BSCI353 Final Exam COMPLETE STUDY GUIDE NEW VERSION UPDATE University of Maryland

BSCI353 Final Exam COMPLETE STUDY GUIDE NEW VERSION UPDATE University of Maryland

Lecture 1 - 8/29 Gene Expression in the Human Brain - Mixture of brain-specific and ubiquitous genes - Expression of a simple gene can be widespread within the brain - Mutation of a gene with widespread expression can have a widespread effect (ex. ASPM gene which controls cell division → microcephaly) - Or a gene can be expressed in only a tiny part of the brain (ex. Localized expression of genes in the hippocampus of a mouse) Structure and Connectivity - Neurons + glia (or neuroglia) - Mid 19th century position: nervous system was a diffuse syncytium of cells with interconnected neuronal cytoplasm; no separate cells; cell theory (1830) did not apply - 1873 Camillo Golgi: Golgi stain - a cytological stain that randomly stains whole individual neurons - 1906 Santiago y Cajal: used Golgi stain to identify individual neurons on many parts of the nervous system; discovered synapses (also proposed by Charles Sherrington) - Principle of Dynamic Polarization: information flows from dendrites to the nerve terminal via the axon - Principle of Connectional Specificity: 1. No cytoplasmic connections between neurons 2. Nerve cells don’t form random networks 3. Each cell makes precise connections with other neurons via synapses Number and Types of Neurons - About 1011 neurons in the human nervous system - Terminally differentiated - Limited capacity for repair - Dendrite(s), cell body, axon(s), and synaptic terminal(s) - Dendrites contain receptors for NTs or sensory receptor proteins that respond to sensory stimuli - Axon terminal makes synaptic contact (releases NTs) onto the dendrites of other neurons or onto endocrine or muscle cells - Bipolar Cells: 1 dendrite, 1 axon - Monopolar (unipolar) Cells: no axon OR no dendrites → cell body has receptor proteins that respond to NTs - Multipolar Cells: several dendrites - Dendritic or axonal branching can occur many times after they leave the cell body - No axon? Dendrites receive AND transmit signals → Principle of Dynamic Polarization doesn’t hold Lecture 2 - 8/31

Basic Structure of Neurons - Cell body is the site of protein synthesis - Dendrites receive information from other neurons; contain NTs or sensory receptor

proteins - Axon terminals make synaptic contact (release NTs) onto the dendrites of other neurons, endocrine, or muscle cells - Vesicles filled with NTs is released into the synaptic cleft - Axon carries action potentials from cell body to the synapses at the axon terminal - Some axons are myelinated to increase transmission speed - Myelinated axons have Nodes of Ranvier - Beginning of the axon is where the action potential is usually initiated; myelination begins here Immunostaining and GFP-Tagging Methods - Localize proteins within cells - Localization of proteins in cells are highly specialized and different types of proteins are distributed differently in dendrites, axons, and cell bodies - Cytoskeletal proteins (widespread protein) expressed differently in different parts of the neuron → localizes ion channels and proteins that bind or release NTs - Tau (red) is localized in the axon - Actin (red) is localized in the growing tips of dendrites and axons - Actin is more uniform in non-neuronal and astroglial cells - Tubulin (green) is more uniform in a typical neuron and non-neuronal cells - Actin (red) also localized in dendrites and axons of neurons that are targets for synaptic contact from other neurons - Cytoskeletal proteins create scaffolds in distinct parts of the neuron that bind to and localize receptor channel proteins in areas where they can best help transmit information - Acetylcholine (red) is clustered under the synaptic terminal ends of axons Glial Cells - Support cells - Regulate environment around nerve cells - Take up NTs around nerve cells - Play a role in defending the brain and spinal cord against injury and infection - Can regulate neuronal growth - Glial stem cells can proliferate and differentiate into new glial cells and neurons - 10-50x more glial cells than neurons in the brain - Do they process info?

- Old Dogma → do not “carry info” - Vital for normal info processing (NT uptake; blocked by psychoactive drugs) Type of Glial Cells - Microglial Cells - Found in CSF and CNS - Small motile phagocytic cells (like macrophages) - Can engulf particles following injury - Can secrete signaling molecules that modulate inflammatory response to injury (ex. cytokines)

- Mobilized after damage - Macroglial cells - Astrocytes are the most common - Potassium uptake around active neurons → to return Vm to normal - Not motile - NT removal around active synapses - A role in guiding axons to their target cells during development (glial scaffold) - Part of the blood/brain barrier between blood and CSF - Regulate vascular blood flow and nutrient delivery - Astrocyte to Neuron Communication - Sense and respond to nearby neuronal activity → process receptors of NTs - Release NTs mostly ATP - Oligodendrocytes: responsible for myelination in the CNS - Schwann Cells: responsible for myelination in the PNS - Glial Stem Cells - Undifferentiated - Proliferate and differentiate into new glial cells → → → new neurons in very few places in the brain - Oligodendrocyte precursor cells: differentiate into oligodendrocytes Lecture 3 - 9/5 Cytological Stains for Neurons - Nissel Stain: labels the ER, shows division of parts of the CNS into layers - Good for distinguishing tissues and layers - DOES NOT distinguish individual neuron types well - Does not stain axon and dendrite patterns - Golgi Stain: randomly stains whole individual neurons (shows dendritic/axonic branching) - Fluorescent Dyes: stains whole cell - Inject into cytoplasm or membrane - Useful after recording electrically from an intracellular micropipette - Water Soluble Dyes: used to inject cytoplasm (most cannot exit the cell) - Lipid Soluble Dyes: used to inject the membrane (most cannot exit the membrane) Identifying a Specific Type of Neuron - Antibody Labeling of Proteins expressed only by a type - In Situ Hybridization to mRNA expressed only by a type - GFP tagging of proteins expressed only by a type - Applying Engineered Enzyme Substrates that produce colored products in types of neurons that specifically express that enzyme - Useful for labeling neurons that use a NT by labeling the activity of the enzyme used to synthesize the NT

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“Tracing” Axons Through the Brain using retrograde or orthograde transport of radiolabeled amino acids, fluorescent dyes, proteins or viruses - Labeled material travels slowly by natural transport to axon terminal (orthograde transport) or to origin of the axon (retrograde transport) - Multi-neuronal pathway can also be labeled if labeled material is secreted into another neuron Neurons as Functional Units - Info is carried by changes in plasma membrane potential (difference between the inside and outside of the cell) - Changes in membrane potential can be: Action Potentials (active) or Graded Potentials (passive) - Graded Potential Changes - Confined to dendrites, cell bodies, short axons - Do not travel more than a few micrometers - Usually have a relatively long duration (10ms - 100ms) - Carry info through dendritic branches - Amplitude is proportional to strength of stimulus (# of channels activated by NTs or the amount of NT released) - Amplitudes can be summed - Can also be initiated in axons by currents flowing in advance of action potentials - Dies away before reaching the axon hillock - Does not reach threshold for an action potential - Sensory Generator Potentials: arise in dendrites from the opening of channels by sensory stimulus - Post Synaptic Potentials: arise from the opening of NT-gated channels in dendrites of neurons - Action Potential - Can travel very long distances (up to meters) along axons - No loss of amplitude - Amplitude is fixed - all or nothing event - Usually short duration (1-10ms) - Triggered in the axon or cell body when a graded potential amplitude reaches threshold value - Larger the stimulus, the higher the frequency of action potentials - Amplitude modulated analog signal (graded potential) → frequencymodulated digital signal (action potential) - Info is limited by the maximum rate that an axon can carry action potentials - Arrays of neurons act as parallel processing to overcome slowness - 1000 action potentials/s is the max rate for a neuron Lecture 4 - 9/7 Neuronal Circuits - Knee Jerk Response 1. Sensory neuron dendrites are stretched 2. Channels open in dendrites to produce a graded potential

