# Fundamentals of Neuroscience # 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