Highlights from the 2017 Society for Neuroscience Meeting

Highlights from the 2017 Society for Neuroscience Meeting I just returned from the annual Society for Neuroscience meeting, the largest neuroscience meeting in the world where 30,021 attendees from 80 countries joined to present 13,552 poster presentations and 902 lecture sessions. In addition, 534 companies held exhibits for their products.

Needless to say, it was an amazing celebration of all things neuroscience. I was lucky enough to be chosen as one of the official bloggers for the conference and so attempted to go to as many posters and lectures as possible to put together the most exciting information about brain health and wellness. Here I highlight some of my favorite moments of this enormous event.

Exercise highlight 1: Increased aerobic fitness is related to increased anterior dentate gyrus/CA3 volume in healthy young adults following exercise training (RK Nauer, MF Dunne, TW Storer, CE Stern, & K Schon) In rodents, aerobic exercise is known to enhance rates of neurogenesis in the dentate gyrus of the hippocampus, which is an effect that has been linked to improvements in hippocampal-dependent cognitive functions such as pattern separation. In humans, aerobic exercise has been shown to increase the volume of the hippocampus. However, it is unknown whether the exercise-induced hippocampal size enhancements in humans are related to gains in cognition.

Therefore, Rachel Nauer and colleagues from Boston University wanted to determine if a 12-week exercise intervention that included either resistance or endurance training in healthy young adults (ages 18 to 35) could lead to increases in the size of the hippocampus as well as changes in pattern separation or “disambiguation of similar stimuli�. Findings: The change in aerobic fitness predicted size changes in the left dentate gyrus/CA3 region (but not the subiculum or CA1), a finding that is consistent with the animal literature. In addition, lower fit individuals showed the largest gains in exercise-induced improvements in a hippocampaldependent cognitive task. These results show that long-term exercise can enhance hippocampal size and that initially low-fit individuals may be the ones to show the largest improvements.

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My Love Affair with the Brain – A movie about the queen of brain plasticity I had the pleasure of viewing the beautiful film by Catherine Ryan and Gary Weimberg, My Love Affair with the Brain – The Life & Science of Dr. Marian Diamond.

This film highlights Dr. Diamond’s monumental 60-year neuroscience career at the University of California Berkeley. My mentor, Dr. Wendy Suzuki, was the MC of this event, and I know personally what an inspiration she was to Wendy. During Dr. Diamond’s career, she shattered many fixed scientific paradigms. When she started her career (as one of the few women in science at the time), the scientific consensus was that the brain was static – determined by the genetic code. By conducting simple, yet elegant experiments where she exposed rats to an enriched environment (the Disneyland of rat cages), she found that the cerebral cortex grew by an amazing 6%. Marian proved for the first time that the brain changes with experience. Marian found that many things change the brain, with the five biggest factors being “diet, exercise, challenge, newness, and love”. Dr. Diamond was the inspiration for the phrase, “use it or lose it”, a phrase that has become a colloquialism. She even had the opportunity to study Dr. Albert Einstein’s brain, finding that he had more glial cells per neuron than the average man. She brought about the idea that glia cells are active participants in brain function – yet another huge paradigm shift in science. Later in life, Marian applied her science, helping to enrich the lives of children through outreach programs around the world. She was an instrumental teacher and mentor in the lives of over 60,000 students and a true inspiration to science. Her lectures can be found on youtube.com and have almost 2 million views.

You can find more information about this fabulous documentary and about the life of Dr. Marian Diamond here: http://lunaproductions.com/.