3. Graded potential becomes an action potential at the axon 4. Action potential travels along axon to spinal cord 5. NT released onto spinal motorneuron (extensor) 6. Motorneuron AP frequency increases 7. Action potential travels along motorneuron axon and synapses onto muscle cells 8. Muscle cell contracts - Larger stimulus strength (stronger tap) → stronger muscle contraction - Max rate of 1000 AP/s - Most cells show a basal resting AP rate - Info can be conveyed as an increase or decrease in AP frequency from basal rate Measuring Neuronal Activity - Extracellular Recording (outside) - Recordings made from a single cell - Recordings made from multiple cells simultaneously - Extracellular electrodes: wires placed outside neurons that pick up currents that circulate around a neuron when it produces an AP; cannot detect slower smaller GP changes from a single neuron - Multielectrode Recordings - Record from 10s-1000s of neurons simultaneously - Laminar probe - Vertical penetration across depth of cortex - Intracellular Recording (inside) - Measure Vm (depolarization = +; hyperpolarization = -), APs, and GPs Optical Techniques to Measure Activity - Image fluorescence of dyes/proteins - Voltage Sensitive → fluorescence depends on membrane potential - Calcium Sensitive → fluorescence depends on calcium ion concentration in the cytoplasm - Engineered proteins that fluoresce more when they bind calcium - Used to image olfactory bulb responding to 2 different smells Noninvasive Optical Techniques to Measure Activity - Computerized Tomography (CT) - MRI - fMRI - PET - Electroencephalography (EEG) - SQUID Magneto-encephalography (MEG) Computerized Tomography (CT) - 3D X-ray image produced using an X-ray camera and source head that rotates around the patient’s head - Computer reconstructs 3D image from the scans Magnetic Resonance Imaging (MRI) - Detects energy emitted by spinning hydrogen nuclei in water molecules - H nuclei lined up in magnetic field and irradiated by a brief radiofrequency pulse

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Image is based on a distribution of water in different tissues and characteristics of the energy emitted by H nuclei in different tissues High resolution Anatomical not functional

Lecture 5 - 9/12 Functional MRI (fMRI) - Hb distorts MRI resonance properties of nearby H+ nuclei - Distortion depends on whether or not Hb is loaded with oxygen - Detection of areas with high oxygenated blood flow (active areas) - Takes seconds for blood supply to increase in response to increased activity - Spatially accurate images of active areas - 1mm resolution - Slow → takes seconds to respond Positron Emission Tomography (PET) - Incorporate unstable, positron emitting atoms into glucose or oxygen - Inject labeled glucose or oxygen into bloodstream → brain - Detect emitted positrons with scanning detectors - Reconstruct location and density of labeled molecules - Active areas will show increased concentrations - Slow → takes seconds for uptake to follow neuronal activity - Poor resolution (few mm) - Needs on-site cyclotron to produce isotopes (short half life) Electroencephalography (EEG) - Arrays of electrodes placed onto a patient’s scalp - Detect minute electrical potential waves flowing between points on scalp (due to currents flowing through active brain tissues beneath) - Can be used to characterize gross functional state of brain - Can be used to detect activity in gross areas of cortex - Fast (10ms) - Poor spatial resolution (cm) SQUID Magnetoencephalography (MEG) - Neurons generate electrical impulses and magnetic fields - Intensity and shape of the fields vary with electrical activity within brain area - Fields are detected and 3D imaged using arrays of super-conducting magnetic detectors around a patient’s head - Very fast (ms) - Poor resolution (1 cm) Nervous System Anatomy

Neuroanatomical Directions - Dorsal → top and back - Ventral → bottom and front - Rostral → towards the head - Caudal → towards the “tail” - Superior → higher - Inferior → lower - Posterior → back - Anterior → front Sectioning the Brain - Horizontal → flat; separate top/bottom - Sagittal → separate left/right - Coronal → separate front/back - Lateral → away from midline - Medial → towards midline

Major Features in a Medial Sagittal Section - Brainstem: respiratory centers, control of movement (pons, medulla, midbrain) - Cerebellum: control of fine movement

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Diencephalon: thalamus (sensory info processing), hypothalamus (hormonal control) Corpus Callosum, Anterior Commissure: tracts of white matter linking cerebral hemispheres Cerebral Cortex: cerebral hemispheres Gyrus → hill Sulcus → valley

Cortical Lobes - Occipital Lobe: vision - Parietal Lobe: somatosensation - Frontal Lobe: motor planning - Temporal Lobe: hearing Structures Seen Below the Cortex, In Coronal Sections - Basal Ganglia: motor planning (caudate, putamen, globus pallidus) - Grey matter of cerebral cortex: the “rind” - Tracts of white matter: send info to/from cortex - Hippocampus: memory - Thalamus: sensory information processing - Amygdala: emotional balance - Ventricles: spaces with CSF

Electrical Basis of Communication - Ionic charges can be separated over very short distances

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Principle of Electroneutrality: Positive and negative particles in a substance are evenly distributed so that the overall charge at any point is 0 Separating charges requires a lot of energy Separation of a tiny % of ions occurs across cell membranes Maintaining separation requires energy via ATP hydrolysis → creates a membrane potential

Lecture 6 - 9/14 Resting Membrane Potential - Due to leak K+ channels

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Vm will approach Ek for any cell membrane which is only or mostly permeable to K+ Sodium potassium pump maintain Vm Vm dependent on open ion channels not ion pumps

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Nernst Equation

Hodgkin, Huxley, and Keynes 1940-19502 - Giant squid axons - High K+ inside cell - High Na+, Ca2+, Cl- outside cell - KCl concentration outside the cell was gradually increased which measuring the Vm of the axon → evidence that resting potential is determined by K+ concentration

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Between 20-50 mM, Vm was approximately = Ek as calculated from the Nernst Equation Next, they stimulated the axons to produce APs → at the peak, the membrane is permeable to sodium ions not potassium ions

Permeability and Action Potentials - At rest → permeable to K+; Vm = -60 to -70 mV; close to Nernst potential of K+ - During AP → increase in sodium permeability; Vm = +58 mV; close to Nernst potential for Na+ - After AP → decline in sodium permeability; increase in K+ permeability;

Vm approaches -60mV

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Goldman-Hodgkin-Katz Equation: Vm depends on relative permeabilities for K+, Cl-, Na+ as well as concentrations in and out of the cell

Electrical Model of the Cell

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Mostly permeable to K+ → Rk << RNa and Vm = Ek Mostly permeable to Na+ → RNa << Rk and Vm = ENa Predicting Vm depends on 1. Ion permeabilities 2. Nernst Potentials Lecture 7 - 9/19 Electrical Model of a Neuron - ECF and cytoplasm function as small value resistors - Lipid bilayer membrane is a capacitor with very high resistance - Ion channels are resistors or as conductances (conductance = 1/resistance) Lecture 8 - 9/21 Conductances - When mostly leak channels are open: gL >> gK, gNa and Vm approaches EL - When mostly voltage-dependent Na+ channels are open: gNa >> gK, gL and Vm

approaches ENa - When mostly voltage-dependent K+ channels are open: gK >> gL, gNa and Vm approaches Ek Changing Membrane Potentials Manually - Forcing or vacuuming current out of a neuron - Applying + or - voltage via a microelectrode and measuring changes in membrane potentials

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For GP → Small amounts of current that do not trigger an AP are well described by an electrical model with only a single fixed resistor and a capacitor - For GP → Adding a current → slow rise in Vm occurs because some of that current has to charge the membrane capacitance - For AP → current driven by “batteries” into VG Na+ channels and out VG K+ and Leak K+ channels; charge flows on and off the capacitor (depol → repol) Voltage Clamp Method - Vm is held a fixed value that you chose - Measure currents flowing through the membrane at these Vm values - Clampin Vm = no action potentials - See how the currents are dependent on time

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Hyperpolarization only elicits a capacitive current and a small leakage current

