Fundamentals of Neuroscience

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MODULE 00: INTRODUCTION TO FUNDAMENTALS OF NEUROSCIENCE (MCB80X)
- Ref: https://www.mcb80x.org/
- http://funcamentalsofneuroscience.org
- Presented by: Dr. David Cox (http://www.coxlab.org/)
MODULE 01:ELECTRICAL PROPERTIES OF NEURONS
- Resting Potential
  - Ref: https://www.mcb80x.org/course/electrical_properties/resting_potential/bioelectricity_history
  - Neuron Types: Lugaro, Renshaw, Interneurons, Pyramidal, Unipolar, Afferent, Medium Spiny, Purkinje, Granule, Efferent, Mutlipolar, Bipolar, Betz,
  - Anatomy of Neuron
    - Soma: cell body (nucleus)
    - Axons
    - Dendrites
    - Cell membrane (Lipid Bilayer): outside of all cell parts
      - Ion Channels: selectively let ions move in/out cell across membrane
  - Membrane Potential: Potential across the cell membrane
    - Resting Potential = -70 mV (20 times smaller than AA battery 1.5V)
      - Resting Potential Value is close to the Nernst Potential of Potasium (K+) -80mV
    - Outside of membrane: Ground (as in electrical circuit)
    - Varies from -40mV to -90mV
  - Composition of Fluid Solution inside/outside cell
    - Water H2O, Proteins (collagen), Sugars (glucose), Ions (Na+,K+, Ca++, Cl-)
      - Cations: + ions | Anions: - ions
    - Molecules: Mg, H, HCO3 (bicarbonate), HPO4 (phosphate), SO4 (sulfate), and many proteins
  - Diffusion and Electrostatics
    - Diffusion: propagation of molecules from high concentration to low concentration
    - Electrostatic Force: +- Attract | ++ and — Repel
  - Physics
    - Electrostatic charge is balanced on either side but not across the membrane
    - The membrane acts as a capacitor
    - Electrostatic Force much much more powerful than Diffusion
    - Only 1 in 100,000 ions need to cross the membrane to generate a -80mV potential
    - This means a very small number of ions move across membrane ion channels
    - Equilibrium is reached with concentration gradient and electrostatic gradients are equal and opposite
  - Nernst Potential
    - re: https://www.mcb80x.org/course/electrical_properties/resting_potential/nernst_potential
    - Nernst Equation: E ion = RT / zF * ln([ion outside cell]/[ion inside cell])
      - E = Nernst Potential, Reversal Potential (ion channels flow) or, Equilibrium Potential
      - R = Universal gas constant
      - T = absolute temperature in Kelvin (little effect in since there is very small variation in cell temperature 37C)
      - v = valence of the ion (Na+,K+ = +1, Cl- = -1, Ca++= +2)
      - F = Faraday’s constant
      - ln([ion outside cell]/[ion inside cell]) = Logarithm of ion outside over inside concentration
    - Nernst Equation helps calculate an individual Ion’s potential at equilibrium
    - Only affected by the relative concentration not the absolute value
    - Typical values in human neurons
      - Concentrations:
        