Exercise highlight 2: Acute mild exercise improves memory by enhancing hippocampal-neocortical connectivity (K Suwabe, K Byun, K Hyodo, Z Reagh, K Saotome, G Ochi, MA Yassa, & H Soya) It is known that long-term exercise promotes plasticity in the hippocampus, especially the neurogenic dentate gyrus. This exercise-induced enhancement in plasticity leads to an increased capacity for pattern separation, or the ability to distinguish between similar sets of stimuli – an ability that is involved for proper episodic memory. However, it is unclear whether a single bout of exercise can enhance patterns separation and it is unknown what the neural correlates of this 2

effect might be. Therefore, Kazuya Suwabe and colleagues from the University of Tsukuba had subjects engage in a mild bout of exercise (10 minutes of cycling at 30% of VO2 peak) and only five minutes after, engage in a hippocampaldependent task called the mnemonic similarity task. Findings: A single exercise session enhanced pattern separation abilities and increased activity in the dentate gyrus/CA3, CA1, and subiculum. Further, the enhanced functional connectivity between the dentate gyrus/CA and regions of the cortex (angular gyrus, fusiform gyrus, and parahippocampal cortex) predicted performance on the task.

These results indicate that acute exercise enhances pattern separation, a behavior that depends on the dentate gyrus subregion of the hippocampus, and that this effect may be driven by functional connectivity between the hippocampus and cortex.

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Learning, Memory, & Decision Making

Making good decisions requires memory. Take for example, the hangover (maybe that some of us are experiencing today after the reunion with some of our favorite science colleagues). We remember that the previous heavy night of drinking brought on this unpleasant state. Therefore, in the next several days, we may make the decision to have a few less cocktails – inevitably the better decision. How is it that we learn from such experiences to make good decisions?

Dr. Daphna Shohamy and her colleagues at Columbia University in New York, NY are exploring just that. In her lecture today, Using Memory to Guide Decisions, Dr. Shohamy discussed how it is not a singular brain region, but rather regions of the brain interacting together that actually support learning and memory and guide our decision-making processes.

The striatum is one such brain region that supports learning and memory, specifically procedural and habitual memory. For example, the ability to learn and remember how to ride our bicycle (an action that is easy to do even if we haven’t attempted it in a long time) is dependent on the striatum. Additionally, our habitual behaviors, like remembering the route we take home on a daily basis is dependent on the striatum. The striatum learns over time, in a gradual way, and it assesses 4

the average value or outcome to determine the best decision to take.

The problem, Dr. Shohamy pointed out, is that most decisions don’t work this way. In this ever-changing world, we are faced with experiences that we have never encountered before. We need to be adaptive. So, how is it, that we can make good decisions when faced with a new problem?

Enter the hippocampus, a flexible brain region involved in many cognitive processes including episodic memory, spatial navigation, and prospection or the imagining of future events. The hippocampus accomplishes all of these tasks by binding elements of both time and space, an area of extensive research that people like Drs. György Buzsáki and Howard Eichenbaum have been studying for decades.

Dr. Shohamy proposes that to understand how we make good decisions, we must look at the interaction between learning, memory, and decision-making.

Traditionally, we’ve examined learning and memory systems in isolation, but Dr. Shohamy proposes that rather than looking at distinct systems, we should think about the interaction between these systems – in this case, the connection between the striatum and hippocampus.

To investigate the interaction between these systems, Dr. Shohamy uses a variety of different methods. First, she utilizes sophistical behavioral tasks. Second, she uses functional magnetic resonance imaging (fMRI) to probe the regions of the brain that are activated during behavioral performance. Third, she studies these things in patients who have damage to the striatum and/or hippocampus.

Using these strategies, Dr. Shohamy sought to determine whether you could link what people are learning to the way they make choices? It turns out that the answer is yes, and she showed this in several different paradigms including reinforcement and associative learning tasks! By using fMRI during the entire learning and decision-making process, you can see what areas in the brain are activated not only during the decision-making process but also during the learning that led to a particular decision. At a behavioral level, she found that memory for an event guides decision-making. At the level of the brain, she found that the hippocampus and striatum work together to support learning and decision-making. In addition, the activation of these brain regions can actually be used to predict the behavioral outcome or decision.