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Depolarization elicits a large transient inward current followed by a delayed outward current Interpretation of Current Traces in Terms of Electric Model - iNa and iK are activated when membrane is depolarized - Early current is iNa (initial inward current; increases without delay; inactivates after a few ms) - Proof = current reverses to outward when [Na+]out is lower than [Na+]in - Late current is iK (delayed outward current; does not inactivate) TEA: blocks K+ channels TTX: blocks Na+ channels

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Modified Ohm’s Law:

Lecture 9 - 9/28 AP Mechanism via Voltage Clamp - Conductances rise in linear proportion to the number of channels open → give a direct measure of the gating of ion channels

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Na+ Channels have activation gates → sense Vm and open the channel pore when Vm exceeds threshold (positively charged amino acid lysine is repelled by positive Vm driving a conformational change to open the gate) Na+ channels also have inactivation gates → sense Vm and close the pore even if Vm remains depolarized under voltage clamp K+ channels have activation gates → sense Vm and open the pore with a delay when Vm exceeds threshold K+ channels have no inactivation gates Voltage dependent opening of the channels is very similar → early Na+ current explained by a faster activation gate opening for Na+, NOT due to greater sensitivity to voltage

AP Down an Axon - GPs decay with distance - APs regenerate at the Nodes of Ranvier

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APs travel faster along larger diameter axons → smaller electrical resistance to passive current flow - Large axons → current will follow path of least resistance and spread further out ahead than exiting the membrane → further and faster propagation - Channels are only present at the Nodes of Ranvier - Myelin insulates axon, preventing passive current leakage, reducing membrane capacitance - Unmyelinated axons → channels have to open at every point along the axon - Unmyelinated axons have to be large - Multiple Sclerosis: autoimmune disease which attacks myelination; lose the ability to speak or walk Lecture 10 - 10/3 Patch Clamp method - Ion conductance is summed behavior of millions of ion channels - Single ion channel activity is monitored through patch clamp method - Erwin, Neher, and Sakmann in 1981 - Attach a glass patch micropipette to the surface of a cell - Control membrane potential across the path of membrane → clamp potential of the solution inside the patch pipette - Measure current passing through the channel into/out of the solution in the patch pipette

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Random Na+ channel openings are observed → max probability of occurrence is a few ms after a step of depolarization - Probability of a Na+ channel opening corresponds to the curve for gNa max vs. membrane potential - Sustained probability of K+ channel opening/staying open (no inactivation) Characterizing Channels - How to verify that a sequenced and located channel has the gating characteristics responsible for the observations from VC experiments?

- Cell cultures induced to over-express sequenced mRNA from channel’s genes - PC method used to measure current flowing through the channels - Apply voltage steps, NTs, sensory stimuli to investigate what gates the channel - See if what you measure is consistent with the behavior of the ion conductance measured under VC - Channel structure can be found out by amino acid sequence (use mutations and use PC to see if anything changes) Channel Proteins - Pore: opening through which ions travel - Selectivity Filter: only allows certain ions to move through the channel; often comprises of a ring of positively charged amino acids lining the inside of the pore - Gate: opens or closes the pore in response to some stimulus (membrane potential, binding of a ligand, temperature, mechanical distortion or pressure) - Voltage-Gated Channels: Na+, Ca2+, K+, Cl- channels - Ligand-Gated Channels (Ionotropic): NT receptor, Ca2+ activated K+ channel, Cyclic Nucleotide Gated Channel - TRP Channel Family: mechanosensitive channels that open when membrane is stretched; includes heat or cold-sensitive channels

Synapses - Transmit AP activity to next cell - A neuron may form 100s of individual synapses with a cell or just 1 - Postsynaptic neuron may receive synaptic contacts from 1-100s of contacts - Electrical Synapse - Gap junctions proteins (connexons) - Direct flow of electrical current and small molecules → cytoplasmic connectivity - No NTs involved - Usually excitatory and cannot amplify - No delay

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Chemical Synapse - No contact between two membranes - No direct flow - Release of NTs - Excitatory or inhibitory - Transmission involves a 1-2 ms delay

Neurotransmitters - Small molecules (ACh, amines, amino acids, ATP) - Peptides (5-20 amino acids) - Gases (NO, CO) Lecture 11 - 10/5

Dale’s Principle - A given neuron only secretes one NT chemical from all of its synapses - Classify a neuron (or a pathway) by its NT - Cholinergic: use acetylcholine - Aminergic: use biological amine like noradrenaline - Peptidergic: use peptides NTs usually co-secreted with a small molecule Differential Release of Neuropeptide and Small Molecule Co-transmitter - Low frequency stimulation - Small molecule in small clear core vesicles (released) - Neuropeptide in large dense core vesicles - Localized Ca2+ increase at postsynaptic terminal - High frequency stimulation - Diffuse increase in Ca2+ concentration - Both neuropeptide and small molecule co-transmitter released Chemical Synapse Sequence of Events During AP 1. VG Ca2+ channels open 2. Ca2+ promotes NT vesicle fusion 3. NT released into synaptic cleft 4. NT binds to ionotropic receptor proteins 5. Channel opens 6. Ions enter postsynaptic cell and change postsynaptic Vm Presynaptic Ca2+ Release - Necessary → injection of a Ca2+ buffer (chelator) into presynaptic terminal blocks transmission of AP in postsynaptic neuron

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Sufficient → direct injection of Ca2+ into presynaptic terminal elicits postsynaptic NT release Neurotransmitter Release 1. Vesicle docks 2. SNARE complexes form to pull membranes together 3. Entering Ca2+ binds to synaptotagmin 4. Ca2+-bound synaptotagmin catalyzes membrane fusion

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Synaptic NT vesicles held close to Ca2+ channels by docking proteins so they are ready to fuse Cycling of Presynaptic Membrane 1. Budding off of an endosome 2. Synapsin assists in docking 3. NSF SNAPs assist in priming 4. SNAREs and Ca2+-bound synaptotagmin assist in fusion 5. Budding from postsynaptic membrane after clathrin coats the membrane 6. Dynamin assists in detaching from postsynaptic membrane 7. HSC70, Auxilin, Synaptojanin involved in uncoating and membrane becomes a part of the endosome How do NTs induce Postsynaptic AP? - Muscle cell Graded End Plate Potential (EPP) = Excitatory Postsynaptic Potential (EPSP) - EPP is a GP whose amplitude is dependent on amount of NT released - EPP results from activation of NT gated channels - Outside out patch clamp → patches of postsynaptic membrane containing NTgated channels can be torn from postsynaptic cell

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EPSPs result from activation of thousands of NT-gated channels simultaneously by release of NT from vesicles - Higher NT release → bigger postsynaptic current → bigger EPSP Excitatory and Inhibitory Synapses - Reversal Potential: average Nernst Potential of the ions flowing through NT-gated channels - Excitatory Synapses (glutamate, aspartate) - Na+ or Ca2+ sensitive or cation non selective - Erev >= 0 mV - Postsynaptic Vm will rise above threshold to trigger AP - Inhibitory Synapses (GABA, glycine) - K+ or Cl- selective

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Erev -50 to -70 mV Postsynaptic Vm will dip below threshold to suppress AP However if postsynaptic channels are K+ or Cl- selective, Erev will be -60 or less, Vm will be forced below threshold, inhibiting APs - Synaptic input from a dendritic tree is summed and either an AP happens or is inhibited High Frequency of Presynaptic AP = High Frequency of Postsynaptic AP - Currents for EPSPs overlap in time → sustained depolarizing current into postsynaptic cell - Depolarization trigger AP in postsynaptic cell → falls down→ another AP - Trains of presynaptic APs = trains of postsynaptic APs - Higher frequency of presynaptic AP → more NT released → larger postsynaptic currents → faster drive to bring Vm back to threshold → higher postsynaptic frequency Ionotropic NT Receptors - Several large subunits - Nicotinic ACh Receptor (NMJ) → 2 ACh required; excitatory - AMPA Receptor: gated by glutamate; excitatory - NMDA Receptor: blocked by Mg ions; gated by glutamate; co-activated by glycine; depolarization drives Mg out; lets Ca2+ and Na+ in - Will only be fully open if cell is previously depolarized (to drive out Mg) - Involved in learning and memory at cellular level - GABA Receptors: gated by GABA; inhibitory; lets out Cl-; binding sites for barbiturate drugs, steroids, and benzodiazepines Lecture 12 - 10/10 Calcium Permeable Receptor Channels - Activate long term cellular transduction pathways - NMDA → increased postsynaptic Ca2+ concentration → Ca2+ dependent pathway activation → protein synthesis, protein kinase function, gene transcription Metabotropic NT Receptors - Usually G protein linked - Initiate intracellular messenger pathways → amplify release of cAMP, cGMP, or Ca2+ ions inside cells - May eventually close or open ion channels but may also activate protein phosphorylation and gene transcription