        Extracellular: K+ = 5 nM | Na+ = 145nM | Ca++ = 0.0002nM | Cl- = 10nM
        
        Intracellular: K+ = 100 nM | Na+ = 5nM | Ca++ = 2nM | Cl- = 140nM
      - Nernst Potentials (Em): K+ = -80 mV | Na+ = +90mV | Ca++ = +123mV | Cl- = -70mV
  - Nernst Potential "Driving Force": E driving force = E membrane - E ion
    - Ions are always trying to reach their Nernst Potential: the farther away the higher the driving force
    - Calcium (Ca++) has a large Driving Force which explains why is used in a wide variety of signaling cascades
      - Membrane Resting potential is around -80mV and Ca++ = +123mV = Large driving Force
  - Ion Channel Filters (Passive Leak Channels)
    - To keep a membrane potential the membrane has to let K+ in but block Na+
    - Sodium ion Na+ radius is only 116 picometers (1/10th of a billionth of a meter) | K+ did = 152 picometers
    - H2O molecules surround Na+ pointing their - side to Na+ creating a Solvation Shell
    - Ion Channel is a molecular arrangement of proteins with a hole that matches a specific Solvation Shell configuration letting only a type of ions pass through
    - Many more K+ channels than Na+ or Cl- channels
    - K+ dominates the Resting Potential because it can travel across membrane a lot easier
  - Sodium/Potassium Pump
    - Moves 3 x Na+ out for every 2 x K+ it pumps into the cell (removes salt from inside cell)
    - This requires lots of energy in the form of ATP
    - About 70% of the energy required for brain function required to maintain the electrical gradient!
    - 1/3rd of what we eat goes to power this pump mechanism
  - GHK Equation
    - Em = RT/F ln ( (Pk[K]e + Pna[Na]e + Pcl[Cl]i) / (Pk[K]i + Pna[Na]i + Pcl[Cl]e)) )
    - Helps calculate a more realistic membrane potential taking into account membrane selective ion permeability
    - By David Goldman, Alan Hodgkin and Bernard Katch
    - It adds permeability coefficients (Pk, Pna, Pcl) to weight ion relative effect in membrane potential
    - Nernst Equation describes equilibrium between ion Influx and Efflux
    - GHK Equation describes a Steady State (resting potential is stable thanks to ion pumps but not in equilibrium)
  - (ion) Permeability (of cell membrane)
    - Na+ has a strong inward driving force but there are few Na+ channels so it has Low permeability
    - K+ has High permeability to exit the membrane = more influence in Overall Resting Potential -70mV (E of K = -80mV)
    - Neurons fire once they reach their Action Potential around -55mV which can be accomplished by letting Na+ in
- Passive Membrane Properties
  - Resistance
    - How difficult is for current to travel across a conductor (copper: low resistance)
    - Conductance: inverse of resistance (copper: high conductance)
    - Resistance is measured in Ohms | Conductance: Siemens
    - Membrane Resistance: Across membrane (Ohms/square mm)
    - Axial Resistance: Along membrane - Less when cytoplasm more salty and when pipe wider
  - Capacitance
    - Cell Membrane behaves as a capacitor
    - Cell walls = Conductors | Membrane = Dialectric
    - Capacitor slows voltage changes
      - i.e.: balloon inflating and deflating with water
  - Ohms’ Law
    - I = V / R (Current (Amps) = Voltage (Volts) / Resistance (Ohms))
      - V = I * R and R = V / I
    - Voltage Clamp (Feedback Amplifier): senses potential and injects just enough current to force desired voltage
      - Very important tool in neurophysiology
  - Length Constant (λ - Lambda) = distance it takes for a potential chance to fall-off 36% of initial value (in mm)
    - λ = Square Root of R-membrane (Ohm x cm) / R-axial (Ohm / cm)
    - λ increases by increasing (↑) Membrane Resistance and decreasing (↓) Axial Resistance (across axoplasm)
  - Membrane Capacitance (Cm)
    - Length Constant - λ increases (↑) when Cm decreases (↓)
    - Affects potential responsiveness: is Membrane Capacitance (Cm) decreases (↓) = responsiveness increases (↑)
  - The Time Constant (τ) = R-membrane x C-membrane = Seconds (s)
    - Time Constant (τ): time it takes for a piece of membrane to charge up to 63% of final value after change in input voltage
  - Phineas Cage
    - Still functional (but altered personality) after damaged prefrontal cortex when tamping iron went through his skull
- The Action Potential (Active Membrane Properties)
  - SpikerBox (Backyard Brains): open source device to detect neuronal activity (in cockroaches legs)
  - All-Or-None Response: a depolarization greater than or equal to the threshold that causes all of the membrane channels to open fully
  - Voltage-Gated Channels
    - Open/Close depending on membrane potential (total time 10ms)
    - Sodium (Na+) Voltage-Gated Channels:
      - Closed when membrane is at resting potential (-70mV)
      - Open when membrane potential is a bit more positive (+) (-56mV - 0.80ms)
      - Inactive shortly after channel opens (-75mV - 4.30ms)
    - Potassium (K+) Voltage-Gated Channels:
      - Open when membrane potential is much positive (+) (+30mV - 2.00ms)
      - Close a bit after (Na+) Voltage-Gated Channels (-76mV - 6.50ms)
  - Phases of Voltage-Gated Channels
    - Phases (6) = Resting, Stimulation, Rising, Falling, Undershoot, Recovery (RSR-FUR)
      - Results from sequential opening/closing Sodium (Na+) + Potassium (K+) Voltage-Gated Channels
      - Rising Phase: Depolarization of cell membrane caused by opening of Sodium (Na+) channels
      - Falling Phase: Repolarization by inactivation of Sodium (Na+) and opening of Potassium (K+) Voltage-Gated Channels
      - Undershoot Phase: hyper-depolarization Potassium (K+) channels still open.
      - Recovery Phase: gradual return to resting potential (-70mV) as voltage-gated Potassium (K+) channels close
  - Channels and Probability
    - Changes are probabilistic affected by large number of molecules and thermal noise (thermal jostling and jiggling)
    - Probability of voltage-gated channels being open/close is a function of voltage
    - Sodium (Na+) Voltage-Gated Channel more stable (more likely) in open state with higher voltage (vice versa)
      - Channels can be still closed in higher voltage (or open in lower voltage) just Less likely
  - Channel Kinetics
    - Probabilistic temporal dynamics of a reaction or movement from one state to another
    - Fast kinetics: can rapidly chance between states (open/closed, active/inactive)
    - Probability + Kinetics affects membrane permeability at different action potentials
    - Refractory Period: period of time when it’s not easy/possible to stimulate another action potential
      - Absolute Refractory Period: caused by inactivation kinetics of Na+ voltage-gated channels (impossible to trigger another Action Potential during this period))
      - Relative Refractory Period: slower to initiate another action potential because voltage is below resting potential
  - Current Behind Action Potential
    - Tetrodotoxin (TTX) blocks voltage-gated Sodium (Na+) channels (novocaine used by dentist)
      - Fundamental toxin used in neuroscience
      - Found in Puffer fish (culinary delicacy) - can kill (asphyxiation) by preventing neurons from firing
      - Cell cannot depolarize (increase in voltage) so it cannot cross the firing threshold
    - Tetraethylammonium (TEA): blocks voltage-gated Potassium (K+)
    - Action Potential current: Sodium (Na+) comes in Rising Phase then Potassium (K+) leaves Falling Phase
    - Potassium (K+) voltage-gated channels act as “delayed rectifier” channels
    - Action Potential ion transfer has minimal effect in ion concentration (only 1 in 100,000 ions need to move to have strong effect in potential)
- Action Potential Propagation
  - Ref: https://www.mcb80x.org/course/electrical_properties/action_potential_propagation/signals
  - Signal is not carried via ions or molecules but by depolarization state propagation (like a wave over water)
  - Hodgkin-Huxley model: A mathematical model that is used to describe the initiation and propagation of action potentials in neurons
  - Directionality of Action Potentials
    - Action Potential is bidirectional across cell membrane
    - 2 action potentials running into each other cancel each other
  - Speed of Action Potential propagation
    - Faster the lower both Axial Resistance (R-axial) and Membrane Capacitance (C-membrane)
      - Slower when Axial Resistance (R-axial) higher as it shortens Length Constant (λ)
        
        Limits the size of the “bubble” of depolarization which limits “reach” of action potential
      - Slower when Membrane Capacitance (C-membrane) higher as is increases Time Constant (τ)
        
        Capacitance increase buffer and delays depolarization limiting how far action potential goes
      - Can increase speed by larger axon diameter which reduces axial resistance (Gian squid axon = 1mm did)
    - Speed is also affected by:
      - “Chain reaction” nature of the action potential (action potential triggers adjacent membrane region action potential)
      - Membrane potential change speed limitation to trigger next action potential
      - Voltage-Gated channel opening speed limitation (relatively slow)
  - Myelination
    - Myelin Sheaths across axon which increases membrane resistance (R-membrane) by blocking ion channels leakage and reduces membrane capacitance (C-membrane)
      - Made of lipids which gives it its white color appearance
      - Also why the white brain matter is white
      - Myelin is produced my Glial Cells (Neuroglia/Glia): non-neuronal cell in CNS that form myelin and support neurons. Types:
        
        Oligodendrocytes (A Supporting Cell): in the central nervous system
        
        Schwann cells: in the peripheral nervous system
    - Nodes of Ranvier: open spaces between myelin that allow for voltage-gated ion channels to work
      - They act as little relay stations where action potential gets boosted again
      - Saltatory Conduction: small boosts in action potential (generation) caused by Nodes of Ranvier
    - Myelin helps keep axon diameter small while increasing speed and distance of action potential propagation
    - Pathology:
      - Demyelinating Diseases: loss of myelin which affects or kills action potential propagation (i.e. multiple sclerosis)
MODULE 02: NEURONS AND NETWORKS
- Synapses
  - Synapses: connections between neurons
    - Dendrites: signal receivers
    - Axons: signal transmitters
  - Synapse types:
    - Electrical synapses
      - Really fast: ideal for escape reflexes
      - Bidirectional: great for synchronous firing. i.e.: heart
    - Chemical synapses
      - Most common neuron type
      - Slower as they rely on chemical diffusion to transmit signal
      - Axon releases chemical into the Synaptic Cleft which goes to the dendrite receptors
      - Synaptic Cleft is a 20-40nm gap between axon/dendrite (1 microsecond to cross)
      - Advantages:
        
        Signal diversity
        
        Neurotransmitters: Increase/decrease firing likelihood
        
        Neuromodulators: modulate neuron activity: ie: dopamine, adrenaline
        
        Unidirectional: signal flows only in one direction
        
        Summation: signal is decoupled. Receptor neuron may need several signals from various axons to reach firing thredshold.
  - Anatomy of a chemical synapse
    - Presynaptic Terminal
      - Bulges and contains vesicles which contain the chemicals (Neurotransmitters/Neuromodulators)
      - Neuromuscular Junction (NMJ)
      - Vesicles
        