The Shohamy lab is also exploring how these decision making process are modulated in different populations and during different stages of development. For 5

example, new work in the lab is showing that activation of the hippocampus during these decision-making tasks may be even more highly engaged during adolescents, a time period when reward processing is evolving. In additions, individuals who have compromised dopaminergic systems, such as those with Parkinson’s disease, show impairments in these decision-making tasks, with improvements coming on board when dopamine agonists are administered. Finally, in decisions that are more difficult to make (such as making a decision between two items that have a similar value (e.g., do I want a candy bar or an ice cream cone?)), the decision takes a longer time because the brain regions involved experience greater levels of activation.

This work excitingly shows that we use our past experiences to inform the decisions that we make in new situations. It also importantly highlights the idea that when thinking about learning, memory, and decision-making, we should study how the memory systems of the brain interact with one another rather than examining them in isolation.

Exercise highlight 3: Acute physical exercise improves memory consolidation in humans via BDNF and endocannabinoid signaling (K Igloi, B Martin Bosch, A Bringard, G Ferretti, S Schwartz) Acute exercise is known to both enhance hippocampal-dependent memory as well as increase levels of brain derived neurotrophic factor (BDNF) and endocannabinoids (especially anandamide) in the hippocampus. However, it is unknown how increases in peripheral levels of these substances relate to exercise-induced improvements in learning and memory. Therefore, Kinga Igloi and her colleagues at the University of Geneva in Switzerland had subjects engage in an associative learning task in a magnetic resonance imaging scanner before and after a period of rest or moderate- (30 minutes at 60% of maximal cardiac frequency) or high-intensity (15 minutes at 80% of maximal cardiac frequency) exercise. Blood samples were also taken both before and after exercise. Findings: Enhanced performance on the associative learning task was seen after moderate- but not high-intensity exercise. In addition, higher anandamide levels after exercise predicted greater hippocampal activation during the task and greater BDNF levels after exercise predicted better decoding of correct trials in the hippocampus. Finally, memory improvements that were maintained 3 months later were dependent on the functional connection between the hippocampus and prefrontal cortex. This exercise-induced long-term memory enhancement was correlated to the increase in peripheral BDNF levels that occurred after the exercise session. These results show that a bout of moderate-intensity exercise may be best 6

to enhance hippocampal-dependent learning and memory and that increases in anadamide and BDNF may underlie these effects.

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Mothering – The Good, The Bad, & The Ugly

Becoming a mother can be one of the most amazing, rewarding, and enriching experiences in life. It can also be one of the most challenging experiences you’ll ever face. My baby girl, Juliette, was born on February 15, 2015. She is now a beautiful and very energetic toddler. Juliette is most definitely the joy of my life, but the past 2.5 years have come with many ups and downs.

There is this expectation that having a baby is meant to be the most joyful time in life, full of pure happiness. Within the framework of being a mother, those moments definitely exist. But in reality, they are mixed with many other difficult moments that are often accompanied by extreme lack of sleep. The truth is that being a mother comes with many unexpected challenges that no one can really prepare you for.

Because of this, motherhood can be accompanied by mental illness, with about 15-20% of new mothers experiencing post-partum depression. Like most forms of depression, post-partum depression is characterized by sadness, hopelessness, and anhedonia or the inability to feel pleasure. In 70% of the cases, post-partum depression is also accompanied by symptoms of anxiety.

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These symptoms, of course, are occurring when there is a helpless infant that needs to be held, cradled, fed, bathed, and watched 24 hours a day. Post-partum depression then leads to some unfortunate consequences for the infant. For example, mothers with post-partum depression are often disengaged, have fewer and less affectionate interactions with the baby, and are overall less responsive and sensitive to cues from the baby. These issues lead to trouble bonding with the baby, and can cause impaired social, cognitive, and emotional development, issues that can continue into adulthood.

Proper maternal care is needed to ensure proper development of the child.