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Subtle, long-term regulation of synaptic sensitivity and growth → plasticity (building block of learning and memory) Drugs and Neurotransmitters - Agonists: mimic - Antagonists: competitive inhibitor - Many inhibit enzymes that synthesize small molecule NTs in nerve terminals - Others inhibit transporters that destroy NTs → increasing NT in synaptic cleft Somatosensory System 1. Mechanosensation (pressure, touch, vibration, perception, proprioception) 2. Pain reception Mechanosensation - Begins with a mechanosensory neuron - Dendrites → layers of skin - Cell body → dorsal root ganglion of spinal cord - Axon → up spinal cord → excitatory contact with 2nd order neurons in medulla - 2nd order axon → crosses brainstem → ends at contralateral VPN thalamus → 3rd order neuron - 3rd order axon → terminates in PCG in cortex → cerebral neurons - Post central gyrus is somatosensory area of cortex - Mechanotransduction: transduction of mechanical stimulus at the skin → increase in frequency of AP through mechanosensory neuron - Stimulus → allow cations in → graded generator potential → AP arrives at spinal cord

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Frequency of AP = stimulus strength until neuron saturates Tonic: slowly adapting mechanoreceptors that continue responding to a prolonged stimulus - Phasic: rapidly adapting mechanoreceptors that only respond to stimulus onset or rapidly changing stimuli - Meissner Corpuscle: touch phasic - Pacinian Corpuscle: deep vibration phasic - Ruffini’s Corpuscle: stretch tonic - Merkel’s Disks: light touch pressure tonic - Free Nerve Endings: pain, temperature, crude touch, tonic, high threshold Proprioceptive Sensory Organs 1. Muscle Spindle → detects muscle length; initiates stretch reflex 2. Golgi Tendon Organ → detects tension in tendon - Proprioceptive sensory neurons have dendrites in sensory structures in muscles, joints, and tendons - Axons pass through dorsal root ganglion to spinal cord - Spinal cord → medulla → thalamus → somatosensory cortex - Inform the brain about position, direction, and velocity of skeletal muscle movements - Control activity of motorneuron in feedback reflexes like the stretch reflex - Do not perceive info send from proprioceptors - Loss of proprioception → use vision to compensate for lost feedback Lecture 13 - 10/12 Dermatomes and Somatosensory Map - Sensory neurons within each dermatome in skin → projects to a particular area in somatosensory cortex - Somatosensory map of body surface - More cortical surface to areas of skin with greater receptor density

How to Map Connections - Record electrical activity of neurons in somatosensory cortex using extracellular electrode - Stimulate various parts of the skin - Examine receptive field of cortical neuron whose activity is being recorded - Receptive fields show excitatory center and inhibitory surround

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Mechanoreceptor → Size of receptive field will depend on spread if its sensory dendrites CNS somatosensory neuron in brain → Size of receptive field will depend on # of receptors connected to it (convergence); some connections may be inhibitory (surround)

Cortical Columns - Cortical columns: columns of neurons with overlapping receptive fields that are arranged perpendicular to the cortical surface - Columns are grouped to create a little module → process info from an individual whisker on a rodent’s snout - Modules sometimes stain differently from surrounding tissues and so can be visualized - Neurons in each column respond to similar sensory stimuli

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Somatosensory cortex is a complex grid where neurons with similar receptive field location and properties are grouped into columns Pain Perception - Painful stimuli are detected by nociceptors - Nociceptors: high threshold sensory neurons - Pain → pain receptors, central pain pathway, referred pain, phantom limbs, labeled lines, modulation of pain sensation in CNS - Experiment that demonstrates nociception involves specialized neurons 1. Heat stimulus and record neuron in arm connected to nociceptor 2. As heat increased very high, nociceptor became more active 3. Initial sensation of heat = immediate activation of thermoreceptor

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Early perception of sharp pain → fast myelinated fibers Later burning sensation → small unmyelinated C fibers Inflammatory Response 1. Tissue injury 2. ATP, Prostaglandin, Bradykinin, 5-HT, H+, Histamine (produced by mast cell or neutrophil) act on nociceptive neuron 3. Neuron releases substance P to neurophil/mast cell as well as blood vessel 4. Neuron also releases CGRP to blood vessel 5. Information sent to spinal cord → anterolateral system Subset of small unmeylinated C fibers → have nonspecific cation channels in dendrites opened by Capsaicin Mechanosensory pathway → ipsilateral spinal cord → crosses over in medulla Pain and Temperature Sensation pathway → 2nd order neuron in dorsal horn spinal cord → 2nd order axon crosses over immediately and travels up contralateral spinal cord → VPN thalamus → 3rd order neuron synapses to PCG → cerebral neurons - Contralateral spinal cord Hemisection

Lecture 14 - 10/17 Referred Pain - Information from visceral pain sensory neurons are merged with those from the skin - Pain in viscera is referred pain Labelled Lines - Neurons are labeled in terms of TYPE of perceptions they evoke - Referred pain from viscera is felt as pain from the skin (type = pain) - Pressure on eyeball → light (eye picks up intensities of light not pressure) - Engineered Prosthetic Senses 1. Track magnetic fields coming from neurons when imagining being touched in various parts of the hand 2. Create a map of feelings in hand vs. groups of neurons in S1 3. Cut into brain, insert electrode close to relevant neurons 4. Blindfold patient and hook up to robotic hand 5. Manually press one finger of prosthetic → communicates with implant → fires neurons corresponding to that finger 6. Location identified correctly by patient 85% of the time → after practice = 100% - Phantom Limb - Due to continuous spontaneous activity of central neurons that would have normally received information from that limb - 2nd order pain neuron in dorsal horn of spinal cord (projection neuron) → descending systems can modulate ascending systems - Descending systems can transmit opiate peptides - Descending systems (parabrachial nucleus, medullary reticular formation, locus coeruleus, raphe nuclei) Vision

- Emmetropia: light converges at retina - Myopia: light converges before it reaches retina - Hyperopia: light converges behind retina Retina - Many layers of ells - Photoreceptors (rods and cones) are in the far back - Layers above photoreceptors are transparent - Ignore shadows cast by blood vessels and nerves overlaying photoreceptors - Types of Cells - Ganglion Cells → produce APs - Bipolar Cells → no APs - Horizontal Cells

- Amacrine Cells → produce APs - Rods: larger, rodlike outer segment → no APs - Cones: smaller, coneline outer segment → no APs Visual Transduction - Photoreceptors hyperpolarize upon illumination - Mechanism → cGMP-gated channels - Dark → Ca2+ and Na+ enter through cGMP-gated channels; inside of rod is LESS negative - Light → Ca2+ and Na+ blocked; cGMP-gated channels closed; inside of cell is VERY negative - Rhodopsin = opsin + 11-cis retinal - Opsin is G-protein linked receptor protein in rod disk membranes - Photon of light changes 11-cis-retinal to trans - Change in structure activates rhodopsin - Rhodopsin → activates phosphodiesterase (PDE) - PDE → closes cGMP-gated channels → hyperpolarization