        Docked and waiting to be docked
    - Postsynaptic Terminal
      - Contains receptors
        
        Receptors bind only to specific molecules
        
        There are many kind of receptors
        
        Ionotropic Receptors: they have ion channels. Can start depolarization
        
        Metabotropic Receptors: trigger gene expression
    - Fast vs Slow synapses
    - Strong vs Weak synapses
    - Excitatory vs inhibitory synapses
  - Signal transmission
    - Neurons firing threshold is dictated by the combined effect of excitatory vs inhibitory neurons
      - Depends on frequency, timing and strength of the excitatory vs inhibitory signals
      - Signal Transduction: the process that is initiated when an extracellular molecule binds to a receptor
    - Postsynaptic potential (neuron to neuron)
      - Excitatory Postsynaptic Potential (EPSP): more likely to fire (threshold potential = -55mv)
        
        Nicotinic Acetylcholine bind to Acetylcholine receptors
        
        Acetylcholine receptors (AChR) mostly related to musculo-skeletar function
        
        300K Acetylcholine receptors need to open to trigger fire
        
        Acetylcholine receptors (AChR) are promiscuous ion channels
        
        They let in positively charged ions: Calcium, Sodium, NMDA, Potassium ions
        
        promiscuous ion channels always show a reversal potential (-10mV)
        
        Desensitization: receptors become inactive
        
        Useful in surgery for muscle relaxant - SuccinylCholine
        
        Sarin: nerve gas that produces receptor desensitization
        
        Curare, Hexamethonium. Alpha Bungarotoxin (venums)
        
        Diseases
        
        Myasthenia Gravis: auto-immune disorder -channelopathy
        
        Symptoms: muscle weakness and fatigue
        
        Medicine: Enzyme Inhibitors and immunosuppresants
        
        Congenital Myasthenic Syndrome (CMS)
        
        Medicine: Enzyme Inhibitors: quinidine, fluoxetine
        
        Glutamate Receptors
        
        Glutamate Receptors are mostly involved in the central nervous system
        
        Glutamate: natural occurring amino acid and building block of proteins
        
        It also acts as a neurotransmitter
        
        Ionotropic Receptors - ion channels
        
        AMPA: promiscuous ion channels like the Acetylcholine receptors
        
        NMDA: related to learning, memory, neuroplasticity (N-methyl-D-aspartate)
        
        Metabotropic Receptors (GPCRs) - detects neurotransmitter and triggers internal cellular reactions
        
        Constitute 4-5% of human genome
        
        Targeted by 40% of modern drugs
      - Inhibitory Postsynaptic Potential (IPSP): (resting potential = -65mV)
        
        IPSP = Action of GABA + Glycine Receptors (spinal cord)
        
        Agonists vs Antagonists
        
        Antagonists: signalling molecules that block
        
        Substances: Strychnine (rat poison), Picrotoxin
        
        Agonists
        
        Produce - Positive Allosteric Modulation
        
        Substances: Barbiturates (old), Benzodiazepines (new), Alcohol
        
        Benzodiazepines “benzos" (Valium, Zanax) to treat anxiety and insomnia
        
        Inhibitory Diseases:
        
        HyperekPlexia (loss of inhibition): neurological disorder - exacerbated response by touch or audio
        
        Treatment: Clonazepam - increases inhibitory effects of GABA
    - Postsynaptic potential (nerve to muscle fiber)
      - End Plate Potential (EPP)
        
        Amplitude affected by concentrations of Ca++ (calcium ions)
        
        Ca++ injected before impulse = increase in amplitude
        
        Ca++ injected after impulse = no effect in amplitude
      - Miniature End Plate Potentials (minis) - blips between signals in absence of stimulation
        
        Caused by probabilistic Presynaptic molecular releases
    - Signal Enhancers/Inhibitors
      - Curare: Inhibitor - blocks Acetylcholine receptors (AChR) receptors
      - Neostigmine: reverses anesthesia - acetylcholinesterase inhibitor
    - Quantal Synaptic Signal Transmission
      - Neurotransmitters are released in groups not individually inside the Vesicles
    - Snare Hypothesis - How Ca++ are related to Vesicle fusion - which releases neurotransmitters
      - Snare proteins
        
        v-snares: Synaptotagmin, Synaptobrevin (in vesicle)
        
        t-snares: Syntaxin, Snap25 (in Presynaptic Terminal wall)
      - Toxins that affect snare proteins: enzymes - Botulinum, Tetanus
        
        Botulinum: inhibits motor function (botox injection)
        
        Tetanus: interferes with release of neurotransmitters in inhibitory neurons
  - Connectomics
    - Science of how neurons connect among each other to store information
    - Take brain slices and analyze then with electron microscope
    - Plots wiring diagrams from brain tissue
    - Voxal = 1 cubic mm of brain matter which contains 2000 Terabytes of synapses
    - Whole brain contains 2 million Petabytes of synapses
  - OptoGenetics
    - Study brain circuitry using genetically encodable proteins that are light sensitive
    - Wikipedia: https://en.wikipedia.org/wiki/Optogenetics
  - Excitation and Inhibition
    - Life cycle of a neurotransmitter (NT) molecule
      - NT travels a v = 0.05 miles per hour
      - 1 microsecond to transverse synaptic cleft (20-40 nm)
      - 1 millisecond to travel out of the synaptic cleft (sideways)
      - NT travels to and binds postsynaptic receptor
        
        NT gets resorved by postsynaptic receptor
      - NT can be broken by enzymes inside synaptic cleft
      - NT can be captured by Glia cells
  - Small Circuits
    - Factors contributing to neuron firing
      - Distance
      - Non-Linear Summation
      - Inhibitory Input Blocking Excitatory Input
      - Temporal Summation
      - Inhibitory Input Blocking Temporal Summation
    - Convergence/Divergence & Recurrence
      - Convergence: multiple inputs sum to trigger circuit (cues that add up to conclusion)
      - Divergence: one circuit triggers many others (conclusion triggers chain reaction)
      - Recurrence: neuron A triggers neuron B which in turns triggers neuron A
        
        CPG: Central Patter Generator - rhythmic contractions - firing loop
  - Neuromodulation
    - Synaptic strength is changed/controlled
      - Structural: synapse structure changes (development/aging)
      - Non-structural: synapses strength efficacy is altered = Neuromodulation
    - PreSynaptic: alteration in neurotransmitters numbers
    - PostSynaptic: alteration to neurotransmitters response
      - Ionotropic Receptors - open ion channels by neurotransmitters
        
        Fast! - Ligand-band
        
        Open channels alter Ion flow which alters neuron potential
      - Metabotropic Receptors - G-Protein Coupled Receptors (GPCRs)
        
