocampus-dependent tasks. This suggests that hippocampus-dependent training does not increase the rate at which neurogenesis occurs, but instead increases the survival rate of new neurons that have already been produced 37. Several more studies have been done to confirm this effect and clarify its mechanisms. An experiment by Dalla and colleagues (2007) found that it is the process of learning the task, rather than the mere exposure to training, that increases new cell survival. Interestingly, they found a significant correlation between task acquisition and BrdU-labeled cell number regardless of whether the animal was trained on a hippocampusdependent or â&#x20AC;&#x201C;independent task 38. This finding was expanded by Waddell and Shors (2008) who found that the cell survival rate was higher in animals that took more trials to learn. They also found that acquisition rate predicted cell survival more accurately than the hippocampal dependence of the task, suggesting that it may be the difficulty of the task (which influences the acquisition rate) rather than the hippocampus-dependence of the task that prompts the recruitment of new neurons into learning-related circuits and thereby increases their survival rate 10. Further evidence for this effortful learning hypothesis comes from a study comparing male and female rats, which found that on average, female rats had a slower acquisition rate on a trace eyeblink conditioning task, but learned the task better overall, than male rats. Female rats also retained a greater number of BrdU-labeled cells, supporting the idea that their survival rate is dependent on actually learning the task, and is increased if the task is more difficult and takes more trials to learn 39. While it remains unclear how the hippocampusdependency of a task is related to new cell survival, it does appear that training on such tasks can increase the survival of new neurons. Furthermore, the fact that this effect is strongest when training begins one week after BrdU administration when the labeled cells are beginning to project axons and become synaptically integrated 10 suggests that the reason for this effect is that the new neurons are being recruited by the learning

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circuits which participate in the task, and are spared from cell death. The fact that survival rate can be predicted by the difficulty of the task and by the successful acquisition of the learned response further suggest that it is in these cases that the new neurons are most necessary and are therefore recruited most heavily.

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between temporally distinct episodes within the same context. Without the continuous proliferation of new granule neurons, specific episodes could not receive unique neuronal ‘tags’ that differentiate them from contextually similar episodes, and interference should therefore be more likely to occur between distinct episodic memories within a given context. This increased A Computational Model of Hippocampal interference between episodic memories would also make it much more difficult to identify and bind toNeurogenesis gether multiple memories for episodes occurring in the Taken together, the current body of research strong- same context, and should therefore impair the ability ly suggests that adult-generated hippocampal neurons to form rich, multifaceted contextual representations play an important functional role in certain kinds of which could later be used to guide the activation of aplearning and memory, and that their survival rates are propriate cognitive strategies when one finds oneself strongly affected by learning experiences. However, the in that context again. Future research using carefully fact that some but not all hippocampus-dependent tasks designed context discrimination tasks will be needed in seem to be affected by hippocampal neurogenesisbegs order to test these predictions. the question of precisely how new hippocampal neurons contribute to the overall function of the hippocamHippocampal Neurogenesis and pus and related neural circuits. Becker and Wojtowicz Affective Disorders (2007) recently proposed a computational model that helps synthesize the current findings on hippocampal Becker and Wojtowicz’s (2007) model may also help neurogenesis with the broader hippocampal literature. explain a growing body of research linking dysfuncIn their view, the hippocampus serves a dual function. tion of the hippocampus, and in particular hippocampal First, it is responsible for creating detailed contextual neurogenesis, to the pathophysiology of mood disorrepresentations that link together many aspects of the ders such as major depressive disorder (MDD). There environment and its associated cognitive and behav- is strong evidence that stress, an important contributioral demands. Second, it acts as a ‘contextual gate’ ing factor to the development of MDD, has an inhibiwhereby it responds to contextual cues by activating tory effect on hippocampal neurogenesis 14, and several the entire contextual representation and priming other known effective treatments for MDD have been shown brain regions involved in behavior, motivation, cogni- to enhance hippocampal neurogenesis, including exertion, and emotion to act accordingly. Newly-generated cise 21, electroconvulsive therapy 41, and antidepressant granule neurons are thought to play a unique role in medications 42. However, it is not yet clear how the hipthis process by virtue of their continuous prolifera- pocampus, known primarily for its role in learning and tion, which allows them to code for separate episodes memory functions, could contribute to mood and its in time without interfering with similar previous epi- dysregulation. sodes, and theirdistinctive maturational properties, Becker and Wojtowicz (2007) propose that the link which allow for an initial high level of plasticity which resides in the role of the hippocampus as a ‘contextual gradually wanes over time as they either mature or die gate’ to rest of the brain, including regions that process off. Unique episodic memories encoded by proliferat- mood and affect such as the amygdala, nucleus accuming granule neurons can then be integrated with other bens, and prefrontal cortex. According to their model, episodic memories that share the same context via as- the hippocampus is normally involved in forming consociational pathways in other hippocampal regions, re- textual representations that can then be activated to sulting in the formation of rich contextual representa- modulate processing in these other functional brain tions made up of many distinct episodic events 40. circuits. However, if hippocampal neurogenesis is disThis model is especially useful because it gener- rupted, for example by the high levels of stress that ofates specific behavioral predictions. For example, it ten precipitate the development of mood disorders, the would predict an irradiation-induced impairment in ability to form contextual representations may become performance on tasks that require one to discriminate interrupted, reducing the ability to flexibly switch