Lecture 15 - 10/19 Fovea - Avascular zone in very center = foveola - Center is HIGHLY concentrated by cones - Periphery is more concentrated by rods

Rods and Cones - Rods only has 1 rhodopsin gene (green; higher wavelength than green for cones; darker) - Cones can have 1 out of 3 different rhodopsin genes (red, green or blue) - No color vision from rods - Genes for green and red lie close on chromosome - Men (XY) with only one copy are more susceptible to colorblindness after crossover event (hybrid gene or loss of gene) - Rods much more sensitive than cones → larger hyperpolarizations, more rhodopsins in disk membrane; less temporal sensitivity because they are slow; response saturates in daylight; better for imaging in dim light - Cones are good for capturing rapidly changing detailed images in dim light On Center/Off Center Retinal Ganglion Cells - In darkness → rod depolarizes and releases glutamate → ionotropic Na+/Ca2+ channel opens in bipolar cell → NT released (no AP) → off center ganglion cell depolarizes → high frequence of APs - In light → rod hyperpolarized (no AP) no glutamate release → ionotropic Na+/Ca2+ channel closed in bipolar cell and hyperpolarizes also → off center ganglion cell hyperpolarizes in light → no APs sent to optic nerve - In darkness → rod depolarizes and releases glutamate → metabotropic Na+/Ca2+ channel closes in bipolar cell → no NT release → on center ganglion cell hyperpolarizes - In light → rod hyperpolarizes and doesn’t release glutamate → metabotropic Na+/Ca2+ channels open in bipolar cell → bipolar cell depolarizes → on center ganglion cell depolarizes → high AP frequency to optic nerve - Antagonistic inhibitory surround (illumination of a surround increases AP frequency of an off center ganglion cell) - Happens at the level of photoreceptor and horizontal cells - Illuminate surround → cone hyperpolarizes → horizontal cell is hyperpolarized → depolarizes center cone (antagonizes hyperpolarizing light falling on the center)

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Ganglion cells with overlapping “center-surround’ receptive fields sample the image of visual space that is projected by the eye’s lens onto the retinal surface Each RGC is receptive to light arriving from a fraction of a degree of space

Lecture 16 - 10/24 Advantage of Center-Surround Antagonism - RGCs are maximally stimulated by edges and lines (where intensity changes a lot) → contrast detectors

Processing of Color - P Ganglion Cell → small receptive fields; slower adapting; detect color - Red on center - Green off center - M Ganglion Cell → large receptive fields; quickly adapting (transient); respond to

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all colors; movement detectors K Ganglion Cell

Response is higher for red dot on blue background >>> red dot on green background (center and surround is activated) - Color contrast (P cells) Projections to Cortex - RGCs terminate on lateral geniculate nucleus (LGN) of thalamus - LGN neurons terminate on striate cortex - Binocular Vision - Info from both eyes taken at corresponding eye - Optic chiasm - Left striate cortex→ right visual field - Right striate cortex → left visual field - Optic chiasm combines fibers from nasal side of one eye with temporal side of another - Due to high density of cones in fovea (or macula) → larger area of visual cortex - Simple, Monocular Receptive Neurons 1. Show cat a bar 2. Insert electrode in visual cortex 3. Monitor activity as orientation of bar changes 4. Neuron activated only when bar is vertical - Shows selectivity of neurons to orientation - Cortical neurons don’t react to spots of light like RGC do

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Electrode can be driven into striate cortex to record from cells of different layers (vertical) - Electrode can follow an oblique path - Monkey striate cortex - Vertical path → layers 1-6; same orientation - Oblique path → changing orientation (0-180 degrees) - Binocular Receptive Field Properties - Axons of LGN in thalamus terminate of layer 4 cortical neurons - Layer 4 neurons send laterally branching axons to cells in other adjacent layers and cortical areas - Adjacent area neurons are driven by input from the eyes - Layer 4 is monocularly driven Lecture 17 - 10/26 Ocular Dominance - Ocular Dominance Group: 1-7 where 1 is left eye dominant and 7 is right eye dominant - Layer 4 is monocularly driven - Drive an oblique electrode through layer 1-3 → mixed interaction of left/right eye where one is more dominant

- Mixing of pathways from two eyes occurs in striate cortex Binocular Disparities - Fixation Point: when an image falls in the fovea of both left and right eye - Binocular Disparity: when an object is closer than the fixation point; image is left of fovea in left eye and right of fovea in right eye Color Vision Mediated by 2 Streams - M Cells → motion sensing → project to layers 1-2 of LGN (magnocellular layers) - P cells → color sensing → project to layers 3-6 of LGN (parvocellular

layers) - P layers contain 2 right and 2 left eye layers - M layers contain 1 right and 1 left layer Extrastriate Area - V1 is primary visual striate cortex to which LGN neurons project - Cells in V1 columns send axons to V2 and others - Each extrastriate region makes its own map of its own set of stimulus features - 2 main pathways 1. V1 → V2 → MT → parietal lobe (spatial and vision; motion sensing) DORSAL 2. V1 → V2 → V4 → temporal lobe (object recognition; color sensation) VENTRAL Sound Waves - Pressure waves of air generated by vibrating molecules - 20Hz - 20kHz can be detected by humans - Phasic difference = time delay

Human Ear - Middle ear bones are impedance matching devices - Airborne vibrations (low impedance) → fluid vibration (high impedance) - Movement of basilar membrane bends stereocilia of hair cells - Inner hair cell sends info to afferent sensory neurons - Outer hair cells receive information from brain along efferent motor axons - Tectorial membrane provides shear force on stereocilia - Organ of Corti: where the 4 rows of hair cells originate from - Scala Tympani: lower bony portion of cochlea - Each part of the cochlea is tuned to a separate frequency of sound - High pitched → close to oval window - Low pitched → far from oval window - Scala Media: cochlear duct with fluid Mechanoelectrical Transduction mediated by Hair Cells

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Fluid in scala media has very high K+ concentration K+ channels in stereocilia of hair cell → connected by protein springs When tectorial membrane moves right, springs stretch and channels open K+ flows in to depolarize cell → NT released onto afferent nerve

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If you attach a small probe to a hair and move it in many directions, only moving it laterally right will depolarize the cell Lecture 18 - 10/31 Mechanoelectrical Transduction of Hair Cells - Low frequencies (below 3kHz) → Vm follows vibration of sound - High frequencies → smooth depolarization - At low frequencies, pitch can be determined by the timing of oscillations - Pitch at high frequencies determined by position of cell on basilar membrane

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Each afferent axon is tuned to a particular range of frequencies of sound → each connected to one hair cell on a particular position in basilar membrane (tuning by position) - Outer hair cells actively vibrate → enhancing the movement of the basilar membrane → sharpening the tuning Transmission to Auditory Cortex

- Auditory nerve enters the brainstem - Branches to innervate 3 divisions of cochlear nucleus 1. Cochlear Nucleus Neurons → terminate in both sides of superior olive in pons and inferior colliculus in midbrain 2. Superior Olive Neurons → terminate in ipsilateral (same side) inferior colliculus 3. Inferior Colliculus Neurons → terminate in MGC in thalamus 4. MGC Thalamus Neurons → terminate in primary auditory cortex in temporal lobe Integration of Sounds from 2 Ears - Role of MSO and LSO - Medial Superior Olive (MSO): uses arrival time differences - Lateral Superior Olive (LSO): uses intensity differences

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MSO → AP arrive faster than sound; A more sensitive to sound from right; E more sensitive to AP from left - LSO → if sound on left is more intense → inhibition of input on right side Lecture 19 - 11/1 Inferior Colliculus - Neurons with cell bodies here array to create an auditory space map - Map based on the calculated output of the LSO and MSO neurons - Highly developed in nocturnal predators like barn owls Medial Geniculate Complex - Neurons here mediate the detection of specific, complex sound patterns - Ex. echolocating neurons in bat MGC → sensitive to particular delays between time of sound and time of echo Auditory Cortex - Tonotopic Map: array of neurons arranged according to their characteristic (best) sound frequencies - Cortical neurons often sensitive to certain sound combinations that characterize vocalizations of an animal