        Slower
        
        Alter electrical and metabolic properties of the postsynaptic neuron
        
        Trigger creation of proteins
        
        Signaling cascades created by chain molecular reactions
        
        Postsynaptic alterations can affect Inotropic Receptors behavior
        
        Over 2000 Metabotropic or GPCR receptor types (10% of human genome dedicated to code GPCR receptors)
        
        G-Proteins
        
        Alpha, Beta, Omega bind Guanamide Triphosphate (GTP)
        
        GTP plays a role in intracellular signaling
        
        Alpha protein can break free (Ga disassociation) and trigger other proteins (activating/deactivating)
        
        Trigger Enzymes which can generate other signaling molecules (2nd messengers)
        
        ATP + Adenyl Cyclase = Cyclic AMP (2nd messenger)
        
        Cyclic AMP (2nd messenger) activates Protein Kinase A
        
        Cyclic AMP can also affect gene expression inside neuron cell
        
        Protein Kinase A triggers many things eventually affecting Ion Flux
    - Serotonin System
      - Plays a role in Mood regulation
      - Main target for anti-depressant drugs
        
        MAOIs Inhibit enzymes that break down serotonin 5-HT
        
        Side effects: don’t eat cheese
        
        Tricyclic Antidepressants - inhibit reuptake of serotonin in the synapse
        
        resulting in serotonin dwelling longer with more time to bind to serotonin receptors
        
        Side effects: can block Sodium/Potasium channels
        
        SSRIs (Serotonin Selective Reuptake Inhibitors)
        
        Prozac, Zoloft, Citalopram
        
        Delayed effect of Anti-depressant drugs: can take several weeks
        
        Serotonin is in the gut and blood (clotting) so these drugs affect other systems
      - Neuropeptides
        
        Neuropeptides are neuromodulators made of proteins
        
        Much larger than classical neurotransmitters
        
        Over 100 types discovered
        
        Only act via Metabotropic Receptors - G-Protein Coupled Receptors (GPCRs)
        
        Examples
        
        Hypocretin: regulates sleep
        
        Leptin: Appetite
        
        Substance-P: modulates pain sensation
        
        Exogenous Opioids - all are small molecules (not protein based or Neuropeptides)
        
        First Pain Killer known to man kind: Regulate pain perception
        
        Morphine (10%) + Codeine (50%)
        
        Synthetic opioids
        
        Heroin (diamorphine) - synthetic opioid developed in 90’s
        
        Hydrocodone
        
        Oxicodone
        
        Oxycontin
        
        4 Opioid receptors: Delta, Mu, Kappa, Nocciceptin
        
        Endogenous Opioids (Natural opioids created in the body)
        
        Enkephalins
        
        Endorphin
        
        Dynorphin
        
        All Endogenous Opioids are Neuropeptides
    - Dopamine System
      - Reward, reinforced learning, pleasure, euphoria, motor function, Compulsion, Perseveration
      - Pathways
        
        Mesocortical Pathway
        
        MesoLimbic Pathway
        
        Nigrostriatal Pathway - Movement (Parkinson’s disease)
        
        Deep brain stimulation (DBS): surgical procedure to treat Parkinson’s disease
        
        Tuberoinfundibular Pathway
      - Drugs:
        
        L-Dopa - awakenings Parkinson’s disease (loses effectiveness over time)
        
        Cocaine: blocks the reuptake of dopamine
        
        Diphenhydramine “benadrome”: antihistamine with anti-Cholinergic effects
        
        Side Effects: anterograde amnesia
        
        Scopolamine: “Date Drug” people forget what happened
    - Cholinergic: via M1 receptors affect muscle, motor control, learning, short term memory, general arousal
    - Noradrenaline System
      - Noradrenaline: Released by cells in the Locus Coeruleus
        
        1500 Noradrenaline recreating neurons in each brain hemisphere
        
        Modulates: general arousal, fight/flight response, activation of the reward system
  - Potentiation And Depression
    - Neuronal Plasticity
    - Show-Term Plasticity and Adaptation
      - Synaptic Enhancement - increase in Excitatory Postsynaptic Potential EPSP
      - Synaptic Depression (Fatigue)
    - Long-Term Potentiation and Long-Term Depression (LTP and LTD)
      - Believed to be the neurological foundation to store memory
        
        LTP may be only partialy explain memory. There are indications that memory could be stored intracellularly
        
        re: http://journal.frontiersin.org/article/10.3389/fnsys.2016.00088/full
      - Donald "Hebb’s Rule" and Associative Learning
        
        Neuron Cells that fire together wire together
        
        Neuron Cells that fire out of sync, lose their link.
      - How LTP works
        
        Increase both the amount of NT released and Number of receptors at the synapse or Increase Receptor effect
        
        Hebian LTP
        
        Neuron Cells that fire together Strengthen
        
        NMDA-Receptor-Dependent LTP
        
        NMDA Ionotropic receptor: (Ca+ goes in) -
        
        Ligand-Gated Needs to Glutamate + Glycine to open
        
        Also Voltage-Gated to open
        
        AMPA receptor helps depolarize post-synaptic axon blocking Ca+
        
        Ca+ triggers Phosphorylation of AMPARs + Insertion of AMPARs
        
        Input Specificity: Synapse Specificity
        
        Associativity
        
        Cooperativity
        
        Persistence: can last for days to months - unique trait of LTP
        
        Non-Hebian LTP
        
        Neuron Cells that fire together wire together but Weaken
    - Long-Term Depression (LTD)
      - Hebian LTD
        
        Neuron Cells that fire out of sync, lose their link.
        
        Hippocampus and Cerebellum are the best understood regions for LTD
        
        Most common LTD neurotransmitter is Glutamate
        
        Cerebellum = LTD from strong synaptic stimulation
        
        Hippocampus = LTD from persistent weak synaptic stimulation
      - Non-Hebian LTD
        
        Heterosynaptic LTD
    - Spike Time-Dependent Plasticity (STDP)
      - LTD that only happens when signals happen at specific intervals or frequencies
      - May be a system to avoid LTD because of neuronal random firing
    - Non-Synaptic Plasticity
      - Happens elsewhere: Axon, neuron, dendrites
      - Referred to as Homeostatic Plasticity mechanisms
      - Very new and under investigation
    - MAPS (Multidisciplinary Association for Psychedelics Studies)
      - Non-profit to help people with psychedelics and marijuana
      - PTSD syndrome treatment with MDMA (3,4-methyleneDioxyMethamphetamine)
MODULE 03: THE BRAIN
- Vision
  - Video series: https://www.mcb80x.org/course/the_brain/vision/welcome_vision
  - Facts
    - About 50% of our brain power is associated to processing visual information
    - Light
      - Wave: Electromagnetic radiation
        
        > 700nm (infrared) to < 390nm (ultraviolet)
      - Particles: Photons - 300km/sec
  - Path
    - Retina
    - Optic Nerve
    - Thalamus (relay station)
    - Visual Cortex
      - Processes: shape, color, object identity, motion
      - Information Flow
        