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between them in order to match specific modes of cognitive and emotional processing to their appropriate context. In the case of MDD, this could cause impairments in peopleâ&#x20AC;&#x2122;s ability to generate appropriately contextualized responses to emotional stimuli, leading to a negative information-processing bias. Forms of such cognitive inflexibility have been found in patients with MDD, who regularly show a strong negativity bias in the face of changing emotional content 43. A greater understanding of the relationship between stress, hippocampal neurogenesis, context representations, and cognitive flexibility should therefore be an important goal of future research aimed at understanding both normal affective processing and the neurocognitive dysfunctions associated with mood disorders.

Conclusions While much more research must be done if we are to fully understand the purpose and functional implications of adult hippocampal neurogenesis, the present literature points to an important role of newly-generated granule neurons in adult learning and memory processes, particularly those that rely on the hippocampus. This relationship appears to be bidirectional, in that learning experiences both require and facilitate the proliferation of new hippocampal neurons. More research is necessary to help clarify exactly how hippocampal neurogenesis contributes to these processes, and may shed light on the role of the hippocampus and its unique neuroplastic properties in learning, memory, context processing, and affective dysregulation. Future research will ultimately provide a greater understanding of why adult hippocampal neurogenesis occurs and how it relates to the function of the hippocampus and cognitive functions it subserves.

Referemces 1. Lledo, P. M., Alonso, M., & Grubb, M. S. (2006). Adult neurogenesis and functional plasticity inneuronal circuits. Nature Reviews Neuroscience, 7, 179-193. 2. Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997). More hippocampal neurons in adult mice living inan enriched environment. Nature, 386, 493-495. 3. Rakic, P. (2002).Adult neurogenesis in mammals, an identity crisis.Journal of Neuroscience, 22, 614-618. 4. Ming, G., & Song, H. (2005) Adult neurogenesis in the mammalian central nervous system. AnnualReview of Neuroscience, 28, 223-250.