- Anterior region → responds to apex of cochlea (low pitch) - Posterior region → responds to base of cochlea (high pitch) Olfaction

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Olfactory receptor cells are continually renewed every 6-8 weeks

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Olfactory cilia detect odorants → generator potential to axon → axon produces AP Whole cell patch clamp recordings show that cilia are main sensory organelles

Olfactory receptor neurons produce AP in response to inward generator currents → can be detected extracellularly (frequency of AP increases with increasing odorant concentration) Olfactory Transduction 1. Odorant binds and activates a G protein 2. G protein activates adenylyl cyclase 3. ATP converted to cAMP → opens Na+/Ca2+ channel cotransporter 4. High intracellular Ca2+ opens Ca2+-gated Cl- channel (moves Cl- out) 5. High intracellular Ca2+ activates Na+/Ca2+ exchanger - Approx 1000 distinct genes for odorant receptor proteins - Each olfactory receptor neuron expresses only 1 or a few odorant receptor molecules - Neurons with same receptors are scattered across epithelium - Each neuron is broadly tuned with varying sensitivity to a range of odorant molecules

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Brain can’t distinguish between low conc of odorant for which receptor is sensitive to or high concentration of odorant that receptor isn’t sensitive to Brain has to compare outputs of arrays of different neurons Topographical mapping: pattern of activity in receptor neurons across olfactory epithelium Projections - ORN project to glomeruli - Glomeruli converge to mitral cells (2nd order) - Convergence amplifies the sensitivity of the detection of weak odors - Granule Cells: localized interneurons that shape the response of mitral cells - Convergence explains how ORNs are scattered - Brain associates patterns of active glomeruli with a specific odor → population coding

Lecture 20 - 11/09 Motorneurons - Lower motor neurons are organized in ventral horn of spinal cord - Motor neurons innervating proximal muscles are closer to the inside of the cervical spinal cord and vice versa

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Motor Unit: a single motorneuron and all the muscle cells it innervates Muscle is innervated by several type of MNs (fast fatigable, fast fatigue-resistant, slow) Standing → slow MNs Running, Walking → fast fatigue-resistant MNs Jumping, galloping → fast, fatigable AP frequency in motor unit determines contractile strength

Nervous System’s Control of Muscle Contraction 1. Recruiting right types of motor units for a task 2. Varying the AP frequency in those motor units by controlling MN AP frequency Control of MN Activity at Spinal Cord Level - Reflexes - Ex. stretch reflex → maintain limp position despite varying loads (holding a mug while its being filled) - Stretch Reflex Circuitry - Stretch activates spindle sensory neurons - Spindle sensory neurons activate flexor muscle alpha MNs and inhibit extensor MNs (arm is raised) - Results in length change in muscle fiber - Spinal reflexes are feedback circuits that allow muscles to respond rapidly to changing

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loads Rhythmic generation of patterns of activity also require reflexes (ex.

Walking → rhythmically firing MNs while walking on a treadmill) Spinally transected cat still shows rhythmic alternating extensor and flexor MN firing (tells us that rhythm must be locally generated)

Descending Projections from Brainstem to Spinal Cord 1. Colliculospinal tract (innervates proximal muscles of trunk) → originates from superior colliculus 2. Rubrospinal tract (innervates distal muscles) → originates from red nucleus Descending Projections from Motor Cortex to Spinal Cord - Neurons in right hemisphere drive spinal MNs on left side - Neurons in left hemisphere drive spinal MNs on right side - Direct Projection: lateral corticospinal tract - Indirect Projection: corticoreticulospinal tract - Sensory cortex located in front of motor cortex - Motor cortex in front of central sulcus Influence of Cortical Upper MNs on Muscle Activity

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Electrode placed in monkey upper MN Myograph taken from muscle in hands Cortical neurons are active just before movement begins → planning movements?

Lecture 21 - 11/14 Basal Ganglia - Involved in gating proper movement initiation

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Monkey was trained to follow a target with its eyes As target was moved, monkey’s eyes followed it with a 300 ms delay Substantia nigra activity dips during eye movement Superior colliculus activity spikes during eye movement Parkinson’s Disease: loss of dopaminergic cells of substantia nigra; symptoms include resting tremor, shuffling gait, facial rigidity, restless limbs - Huntington’s Disease: degeneration of caudate region of basal ganglia; associated with dominant autosomal mutation of huntingtin gene (essential for development) - Both can be lethal in long term due to difficulty breathing, eating, and swallowing - Neither affects gross movement only initiation and control of movement Cerebellum - Lesions lead to persistent errors in movement - Cerebellar Ataxia: jerky imprecise movements - Inputs from contralateral cerebral cortex, ipsilateral brain stem and spinal cord - Cortex = largest source of inputs to CB (both sensory and motor) - Contains many somatotopic maps - CB outputs ONLY to deep cerebellar nuclei → VL thalamus → primary motor and premotor cortex

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Role = receives sensory signals and motor commands from cortex and brainstem; compares intended movement with actual movement; computes motor error; sends signals to upper MNs in cortex to correct error Weakening of synaptic connections that yielded incorrect movement → reducing output of CB to cortex when incorrect movement is made → reducing future movement error 3 Layers 1. Molecular 2. Purkinje 3. Granule 5 Cell Types 1. Purkinje 2. Stellate (inhibitory) 3. Basket (inhibitory) 4. Golgi (inhibitory) 5. Granule 2 Inputs 1. Mossy Fibers 2. Climbing Fibers: originate from inferior olive in brainstem (carry error info from motor learning) 3. Parallel Fibers: originate in cortex, pons, spinal cord, and vestibular system carry proprioceptive and sensory info

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Parallel and Climbing fibers are inputs of purkinje cells Granule cell talks to parallel fiber (sensory input patterns) Purkinje cell → deep cerebellar nuclear cell (control movement) Climbing fiber → error message to purkinje cell Parallel fiber → specific pattern (error message) to purkinje cell Long term depression: weakening of synapses between purkinje cell and parallel fiber Over time, purkinje cell activity will be greater during correct movement → motor learning Vestibulo-ocular Reflex in Monkeys - Vestibulo-ocular reflex: keeps eyes fixed ahead on a target during head movements 1. Put glasses on monkey to minimize world view 2. Eye movements undercompensate for head movements (eyes drift off target) 3. After several hours VOR is gained due to cerebellar motor learning

Lecture 22 - 11/16 Non-Associative Learning - No specific timing between stimuli required for learning process - Habituation: decrease in response to repeated stimulus - Sensitization: generalization of an aversive stimulus to non-aversive stimuli - Aplysia Gill Withdrawal Reflex - Normally withdraws its gills when siphon is touched - Habituation → decrease in gill withdrawal after repeated touching of siphon - Sensitization → generalization of shock to the tail to touching of the siphon (increased sensitivity of gill withdrawal reflex after shock to the tail)

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Mechanism for Habituation - Changes in axon terminal of sensory neuron → presynaptic depression of NT release onto motor neurons - Depletion of NT vesicles - Inactivation of N-type Ca2+ channels Mechanism for Sensitization - Heterosynaptic facilitation → interneuron activates motor neuron - Release of serotonin by facilitatory neuron → G-protein linked metabotropic receptor → adenylyl cyclase → increase cAMP levels in presynaptic terminal → PKA → phosphorylates K+ channels → channels close → duration of AP increases → more Ca2+ entry → more NT release → increased MN response Short term changes in synaptic strength are mediated by post translational modifications to proteins that mediate/modulate synaptic transmission Long term changes in synaptic strength are mediated by protein synthesis (translation + transcription) - Repeated serotoninergic interneuron activation - Activation of CREB transcription factor → synthesis of protease ubiquitin hydrolase