        Sequential
        
        Parallel
  - Anatomy
    - Cornea
    - Pupil - aperture regulation via Iris
      - Iris: aperture/depth of field
    - Lens - focus
      - changes shape with ciliary muscles
    - Retina
      - Image sensor via Photoreceptors (100 million per eye)
      - Fovea: high density of photoreceptors
      - 1 million axons carry information away from the retina
        
        ie: 1 megapixel camera
      - Anatomy
        
        10 distinct Layers (3 main functional states with 2 synaptic layers)
        
        Photoreception
        
        Internal transmission
        
        Output to the deeper brain
        
        Via Interneurons (50 different types)
        
        Bipolar Cells
        
        Retinal Ganglion Cells (feature detectors) (30 types)
        
        Bundle into the Optic Nerve
        
        Send parallel action potentials
        
        Horizontal and Amacrine Cells: located at each synaptic stage
        
        Synchronization and integration of signal input
    - Optic Nerve
    - Oculomotor muscles: Eyeball movement + optokinetic reflex
  - Processing
    - Eye has great dynamic range
      - Sensitivity to very dark to very bright light
    - Photoreception
      - Photoreceptors
        
        Anatomy
        
        Outer segment
        
        Electromagnetic → Chemical energy conversion
        
        Inner Segment
        
        Chemical → Electrical energy conversion
        
        Synaptic Terminal
        
        Electrical → Chemical energy conversion
        
        Types
        
        Rods
        
        Detect low light levels
        
        20 times more rods than cones
        
        Peak sensitivity at 498nm
        
        Cones
        
        High light levels and colors
        
        S-Cones (Short-wave cones): blue light - 420-440nm
        
        M-Cones (Middle-wave cones): green light - 535-550nm
        
        L-Cones (Long-wave cones): red light - 565-580nm
        
        Operation
        
        Phototransduction = Convert: Electromagnetic → Chemical → Electrical Energy
        
        Converts light energy (photons) into membrane potential in Photoreceptors cells
        
        Rods convert Electromagnetic → Chemical via Rodhopsin (protein)
        
        Rodhopsin: Made up of a G-protein Coupled Receptor (GPCR) = Retinal + opsin, and its ligand
        
        Retinal also known as Vitamin A adelhyde (carrots)
        
        GPCR activation: Photon is absorbed by Retinal it changes from 11-CIS-retinal to All-Trans-Retinal which causes changes in the Opsin backbone which causes activation of G-Protein Transducer
        
        This was discovered by Harvard George Wald which received Nobel Prize for it and the study of photopsins in 1967
        
        Only One photon required to trigger this reaction due to the amplifying nature of Rodhopsin chain reaction
        
        Transducer changes cytoplasmic concentration of cGMP (second messenger molecule) by the action of an enzyme known as cGMP phosphodiesterase
        
        cGMP phosphodiesterase modulates cGMP-gated ion channels which change the membrane potential
        
        Absence of Light (Dark-scotopic): cGMP opens Na+ and Ca+ ion channels in the Outer Segment of the photoreceptor which depolarizes the cell after Na (sodium) influx
        
        Light: depletes cyclic GMP (cGMP) in the Outer Segment which closes Na+ and Ca+ ion channels hyperpolarizing the cell
        
        Neurotransmitter is released in Dark not in Light
        
        Cone Phototransduction (Color vision)
        
        Work better with more light and faster at detecting changes
        
        3 Types
        
        S-Cones (Short-wave cones): Blue light - 420-440nm
        
        M-Cones (Middle-Wave cones): green light - 535-550nm
        
        L-Cones (Long-wave cones): red light - 565-580nm
        
        All cones receptor contain GPCR protein: Photopsin (coneopsin)
        
        Work same as Rods (11-Cis-retinal to All-Trans-Retinal)
        
        Trichromat vision: Color is perceived by relative activation of 3 types of cones
        
        Metamers: colors that render the same bc cannot render all spectrum
        
        Tetrachromats: Fish and birds have four pigments for vision
        
        Some women have are Tetrachromatic (X-chromosome mutation)
        
        Colorblindness: mutations in the photopsin GPCR protein
        
        Deuteranopia: Red-green colorblindness (lack of M-Cones)
        
        Scotopic vision (Nighy vision): Rods active. Cones inactive = Hard to see colors in the dark
        
        Photopic vision (Daylight vision): Rods inactive. Cones active
    - Retinal Processing
      - 3 main functional states with 2 synaptic layers
        
        Outer nuclear layer contains photoreceptors: rods + cones
        
        Inner nuclear layer: bipolar, horizontal and amacrine cells
        
        Ganglion layer: output neurons → action potentials via optic nerve to brain
        
        Only cell type in retina capable of generating action potentials
        
        All other react to graded changes in membrane potential
        
        Receptive Field: region of visual space when stimulated evokes a response in the cell
        
        Organized in a Center-Surround organization
        
        On Center cells: + in center, - outer
        
        Off Center cells: - in center, + outer
        
        Kuffler (1950) recorded electrophysiological responses from retinal ganglion cells of anesthetized animals
        
        John Dowling and Frank Warbling (70’s Harvard): cellular ganglion responses are built from interactions of upstream bipolar and horizontal cells
        
        Each photoreceptor and interneuron can be part of the center and surround of different retinal ganglion cells
        
        Lateral pathways (amacrine cells) responsive for the center-surround organization
        
        Most retinal ganglion cells respond better to well-aimed small spot of light than to diffuse light. Thought because of center-surround organization of receptive field enhances sensitivity to edges and contrast (bright/dark border)
    - Retinal Circuit
      - Direct Pathway: Input photoreceptor → bipolar cell → output retinal ganglion cell
        
        Input photoreceptor → bipolar cell
        
        Main neurotransmitter = Glutamate (amino acid)
        
        Depolarization: when Dark area appears in retina releases neurotransmitter (glutamate)
        
        Bipolar Cells
        
        Two Cell types
        
        Off Cells
        
        Light off = more glutamate
        
        Glutamate-gated cation channels depolarization triggers EPSP (Excitatory PostSynaptic Potential) after Sodium (Na+) influx
        
        On Cells
        
        Light On = less glutamate
        
        G-protein coupled receptors respond to Glutamate released by photoreceptors via hyper polarization
        
        Operation
        
        Each bipolar cell receives input from a cluster of photoreceptors (1 to thousands)
        
        Each bipolar cell also connected via horizontal cells to a ring of photoreceptors that surround the central direct cluster
        
        Center-Surround:
        
        Center Area: connected to cluster of photoreceptors in center
        
        Surrounding Area of retina: input via horizontal cells
        
        The differential firing accounts for unique firing patters depending on shapes and areas covered (centre vs surround)
        
        Bipolar cell → output retinal ganglion cell
        
        Connection happens via synapses in the ganglion cell layer
        
        Modulated by lateral connections of Horizontal Amacrine cells from the Lateral Pathway which coordinates and integrating rods and cone inputs
        
        Retinal ganglion cell: about 1 million in each retina
        
        They also have a centre-surround receptive file organization like bipolar cells
        
        On-center retinal ganglion cell: depolarized if center is illuminated
        
        Off-center retinal ganglion cell: responds to dark spot in centre of receptive field
        
        Some RGCs (retinal ganglion cells) have more complex receptive fields and respond to particular colors or movement of light patterns
      - Lateral Pathway: At each synaptic connection neuronal responses are modulated by lateral connections of Horizontal Amacrine cells
        
        30 types of amacrine cells and about dozen types of bipolar cells
        
        All these types allow for many types of pattern/movement recognition which we know little about. Some may allow to compensate for oculomotor reflexes (optokinetic reflex))
    - Retinofugal Projection
      - Where does all the retina output go to?
        