Considering that 1 in 5 mothers are suffering from post-partum depression, this is a critically important issue. Surprisingly, little is known about the underlying neurobiological mechanisms of post-partum depression. Neuroscientists are starting to reveal some interesting information about the brain of mothers with post-partum depression, and they shared their most recent findings with us today at the Society for Neuroscience conference.

One research scientist, Aya Dudin, a graduate student at McMaster University, discussed her work on the involvement of the amygdala in post-partum depression.

She explained that the amygdala is central to the expression of mothering as it is involved in the detection of socially and emotionally salient stimuli. For example, non-depressed mothers show a greater level of amygdala activation when looking at images of their own rather than another baby, especially when the baby has a happy expression. When imaging the brain of mothers with post-partum depression, however, you see a blunted or irregular response in the amygdala.

For example, when viewing images of babies, their own or others, the response looks more like that of non-mothers. Therefore, these results suggest that normal infant-related amygdala function is needed for normal parenting.

Exposure to chronic stress during pregnancy is a major predictor of developing post-partum depression. Benedetta Leuner, Assistant Professor at the Ohio State University, took advantage of this fact to create an animal model of post-partum depression. To do this, Dr. Leuner exposed pregnant dams to a chronic stress paradigm throughout the gestational period. By doing this, she saw similar behavioral outcomes in the post-partum period to what is seen in humans with post-partum depression. First, gestational weight gain as well as pup weight at birth was reduced. Second, gestational stress caused depressive- and anxiety-like 9

behaviors as well as anhedonia during the post-partum period. Third, motivation for and the expression of maternal behavior were impaired.

Dr. Leuner then used this animal model to assess the changes in the brain that underlie the symptoms associated with post-partum depression. She found distinct changes in the neuronal circuitry associated with both dopamine and oxytocin, two neurochemicals involved in reward and maternal behavior. Specifically, the gestational stress paradigm disrupted dopamine signaling in the nucleus accumbens by lowering dopamine content, reducing dendritic complexity (length and branching), and decreasing spine density. Reduced oxytocin signaling as indicated by reduced oxytocin fiber density and decreased oxytocin receptor density was also found in the ventral tegmental area. These results indicate that specific changes in the reward circuitry may be underlying post-partum depression.

Collectively, this research shows that mothers with post-partum depression may show altered functional and structural changes in regions involved in both emotional processing as well as reward evaluation. This is an important area of research that warrants further examination. Certainly, identification of these issues early on in the post-partum period will be instrumental in helping mothers and their babies develop healthy and loving relationships.

Exercise highlight 4: The exercise hormone FNDC5/irisin is required for the exercise-induced improvements of spatial learning and memory (CD Wrann, MF Young, MR Islam, MP Jedrychowski, KK Gerber, BJ Caldarone, H Van Praag, BM Spiegelman) This group previously demonstrated that exercise upregulates FNDC5 and its secreted form irisin. It is unknown, however, how these molecules support exercise-induced improvements in spatial learning and memory. To further investigate the involvement of these molecules, Wrann and colleagues at Massachusetts General Hospital and Harvard Medical School created a FNDC5 knockout mouse. Though these mice ran similar distances as their wild type counterparts, they showed baseline cognitive impairments and were resistant to the exercise-induced improvements in spatial learning and memory (studied via the Morris Water Maze). In addition, FNDC5 knockout mice show impairments in running-induced increases in hippocampal expression of BDNF and other markers as well as neurogenesis and long-term potentiation. These results indicate that FND5/irisin is an important moderator of the beneficial effects of exercise on cognitive function.

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Smells Like Teen Spirit: The Ever-Changing Adolescent Brain

When I look back on my teenage years, I don’t remember the easiest of times. I remember a period of physical and emotional change that was often accompanied by uncertainty, angst, and turmoil. I also remember times of excitement – many firsts including boyfriends, going to the mall without parents, cruising around in the car with friends, and drinking. Teenagehood was definitely a roller coaster ride of emotions.