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Ubiquitin hydrolase promotes degradation of PKA subunit that regulates active PKA subunit - PKA activity is prolonged → long term phosphorylation of K+ channels (closed) → long AP → more NT release Associative Learning - Timing is critical - Pavlov’s dog → bell has to be rung BEFORE dinner is served - Fruit fly → pair shock/bright light to odor → avoidance of odor - Rutabaga mutants: adenylyl cyclase mutation (reduces cAMP levels) - Dunce mutants: PDE (degrades cAMP) mutation - Associative learning is also mediated by cAMP dependent process - Learning: change in behavior over trials - Memory: retention of something learned - Mammalian hippocampus encodes spatial info, consolidates short-term → long term memories - Rat with lesioned hippocampus couldn’t find its way through a maze after 10 trials (Morris Water Maze) - 2 Pathway Experiment - CA3 pyramidal neurons (of hippocampus) terminate at dendrites of CA1 pyramidal neurons using Schaffer collaterals - Stimulate either pathway 1 or 2 and record postsynaptic potential on CA1

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Pathway 1 is stimulated with tetanus (high frequency stimulation)

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Pathway 1 synapse is strengthened with tetanus (not pathway 2) → higher EPSPs in CA1 (specificity) - Long Term Potentiation of CA1 neuron with tetanus - Pair stimulation of pathway 1 with depolarization of CA1 neuron (delivered 100ms of each other) → LTP - Pathway 2 synapse is strengthened if pathway 2 is paired with strong stimulation of pathway 1 (association) - Activity in pathway 1 can strengthen pathway 2 to activate CA1 only if 2 pathways are active at the same time Molecular Mechanism of LTP - Glutamate released in postsynaptic neuron - Opens AMPA receptor to let Na+ in - Closed NMDA receptor (Mg+ blocks it) → LTP pushes Mg out to open channel - Both receptors let Ca2+ in - Ca2+ bind to calmodulin → activates CaM kinase II → phosphorylates downstream enzymes and transcription factors → strengthen synapse 1. Increase number of AMPA receptors in postsynaptic membrane 2. Growth of new dendritic spines in CA1 neurons Lecture 23 - 11/21 Long Term Potentiation - In the intact animal, using implanted electrodes, LTP in the hippocampus can last for months - Maintaining synaptic strength requires protein synthesis

Long Term Depression - Weakening of synapses - Initiated by prolonged low frequency stimulation

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Glutamate is released from presynaptic terminal AMPA receptor open to allow Na+ in NMDA receptor open to allow Ca2+ in Ca2+ → activates protein phosphatases (active with low frequency prolonged stimulus) → dephosphorylate substrates → internalized AMPA receptors in dendritic spine Why are LTP and LTP Good Models for Memory?

- Activity dependent - Synapse specificity and associativity - Many manipulations that inhibit memory formation inhibit LTP in animal models - HM → damaged hippocampus → removed → unable to form new memories Modification of Neuronal Circuits - # of synapses peaks in first months after birth and slowly declines (area 17 V1 synapses) - Critical Period: a period in which synaptic plasticity and remodeling occurs in humans and lasts through the first 5 years of life

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Both growth and loss occurs in critical period Hebb’s Postulate (1949): when cell A is near enough to excite cell B and it repeatedly fires, some process takes place in A and/or B that increases A’s efficiency to speak to B

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Changes in synaptic strength mediated by Ca2+ signaling - Increase in Ca2+ → calmodulin kinase 2/4 and ERK → CREB → growth factors, kinases, or cytoskeletal growth Three-Eyed Frog (19702 by Martha Constantine Patton) - Implanted third eye close to right eye - Two right eyes compete for space in optic tectum Visualizing Ocular Dominance Layers in LGN 1. Inject one eye with radiolabeled amino acids 2. Amino acids will follow pathway to LGN of thalamus → striate cortex 3. LGN will show alternating dark/light bands corresponding to left/right dominance 4. White stripes = radioactivity

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Cat eye-closure experiment - Stimulate both eyes of normal adult cat → normal Ocular Dominance Histogram - Suture one eye (kitten) and eventually undo sutures (adult) → complete ipsilateral eye domination → use it or lose it - Suture one eye (adult) and open it many months later → not much of a shift (support for critical period) - 3 days of MD → shift has begun; 6 days of MD → shift is complete (kitten) Hubel and Weisel: Nobel Prize (1980) 1. Structure and function of cortex regulated by experience 2. Experience-dependent plasticity highest during postnatal critical period 3. No changes in response properties of retinal ganglion cells 4. No changes in response properties of the thalamus - Areas of visual cortex that receive input from the functional eye expand and those that receive input from sutured eye are reduced - 1 week → drastic reduction in terminal branching of LGN neurons carrying information from deprived eye in layer 4 to cortex V1 Lecture 24 - 11/28 Ocular Dominance - Strengthening can happen at synapses from Layer IV neurons → other layers (less binocularity) - Weakening of eye muscles so eye don’t converge (strabismus) → shift in ocular dominance histograms (APs from RGCs in each eye are not correlated) Role of Environment in Synaptic Plasticity

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Mice in standard cage vs. enriched cage Cerebellum cells have more dendritic spines if mice lived in enriched cage Enhanced environment results in - Enhanced cortical thickness - Enhanced brain weight - Enhanced CREB-mediated gene expression - Enhanced dendritic branching - Enhanced oligodendrocyte:neuron ratio - Enhanced number of synapses per neuron - Examples of critical period - Maternal imprinting → geese chicks follow mom - Learning of birdsong’s by young zebra finches - First vs. second language acquisition Memory - Declarative (available to consciousness) or non-declarative (not available to consciousness) - Immediate Memory: fractions of a second - seconds - Working Memory: seconds to minutes - Long Term Memory: days - years - Clinical Case of HM - Remembered childhood, name, family history - Couldn’t form new memories or remember things happening up to 11 years prior to surgery

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He could store procedural memories but didn’t remember (after many trials) that he had done the same task before - Lost declarative memory - Hippocampus isn’t storage unit; it is needed to lay down new memories - Engrams: storage sites for declarative memories - Lashey’s Lesion Study - Destruction of rat cortex - Ability to solve a maze was proportional to % of cortex destroyed - No difference which areas were destroyed Alzheimer’s Disease - Most common of progressive dementia

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10% of people over 65; 45% of people over 85 Early onset → < 65 years old (5-10%) Deficiency or mutations in presenilin 1 and 2, apolipoprotein E Early signs: retrograde amnesia, progresses to anterograde amnesia, personality changes Late signs: decay of language skills, problem solving, judgement No fully validated biomarkers Includes hippocampus but is very widespread

- Senile plaques and neurofibrillary tangles - Plaques found in neocortex, hippocampus, and subcortical areas - Tangle density correlates with disease duration and severity of dementia - Amyloid deposits - Hyperphosphorylated tau Evolution of Hypothesis and Treatments for Alzheimer’s Disease - Cholinergic Hypothesis: damage or abnormality in cholinergic pathways (especially basal forebrain projections) - Drugs target and increase cholinergic transmission - Acetylcholinesterase inhibitors → inhibit ACh breakdown in synapses - Also damage to monoaminergic system (adrenaline, dopamine, serotonin), hippocampus, amygdala, entorhinal cortex, neocortex - Hyperphosphorylated Tau Hypothesis - Tau: microtubule associated protein that normally stabilizes microtubules - Tau accumulates when hyperphosphorylated by glycogen synthase kinase 3 (GSK-3) - Formes tangles - Amyloid hypothesis/APOE4 - APP: amyloid precursor protein - Cleavage by alpha-secretase (non pathological) - Dual cleavage by beta-secretase and gamma-secretase → toxic Abeta42 - APOE: normally chaperones cholesterol through blood; enhances proteolysis of Abeta42 plaques - APOE4 best correlated as a risk factor for AD