        Tectum or Superior Colliculus: Retinotectal Projection
        
        Helps in orienting to stimuli in the environment
        
        Accessory Optic System (nuclei)
        
        Optokinetic reflex
        
        Vibration dampening system
        
        Thalamus
        
        Real station in the middle of the brain
      - 5 Major Parts (towards the visual cortex)
        
        Optic Nerve
        
        Input from left eye → right cortical hemisphere
        
        Input from right eye → left cortical hemisphere
        
        Optic Chiasm
        
        Decussation = Nerves from both eyes combine signals
        
        Nerves from each half Right retina → sees Left side of visual field
        
        Nerves from each half Left retina → sees Right side of visual field
        
        Optic Tract
        
        Lateral Geniculate Nucleus (LGN): inside the Thalamus
        
        Located in the dorso-lateral part of the Thalamus
        
        Left hemisphere LGN process information from Right visual field
        
        Right hemisphere LGN process information from Left visual field
        
        Ipsilateral (same side) and Contralateral axons (opposite side)→ 3 layers each (6 total)
        
        Two most ventral layers
        
        M-Type large neurons (Magnocellular)
        
        Large receptive fields: respond to moving objects
        
        Four more dorsal layers
        
        P-Type smaller neurons (Parvocellular)
        
        Small center-surround receptive fields: respond to shape
        
        In between layers
        
        Koniocellular neurons
        
        Represent certain color information
        
        All layers innervated by retinal ganglion cells
        
        Connectivity
        
        Most (80%) incoming connections (axons) to the LGN come back from the visual cortex
        
        20% from the retina
        
        This creates a feedback loop (poorly understood) which can be measured with electroencephalography (EEG)
        
        Optic Radiations
        
        Visual Cortex: central processing of most visual information
        
        Made of 6 layers (2mm thick)
        
        Primary Visual Cortex V1 (Striate Cortex)
        
        Located at the very back of the brain in a deep fold called the Calcarine Sulcus
        
        Name Striate Cortex comes from dark stripe called Stria of Genari
        
        Stria of Genari coincides with Layer 4 where all LGN axons enervate the cortical sheet
        
        Retinotopy (orderly pattern of connections): LGN axons innervate preserving spatial x-y organization in the spatial dimensions of the 2D cortical sheet
        
        Layer 4: receives largest LGN input in spiny stellate neurons
        
        Gets information from magnocellular and parvocellular neurons from LGN
        
        Input is segregated from Left/Right eyes in Ocular Dominance Columns (OCDs): Laid out in a striped patter across V1 surface
        
        Monocular deprivation will cause affected eye OCD’s to degrade and taken over working eye OCD columns.
        
        Later 2 and 3: receive primary input from koniocellular axons from LGN
        
        Physiology of Area V1
        
        Serve as edge detectors
        
        Ocular Dominance Columns (OCDs) showed Ocular Dominance
        
        Historical development
        
        Tungsten microelectrode: thin wire insulated except in tip (sharpened to the size of a single neuron) that records extracellular potentials (100mV) of neuronal activity
        
        Developed in 1950s by Harvard neurophysiologists David Hubel and Torsten Wiesel derived from Kuffler’s studies of retinal ganglion cell (won Nobel Prize for their work = considered fathers of modern cortical neuroscience)
    - Visual Pathways
      - Light goes to Eye
      - Eye transduces light into axon potentials via the retina
      - Optic nerve to Lateral Geniculate Nucleus (in Thalamus)
      - Optical Cortex - Area V1 (back of the brain in the Occipital Lobe)
        
        Ventral Pathway: The WHAT pathway
        
        V1→IT = receptive fields increase in size + complexity of stimuli
        
        V1: sensitivity local orientation, small lines
        
        V2: longer lines
        
        V4: curvature, shapes
        
        IT (Inferior Temporal cortex): in human/primates: process complex shapes: faces
        
        Dorsal Pathway: the WHERE/HOW pathway
        
        MT (Middles Temporal area): direction of movement
        
        PPA (Posterior Pariental Area): directing attention to visual space areas = Special Attention
  - Lessions of Visual Cortex
    - Experimentally Induced Lesions (Animals Only)
      - Permanent
        
        Suctioned Out
        
        Chemically damaged
      - Temporary
        
        Drug Injection
        
        Optogenetics (new): shining light in specific neurons
    - Observed Lesions (in Humans)
      - Disease
      - Stroke
      - Injury
        
        Concussions
        
        Firearms (WW2)
    - Ventral Pathway Lesions:
      - V1→IT: scotomas = blind spot
      - Closer to IT: more complex disorders = Agnosias
        
        Cannot process Objects
        
        Cannot recognize Faces: Prosopagnosia = Face Blindness
        
        Oliver Sacks wrote about Prosopagnosia in “The Man Who Mistook His Wife For A Hat”
    - Dorsal Pathway Lesions
      - MT damage: Akinetopsia = motion blindness
      - PT cortex: visual neglect: cannot pay attention to certain areas of visual field
        
        Damage to Half PT cortex:
        
        May only eat half of food on plate, other side ignored
        
        Will only draw half of a clock
        
        Can experience that half of their body or a part does't belong to them
        
        Damage to Both hemispheres PT cortex
        
        Balint syndrome = Simultagnosia: cannot experience the world as a whole
  - Binding Problem
    - How do we make sense of the information from all visual cortex pathways?
      - We don’t know the answer :(
- Audition
  - Sound waves - create rarefaction waves
  - Human can hear: 20K Hz
  - Process
    - Sound waves Tympanic Membrane
    - Tympanic Membrane vibrate bone (3 Ossicles in Middle Ear)
    - Bones vibrate fluids - (in Cochlea )
    - Fluids fluctuate a membrane - (Tectorial membrane)
    - Membrane moves cells (hair cells in the Organ of Corti)
    - Cells open Ion channels
    - Open Ion channels cause depolarization
    - Signal is carried to brain via auditory nerve
  - Auditory Anatomy
    - Outer Ear (Pinna)
    - Middle Ear
      - 3 Ossicles
        
        Malleus (Hammer), Incus (Anvil), Stapes (Stirrup)
    - Inner Ear
      - Cochlea
        