When we think about the brain, adolescence is a time of significant change.

During this time, the brain continues to grow, developing into its fully functional adult form. One of the hallmarks of adolescents is puberty, the time period of becoming sexually mature. Hormones released from the gonads signal the brain to undergo a variety of physical and emotional changes. One of these changes is our response to the opposite sex – boys or girls somehow and all of a sudden seem appealing to us (thus those first kisses).

One session at the conference, Adolescence and Reward: Making sense of neural and behavioral changes amid the chaos, explored this very exciting topic. During adolescence, social, emotional, and cognitive skills develop at an expedited rate.

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This occurs while exploring and risk-taking also significantly increase. In the adolescent brain, the reward circuitry undergoes distinct changes, making stimuli more rewarding. This occurs while the inhibitory control circuits remain underdeveloped – creating a state that causes a “hypersensitivity to reward.”

Several researchers spoke about their work in this area including Dr. Deena Walker who studies sex differences in the amygdala and reward circuitry during adolescence and Dr. Joshua Gulley who studies maturation of the corticoaccumbens circuit.

Dr. Margaret Bell from Depaul University uses the male Syrian hamster to study the underlying neural circuitry in the gains in social reward that occur during adolescence. Hamsters are very sensitive to olfactory cues, and male hamsters are especially sensitive to how their female counterparts smell. She uses a behavioral task called the conditioned place preference model to examine the olfactory cues that males like. Animals will spend more time in a place where they find rewarding stimuli such as sugar, drugs, or pups (if you’re a mom). In this case, Dr. Bell used vaginal secretions from the female hamster to identify whether males found the smell rewarding. She found that the smell of the female only becomes rewarding during the adolescent period. Further, she revealed that thissocial response is dependent on both the maturation of both the testosterone system and the dopamine system. That is, in the male hamster, the gonadal system interacts with the reward system to produce an appropriate adult social response to the female hamster.

In another session, Dr. Cecilia Flores at McGill University discussed the role of netrin in the involvement of brain development in the adolescent brain. Netrins are a class of proteins that are involved in axon growth, target recognition, axon arborization, and synaptogenesis, leading neurons to their final destination in the brain. There are two netrin receptors – DCC and UNC-5. Normal expression of netrin as well as its receptors are needed for proper brain development to occur.

DCC receptor signaling in the dopamine neurons, specifically during adolescence, determines the extent of their innervation to the medical prefrontal cortex in adulthood. Proper connections in this region of the reward circuitry are needed for our ability to stay motivated as well as our response to rewarding stimuli.

Additionally, proper dopaminergic innervation of the prefrontal cortex translates into proper behavioral responses in areas such as cognitive flexibility, response inhibition, and sensitivity to drugs in adulthood. Dr. Flores importantly highlighted that experimenting with drugs during adolescence alters the expression of both netrin and its receptors – thus altering how dopamine neurons innervate their final targets. For example, amphetamine exposure during adolescence down12

regulates DCC expression, causing an expanse of dopamine terminals in the medial prefrontal cortex. Therefore, experimentation with drugs during adolescence may have severe consequences for the structure of the prefrontal cortex as well as a variety of behavioral outcomes.

Collectively, this work highlights that the adolescent period is a time of extensive brain development. Proper brain development during this time is needed for proper behavior to emerge in adulthood. Therefore, it is an extremely important time to engage in healthy behaviors and to stay away from stimuli like drugs and alcohol, which may have severe consequences for structural and functional outcomes in adulthood.