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5. Cameron, H. A., &McKay, R. D. (2001). Adult neurogenesis produces a large pool of new granule cellsin the dentate gyrus. Journal of Comparative Neurology, 435, 406-417 6. Nixon, K., & Crews, F.T. (2002). Binge ethanol exposure decreases neurogenesis in adult rathippocampus. Journal of Neurochemistry, 83, 1087-1093. 7. Van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., & Gage, F. (2002). Functionalneurogenesis in the adult hippocampus.Nature, 415, 1030-1034. 8. Doetsch, F., & Hen, R. (2005). Young and excitable: the function of new neurons in the adult mammalian brain. Current Opinion in Neurobiology, 15, 121-128. 9. Dayer, A. G., Ford, A. A., Cleaver, K. M., Yassaee, M., & Cameron, H. A. (2003). Short-term and longterm survival of new neurons in the rat dentate gyrus.Journal of Comparative Neurology, 460, 563-572. 10. Waddell, J., & Shors, T. J. (2008).Neurogenesis, learning and associative strength. European Journal ofNeuroscience, 27, 3020-3028. 11. Hastings, N. B., & Gould, E. (1999). Rapid extension of axons into the CA3 region of adult generatedgranule cells. Journal of Comparative Neurology, 413, 146-154. 12. Zhao, C., Teng, E. M., Summers, R. G., Ming, G., & Gage, F. (2006). Distinct morphologicalstages of dentate granule neuron maturation in the adult mouse hippocampus. The Journal of Neuroscience, 26, 3-11. 13. Tashiro, A., Makino, H., & Gage, F. H. (2007). Experiencespecific functional modification ofthe dentate gyrus through adult neurogenesis: A critical period during an immature stage. The Journal of Neuroscience, 27, 3252-3259. 14. Mirescu, C., & Gould, E. (2006).Stress and adult neurogenesis.Hippocampus, 16, 233-238. 15. Drapeau, E., Mayo, W., Aurousseau, C., Le Moal, N., Piazza, P. V., & Abrous, D. N. (2003). Spatialmemory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proceedings of the National Academy of Science, 100, 14385-14390. 16. Matthews, D. B., & Silvers, J. R. (2004). The use of acute ethanol administration as tool to investigatemultiple memory systems. Neurobiology of Learning and Memory, 82, 299-308. 17. Abrous, D. N., Adriani, W., Montaron, M. F., Aurousseau, C., Rougon, G., Le Moal, M., & Piazza, P. V.(2002). Nicotine self-administration impairs hippocampal plasticity. Journal of Neuroscience, 22, 3656-3662. 18. Scerri, C., Stewart, C. A., Breen, K. C., & Balfour, D. J. (2005). The effects of chronic nicotine on spatiallearning and bromodeoxyuridine incorporation into the dentate gyrus of the rat. Psychopharmacology, 16, 1-7. 19. Eisch, A. J., Barrot, M., Schad, C. A., Self, D. W., Nestler, E. J. (2000).Opiates inhibit neurogenesis inthe adult rat hippocampus. Proceedings of the National Academy of Science, 97, 7579-7584. 20. Spain, J. W., & Newsom, G. C. (1991). Chronic opioids impair acquisition of both radial maze and Ymaze choice escape. Psychopharmacology, 105, 101-106. 21. Van Praag, H., Christie, B. R., Sejnowski, T. J., & Gage, F. H. (1999). Running enhances neurogenesis,learning, and long-term potentiation in mice. Proceedings of the National Academy of

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two rat strains increases the expression of the polysialyated form of the neural cell adhesion molecule in the dentate gyrus but has no effect on hippocampal neurogenesis. Behavioral Neuroscience, 119, 926-932. 37. Gould, E., Beylin, A., Tanapat, P., Reeves, A., & Shors, T. J. (1999). Learning enhances adultneurogenesis in the hippocampal formation. Nature Neuroscience, 2, 260-265. 38. Dalla, C., Bangasser, D. A., Edgecomb, C., & Shors, T. J. (2007). Neurogenesis and learning: Acquisitionand asymptotic performance predict how many new cells survive in the hippocampus. Neurobiology of Learning and Memory, 88, 143-148. 39. Dalla, C., Papachristos, E. B., Whetstone, A. S., & Shors, T. J. (2009). Female rats learn trace memoriesbetter than male rats and consequently retain a greater proportion of new neurons in their hippocampi. Proceedings of the National Academy of Science, 106, 2927-2932. 40. Becker, S., & Wojtowicz, J. M. (2007). A model of hippocampal neurogenesis in memory and mooddisorders. Trends in Cognitive Science, 11, 70-76. 41. Scott, B. W., Wojtowicz, J. M., & Burnham, W. M. (2000). Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Experimental Neurology, 165, 231-236. 42. Malberg, J., Eisch, A. J., Nestler, E.J., & Duman, R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience, 20, 91049110. 43. Leppanen, J. M. (2006). Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings. Current Opinions in Psychiatry, 19, 34-39.

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