        3 coiling tubes
        
        Scala Vestiboli
        
        Scala Media
        
        Tectorial membrane
        
        Stereocilia (hair cell bundles)
        
        Activated mechanically
        
        Organ of Corti
        
        Scala Tympani
        
        2 membranes
        
        Reissner’s Membrane
        
        Basilar Membrane
        
        Fluids
        
        Endolymph (hi K+, lo Na+) - Scala Media - -80mV
        
        Perilymph (lo K+, hi Na+) - Scala Vestiboli and Scala Tympani
      - Semicircular Canals - Balance
      - Vestibule
    - Subcortical Auditory Pathways
      - Cochlear Nucleus
        
        Arranged tonotopically
      - Superior Olive
        
        Where both ear signals are integrated
      - Inferior Colliculus - Midbrain
        
        Helps orient towards sound
      - Medial Geniculate Nucleus (MGN)
        
        Process audio, Helps maintain attention to specific sound
      - Auditory Cortex
        
        Located in areas 41 and 42
        
        Where audio is processed consciously
        
        Layers
        
        A1: Few cell bodies (Primary Processing)
        
        Each cell is tune to each frequency
        
        Isofrequency bands - columns of A1 cells
        
        A2: Pyramidal neurons (Specialized Processing)
        
        Phonemes (da, ba, la, etc)
        
        A3: Pyramidal neurons
        
        A4: Granule cells
        
        A5: Pyramidal neurons
        
        A6: Pyramidal neurons
  - Intensity control
    - Impedance Matching
    - Gating - muscles contraction to protect from loud noises and when speaking
  - Frequency Detection
    - Basilar membrane decreases in width
    - Total membrane length 30 mm
    - Basilar membrane: Tonotopic Map
      - Apex - low - 20Hz
      - Base - high - 20KHz
    - Place Coding: Stereo cilia activates according to position along membrane
  - Amplitude Detection
    - Level of activity of the hair cells
  - Localization
    - Interaural Time Differences = ITDs (0.5ms between ears)
    - Endbulb of Held
      - Large enveloping synapses that conduct signals better
      - Differential firing is used to ascertain Left/Right input
    - Interaural Level Differences = ILDs
      - Propagation distance: intensity decreases over distance
  - Auditory Issues
    - Conduction Deafness
      - Caused by damage on the physical auditory channel
    - Sensorineural Deafness
      - Damage to inner ear - hair cells
      - Aging, trauma, disease, genetic
      - Can be partially fixed with Cochlear implant
- Taste (Gustation)
  - Factors that affect taste
    - Chemical Perception
    - Smell
    - Texture
    - Temperature
    - Pain
  - Axes of Taste
    - Sweet: Sugars, Starches
    - Salty: Na+, K+
    - Sour: Acids - H+
    - Bitter: Bless, Toxins
    - Umami: MSG, Soya sauce
  - Anatomy
    - Tongue
      - Taste Buds
      - Taste receptor cells
      - Gustatory Nerve Fibers
  - Pathways
    - Cells not receptors carry neurological meaning
    - Receptors only detect chemicals but the taste is dictated by the cell
- Olfaction
  - Slower than vision and audio (2 secs to register, many seconds to reset)
  - Most processing happens in the right side of the brain
  - Odor
    - How the odorant is perceived
    - Odorant is the chemical that binds to olfactory receptors
    - Compound must be volatile
    - Hydrophobic = doesn’t mix with water
  - 1000 categorized genes that detect odor
    - Many are pseudogenes
      - Dogs 80% are expressed
      - Humans only 40% expressed
  - Shape-Pattern Theory
    - Explains how super-tasters can distinguish up to 100K odors
    - Stereoisomers
      - d-carvone - caraway smell
      - I-carvone - Spearmint
    - Quantity, Timing, and Order affect smell perceived
  - Pathways
    - Nostrils
    - Olfactory Epithelium
      - Supporting cells
      - Basal cells
      - Olfactory Sensory Neurons
      - Olfactory Nerve: regenerates! - studied to learn to regeneration in nerves
      - Olfactory Bulb
      - Primary Olfactory Cortex
        
        Amigdala
        
        Hippocampus
        
        Limbic System (emotion, memory, behavior, motivation)
        
        This explains why smells can trigger memories and emotions
  - Problems
    - Anosmia: loss of smell
      - Due to trauma and aging
      - by age 85 about 50% population is anosmic
      - Anosmia causes loss of taste
- Touch (Somatosensory receptors)
  - Modes: Pressure, Stretch ,Temperature ,Vibration
    - Proprioception: body movement
    - Mechanoreception: touch
    - Thermoception: temperature
    - Nociceotion: pain
  - Cutaneous Sensations
    - Touch, pressure, heat, cold, pain
    - Free nerve endings: heat, cold, pain
      - Transient receptor potential channels (TRP)
        
        Pressure, volume, stretch, vibration, tastes
      - More cold receptors than heat receptors (heat receptors are deeper)
  - Processing
    - Primary, secondary, tertiary neurons
    - Cortex sensation is arranged somatotopically
- Motor System
  - We know less about how it works as we trace motor impulses back to the brain
  - Inputs
    - Vestibular System, Proprioception
  - Anatomy
    - Muscles
      - Cardiac Muscle
      - Smooth Muscle
      - Skeletal Muscle
        
        Myocytes: main type of muscle cell. Elongated with perpendicular Striations
        
        Multiple Nuclei
        
        Filled with Myofibrils: long bands of protein
        
        Actin: thin filaments
        
        Myosin: thick filaments
        
        Muscle Contraction
        
        Myosin binds to Acting that causes filaments to slide against one another
        
        Sarcomeres: main Myocytes units
        
        Axial Musculature
        
        Proximal Musculature
        
        Distal Musculature
        
        Facial musculature: brain nerve 7
    - Lower Motor Neurons
      - Also knowns as Alpha motor neurons
      - Final common pathway
      - Motor Units: bundles of motor neurons from the spinal cord
      - Henenman’s Size Principle: motor units are fired in size order which allows to vary applied force
    - Dorsal Ganglion Root Cells
    - Excitatory & Inhibitory Spinal Interneurons
    - Upper Motor neurons: connect to the brain
      - Penfield: Canadian neuroscientist pioneered brain study via electrodes
      - Created the Homunculus (small man) cortical map of muscle activation
      - From area M1
    - Cortocospinal Neurons
  - Intrinsic Motor circuits
    - Reflexes
      - Short
      - Automatic
      - Involuntary
      - Myotatic Stretch Reflex: compensates for sudden muscle stretches.
        