- Enrichment of environment helps reduce amyloid plaque volume Lecture 24 - 11/30 Association Cortices - Underlie cognition - To know the world - To attend to, identify/recognize, and plan for interaction with external stimuli or internal motivation - Incoming signals → layer 1-3 - Thalamus → layer 4 - Brainstem → modulates layers 1-6 - Outgoing signals → white matter under layer 6 Localizing High Order Function to a Brain Region - Correlations - Natural lesions (stroke, damage) - Lesion studies in animals - Non-invasive imaging in humans - Causation - stimulate/record from experimental animals Methods for Noninvasive Imaging - CT: better for hard tissue - PET: track metabolic activity - fMRI: high spatial/low temporal resolution - EEG/MEG: low spatial/high temporal resolution Contralateral Neglect Syndrome - Damage to right parietal lobe → ignore vision in left visual field

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Left side neglect is more common than right side neglect Right hemisphere dominates control of attention to visual field Damage to right parietal lobe → less attention to left visual field Partial bilateral lesion = very uncommon lesion leading to right side neglect Asymmetric metabolic activity in coronal sections when attending to R/L visual fields

- Lots of competition for space on left side (language processing) Attention Neurons in Parietal Lobe - Monkey’s parietal neuron recorded - When monkey presses a bar after attending to a visual target → receives juice - Greater speed and accuracy of behavioral responses to attended stimuli vs. unattended stimuli - fMRI of humans → greater activity in cortical areas concerned with vision when stimuli are attended to Temporal Cortex - Identification/Recognition - Agnosia: not knowing - Prosopagnosia: face blindness - Inferior temporal cortex recorded in monkey which was shown faces; neuron responds very well to faces - Another neuron responds really well to profiles - As a face rotates → activity pattern of neurons shifts across a small patch on the cortex (columns of neurons that respond to different angles of rotation on the face) Prefrontal Cortex - Planning - Monkey is shown a reward, presented with a delay, and has to remember which tray the reward was in - Monkeys with PFC lesions can’t perform task

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Neuron in dorsolateral PFC recorded → active during anticipation of the reward not during collection of the reward - Wisconsin Card Sorting Test: sort a bunch of cards by color, shape, and number → people with PFC lesions can’t do this well - Phineas Gage → spike through frontal lobe; poor planning + personality changes Speech and Language - Language: system of symbolic representations for social communication with grammatical rules, syntax (order), and emotional tone, rhythm, and pitch (prosody) - Noam Chomsky → we have an innate knowledge of language (universal grammar) - Aphasia: inability to produce or comprehend language - Broca’s Aphasia: expressive/productive aphasia; halting speech, disordered word structure, word repetition, disruption of grammar and syntax; comprehension intact - Wernicke’s Aphasia: sensory/receptive aphasia; fluid speech; no word repetition; adequate grammar and syntax; contrived/nonsensical words; disordered comprehension of language - Not alexia (inability to read) or agraphia (inability to right) - Not dysarthria (inability to move facial muscles) - Language occurs in large areas of cortex - Language is lateralized to left hemisphere in 97% of population Lecture 25 - 12/5 Lateralization of Language Tasks - Split Brain Surgery by Roger Sperry - Corpus callosum and anterior commissure was cut in epilepsy patients - Stereognosis: tactile recognition; naming an object by touching - Split brain patients able to name objects by touching in right hand but not left - Right hand somatosensory receptors project to S1 in left hemisphere where language is processed - Split brain patients also unable to verbally describe stimuli in left visual field - Aphasia Due to Focal Lesions in Polyglots - If languages learned independently, aphasia likely to be language specific - If languages learned concurrently, aphasia likely observed in all languages (could

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result in loss of single class of words or loss of languages with similar grammar) Sign Language: system of symbolic representations for social communication (grammar, syntax, prosody) Lesions in areas of left cerebral hemisphere in patients who have been deaf since birth result in deficits in sign language (aphasias)

Emotion - Affective/subjective aspects of consciousness - Biological/physiological aspects of experiences - Autonomic and somatic component for self preservation → Darwin (ex. Fight or flight) - Characteristics of Rage - Decerebrated cats showed sham rage after surgery ONLY if hypothalamus was intact

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Hypothalamus: coordinator of activities of internal organs - Targets: reticular formation → regulation of sleep, respiration, vomiting, swallowing, cardiovascular targets Electrical stimulation of some hypothalamic sites → rage and attack postures in awake cats Lesion in Motor Cortex → unable to show teeth equally on both sides; can smile symmetrically in response to a joke (voluntary facial paresis) Lesion in Extrapyramidal Motor Pathway → able to show teeth equally on both sides; can’t smile symmetrically in response to a joke (emotional facial paresis) Amygdala: nuclei in temporal lobe; associate sensory experience + emotion; houses emotional memory - Surgical interruption of MGN connection to auditory cortex → didn’t stop fear conditioning/freezing - Surgical interruption of MGN connection to amygdala → stopped fear conditioning/freezing - Fear conditioning lasts for days → LTP - Foot shock (strong stimulation) and sound (weak

stimulation) → shows plasticity properties similar to hippocampal CA1 neurons when paired - Urbach-Wiethe Disease: autosomal recessive; causes calcification of amygdala - Showed no fear during fearful tasks - Cannot recognize fear in facial expressions of other people - Unipolar Clinical Depression - 10-25% in women; 5-12% in men - Abnormal mood everyday for at least 3 months - SSRIs - MAOIs → inhibit monoamine oxidase (enzyme that breaks down dopamine and serotonin) - Tricyclic Antidepressants → inhibit reuptake of dopamine and serotonin Lecture 26 - 12/7 Sleep and Wakefulness - Sleep: loss of consciousness that occupies ⅓ of lives - During sleep, brain is still active - Temp drops, GH release increases, and cortisol increases and spikes in morning - Sleep spindle occurs in stage 2 - Styles of sleep varies → dolphins can sleep one hemisphere at a time - Total sleep deprivation in rats → body weight falls and food intake spikes until death Circadian Rhythm - Circadian rhythm is roughly 24 hours even without light cues (non-photo entrained) - Photo entrained by light sensitive retinal ganglion cells containing melanopsin that project to suprachiasmatic nucleus (SCN) of anterior hypothalamus

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Melanopsin absorption peaks in blue light → concern for nighttime use of LED screens (emit blue light) Removal of SCN results in abolition of circadian rhythm SCN neurons in culture exhibit circadian rhythms of gene expression 1. Light dependent transcription of Clk and Bmal1

2. Clk and Bmal1 associate as dimers 3. C-B proteins bind to E boxes and act as transcription factors 4. Proteins are synthesized and temporarily regulated (Cry, Ccg, Per1, Per2, Per3) 5. CRY-PER2 proteins associate as dimers and diffuse into nucleus 6. CRY binds and inhibits C-B 7. PER2 stimulates transcription of Clk and Bmal1 SCN activity → pineal gland → sleep promoting hormone melatonin

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EEG Recordings of Stages of Sleep - Delta waves in stage 4 - Sleep spindle in stage 2 - REM Sleep: 8 hours → 45 mins; birth - 70 years old - REM → Heart rate, respiration rate, and penile erection spike; increased limbic activity; decreased frontal cortex activity - Cholinergic neurons in brainstem (reticular formation) active in awake and REM sleep; desynchronize EEG waves when stimulated - Serotonergic raphe nuclei active in awake state - Norepinephrinergic Locus Coeruleus active in awake state - Histaminergic tuberomammillary nucleus of hypothalamus active in awake state - VPLO neurons induce sleep → inhibit TMN and brainstem nuclei - Orexin Neurons in hypothalamus → promotes waking up; activates TMN and brainstem nuclei - Thalamocortical Interactions in Sleep - 2 States of Activity 1. Tonically Active: reticular activating system active; spike trains convey sensory info to cortex 2. Oscillating: sleep; no sensory info to cortex → account for sleep spindles (bursts of synchronized EEG activity every few seconds during sleep) - Sleep Apnea: prevents patients from entering REM sleep; tired prone to depression; caused by interrupted breathing in overweight men