Exercise highlight 5: Voluntary exercise restores adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons in adulthood (RP Vetreno, FT Crews) The adolescent brain is in a constant state of change and therefore has a heightened capacity for neural plasticity. Unfortunately, binge drinking is a common occurrence during this critical time of development. Using a rodent model of adolescent binge drinking, this group found that intermittent alcohol exposure during adolescence decreased levels of cholinergic neurons in the basal forebrain in adulthood. These mice also showed impairments in behavioral flexibility (as measured through a reversal learning paradigm) as adults. They then exposed the mice to voluntary wheel running throughout the adolescent period to see if this healthy behavior could restore the alcohol-induced cell loss. When mice received both exercise and periodic binge drinking, the cholinergic cells of the basal forebrain were preserved and they did not show the behavioral impairments associated with binge drinking. Further experiments indicated that both immune system and neurotropic factor mechanisms might be at play in this exercise-induced restoration effect. These results indicate that the adolescent brain is an especially plastic time of brain development, and that exercise may help to restore neuronal loss due to episodes of heavy drinking, which are common during this exploratory time period.

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Sense & Movement – A Surprisingly Unique Phenomenon

The ability to adapt your movement to signals or cues in the environment is known as sensorimotor adaptation, the focus of one of the many minisymposiums at the conference. Dr. Rachael Seidler and her colleagues at the University of Florida study this phenomenon using the sensorimotor adaptation task, a task where you are equired to move a joystick with your hand to hit a target on the computer screen.

Over time, people gradually adapt their movements to account for distortion of the presented image. Interestingly, there are quite large individual differences in adaptation rates. Sensorimotor adaptation decreases with age; however, even in older populations, a large spread of abilities are seen. Dr. Seidler was curious whether anything about these older adults predict their excellent performance? First, she found that those individuals who have better spatial working memory abilities have better sensorimotor function. She then examined the brains of individual performing the sensorimotor adaptation task while in a magnetic resonance imaging scanner. Higher levels of activation of the right dorsolateral prefrontal cortex, a region of the brain involved in higher-level cognitive functioning, predicted better performance on this task. She then examined whether any underlying genetic effects predicted good performance in sensorimotor adaptation – she focused on two dopamine genes (COMT and DRD2). Those individuals who had a 14

genotype that coded for the highest levels of dopamine transmission in the brain showed the greatest performance in sensorimotor adaptation. She then examined the relationship between motor movement and dopamine genotype (low versus high dopamine transmission) in Parkinson’s patients, a group of individuals with impaired dopamine signaling. Parkinson’s patients with the genotype that coded for low dopamine signaling walked more slowly and took smaller steps. When she examined responses to the drug L-DOPA, she saw something interesting. Those with the highest dopamine transmission genes, showed better baseline gait function but no response to treatment. Contrarily, those with the low dopamine transmission genes, showed a worse baseline gait function but a better response to medication.

Future research will be needed to investigate other behavioral, brain, and genetic factors that contribute to individual differences in sensorimotor adaptation, how this behavior is modulated by age and disease states, and techniques to improve sensorimotor processing.

Exercise highlight 6: The effects of a semester of aerobic exercise on fitness, cognition, mood, and GPA in college students (Basso JC, Crosta C, Raskin M, Wang A, Kadakia D, Choi J, Milburn E, Trivedi R, Suzuki WA) Long-term aerobic exercise enhances mood state and improves a range of cognitive functions including attention, information processing speed and both short- and long-term memory. Though a recent study found that first-year medical school students who regularly exercised attained higher grades than those who remained sedentary, little has been done to assess whether long-term exercise in undergraduate students positively influences cognitive function and academic performance. Therefore, we examined the effects of an aerobic exercise intervention on mood, cognitive function and academic performance in first-year college students. Previously sedentary students engaged in one typically sedentary semester and one semester where they exercised approximately 3 times per week.

Before and after each semester, students were tested on cardiopulmonary fitness, cognitive functioning, mood state, and their learning and studies strategies.

Compared to a sedentary experience, exercise enhanced the ability to recall information, increased information processing speed, and improved creative thinking. Exercise also increased the motivation to exercise and enhanced mood state (via a decrease in negative affect), with those individuals gaining the most in the their fitness, showing the largest behavioral improvements. These findings have important implications for academia and indicate that students should be exercising along with their studies to possibly enhance academic performance.

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