        Muscle Spindle detects stretch via Proprioceptors
        
        Intrafusal Muscle fibers: detect stretch
    - Central Pattern Generators
      - Helps locomotion, walking, fish tail movement
  - Brain control of movement
    - Dorsolateral Path
      - Fina motor control of extremities
    - Ventromedial Path
      - Controls posture
  - Problems
    - Total Locked In Syndrome
    - Motor Cortex Lessions
      - One side affects the other, contralateral side
      - Paresis: muscle weakness
      - Hypertonia: too much tension
      - Hyperreflexia
- 9 Subcortical Brain Areas
  - Function
    - Most vital functions
    - Works autonomously and can override conscious inputs (breathing)
  - Parts:
    - Hindbrain
      - Functions
        
        Heart rate
        
        Respiration
        
        Swallowing
      - Parts
        
        Brain Stem
        
        Medulla
        
        Connect to higher brain
        
        Posture
        
        Protective motor reflexes
        
        Coughing, sneezing and swallowing
        
        ANS: Autonomic Nervous Systems
        
        Breathing, Hear rate, blood pressure, digestion
        
        Interacts with the sympathetic and parasympathetic nervous system
        
        Pons (bridge)
        
        Relay station between the medulla, cortex, cerebellum
        
        Pontine nuclei
        
        Sleep, respiration
        
        Swallowing, chewing, bladder control,
        
        Some eye movement, facial expressions, and upright posture
        
        Reticular formation
        
        Runs throughout the brain stem
        
        Note: Brain Stem injuries can cause instant death
        
        Disease: Central Pontine Myelinosis
        
        Loss of myelin in axons which inhibits signal transmission
        
        All brain stem related functions can be affected
        
        Locked In Syndrome (LIS): worsened scenario where patience is aware but immobile
    - Midbrain
      - Functions:
        
        Vision, hearing, motor control
        
        Sleep/wake cycle
        
        Alertness
        
        Temperature regulation
      - Parts:
        
        Tectum: top part
        
        Auditory and visual reflexes
        
        Parts:
        
        Colliculi (little hills)
        
        Superior Colliculi
        
        Ocular muscle reflex control - eye orientation
        
        Present during REM sleep
        
        Inferior Colliculi
        
        Auditory processing
        
        Orientation control: startle response
        
        Cerebral Peduncles
        
        Bridge motor impulses between neocortex and lower brain areas
        
        More involved in voluntary body movement
        
        Tegmentum
        
        Controls voluntary movements, various reflexes and homeostatic circuits
        
        Hunger, thirst, sex, habitual automatized behavioral patterns
        
        Substantia Nigra
        
        Tied to basal ganglia and motor function
        
        Is a dark area due to presence Melanin
        
        Synthesizers many dopamine neurotransmitters
        
        In Parkinson’s disease this area decays
    - Cerebellum
      - Contains 50% of all brain neurons
      - Functions
        
        Motor programming
        
        Motor learning
        
        Language
        
        Maybe involved in the pathogenesis of several neuropsychiatric disorders such as autism
      - Anatomy:
        
        Purkinje Cells
        
        Very large neuron cells with huge dendritic arbors in outer layer
        
        GABA, Inhibitory
        
        Information only leaves the cerebellum though these cells
        
        Due to consistent parallel fiber stimulation they fire about 70 times per second atomically inhibiting the cerebellar nuclei
        
        Climbing fiber activation is much more rarer but can yield more permanent changes in the excitability of Purkinje cells
        
        Climbing fiber stimulation is thought to underlie motor learning in the Cerebellum
        
        Granule Cells
        
        Smallest neuron cells in inner layer
        
        Glutamate, Excitatory
        
        Mossy fibers
        
        One mossy fiber innervates hundreds of granule cells
        
        Climbing fibers
        
        Come from the medulla region Inferior Olivary
        
        Each connect with about 10 Purkinje cells in about 300 places each
        
        Parallel fibers
        
        Axons of the granule cells which split into the top most cortical layer
        
        Run in parallel to the folds of the cerebellar cortex
        
        Run perpendicular to the Purkinje cell dendritic arbors
      - Modulatory input also comes via dopaminergic, serotonergic, noradrenergic and cholinergic pathways
    - Forebrain (prosencephalon)
      - Anatomy
        
        Cerebral cortex
        
        Basal Ganglia
        
        Functions
        
        Voluntary movement
        
        Emotional & Cognitive functions
        
        Procedural Learning (learning piano, tennis)
        
        Anatomy
        
        Pathways
        
        Direct
        
        Excite thalamic neurons
        
        Indirect
        
        Inhibit thalamic neurons
        
        Pathology
        
        Extrapyramidal Syndromes: imbalance between direct/indirect pathways
        
        Parkinson’s Disease (PD): loss of dopaminergic neurons in the substantial nigra
        
        This reduces Basal Ganglia’s pathways indirect activity
        
        Huntington’s Disease (HD): choreiform movements. Involuntary abrupt movements. Opposite of PD. Affect extremities and face.
        
        Striatum damage which affects indirect pathways
        
        Thalamus
        
        Relay station between sensory and subcortical structures and higher subcortical cortex
        
        Connected to most information pathways in the brain
        
        Referred to as the Gateway of the cortex
        
        Some sensory processing
        
        State regulation (arousal, awareness)
        
        Pathology
        
        Damage can lead to permanent comma
        
        Fatal Familial Insomnia: inability to fall sleep leading to death
        
        Limbic System
        
        Functions
        
        Rewards, reinforcements, threats, punishment
        
        Creates emotional and motivational context
        
        Controls fear, pleasure, adrenaline
        
        Formation of memories (emotional memories)
        
        Anatomy
        
        Olfactory bulbs
        
        Hippocampus (seahorse)
        
        Two, one on each brain side
        
        Consolidating memories
        
        Spatial navigation: place cells
        
        H.M case: could not form short-term memories (anterograde amnesia)
        
        Neurogenesis happens here which may help in write over existing memories
        
        Amygdala (almond)
        
        The are two amygdala
        
        Taste, touch, small, vision, olfactory
        
        olfactory nerves connect directly, others via Thalamus and else
        
        Memory, decision making
        
        Associated with emotional states
        
        Associations are formed via Emotional Conditioning
        
        Anterior Thalamic Nuclei
        
        Fornix
        
        Septum
        
        Habenula,
        
        Cingulate Gyrus
        
        Limbic Cortex
        
        Midbrain areas
        
        Hypothalamus
        
        Thermostat for the body’s internal milieu (temperature, heart rate, plasma sodium concentration)
        
        Homeostasis: steady state of equilibrium and physiological constancy
        
        Engages autonomous nervous system, endocrine system, behavioral system
        
        Send commands to the brain stem and the spinal cord that activate autonomic preganglionic neurons to mount a fight/flight/rest and digest response
        
        Activates basal ganglia and cortex
        
        Controls hormone release via the Pituitary Gland
        
        Triggers thirst, hunger, fatigue, need for sleep, circadian rhythms
        
        When cold it triggers a response (shivering, artery constriction, increased metabolism)
        
        Regulates sex drive, parenting, and attachment behaviors
        
        Pathology
        
        Hypothermia
        
        Appetite disruption
- Brain Anatomy (3.7)
  - re: https://www.mcb80x.org/course/the_brain/brain_anatomy/overview
  - Visual System
    - 125 million photoreceptors (rods and cones) in the retina
  - Auditory System
  - Olfactory System
  - Gustatory System
  - Motor System

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