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Neuroscience

Neuroscience. Crystal Sigulinsky Neuroscience Graduate Program University of Utah crystal.cornett@utah.edu. Housekeeping Notes. Posting lectures online Writing Assignment Listed as #4 due Monday July 7 th July 6 th = Monday Office hours

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Neuroscience

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  1. Neuroscience Crystal Sigulinsky Neuroscience Graduate Program University of Utah crystal.cornett@utah.edu

  2. Housekeeping Notes • Posting lectures online • Writing Assignment • Listed as #4 due Monday July 7th • July 6th = Monday • Office hours • Friday, July 3rd, 5-6 pm, Moran Eye Center 3rd floor lobby • By appointment • Test • Friday, July 10th

  3. Physics in Visual Processes • Imaging in the eye • Optics • Absorption of light in the eye • Quantum mechanics • Nerve conduction • Visual Information Processing http://en.wikipedia.org/wiki/File:Gray722.png Gray's Anatomy of the Human Body, 1918

  4. Neuroscience • Scientific study of the nervous system • Highly interdisciplinary • Structure/function • Development/Evolution • Genetics • Biochemistry • Physics • Physiology • Pathology • Informatics/Computational http://en.wikipedia.org/wiki/Image:Sagittal_brain_MRI.JPG

  5. Objectives • Basic Anatomy of the Nervous System • Organization • Cells • Neurons • Structure • Mechanism of function • Modeling neurons • Neurodegenerative Diseases

  6. Nervous System • Multicellular organisms • Specialized cells • Complex information processing system • Innervates the entire body • Substrate for thought and function • Gathers information • External = Organism’s environment • Internal = Organism’s self • Processing • Response initiated • Perception • Muscle activity • Hormonal change

  7. Nervous System Anatomy: Gross Organization • Central Nervous System (CNS) • Brain • Spinal cord • Peripheral Nervous System (PNS) • Cranial and spinal nerves • Motor and sensory • Somatic NS • “Conscious control” • Autonomic NS • “Unconscious control” http://en.wikipedia.org/wiki/File:Nervous_system_diagram.png

  8. http://en.wikipedia.org/wiki/File:NSdiagram.png

  9. Nervous System Anatomy: Cells • Neurons (Nerve Cells) • Receive, process, and transmit information • Glia • Not specialized for information transfer • Primarily a supportive role for neurons

  10. Neurons Wei-Chung Allen Lee, Hayden Huang, Guoping Feng, Joshua R. Sanes, Emery N. Brown, Peter T. So, Elly Nedivi http://en.wikipedia.org/wiki/File:Smi32neuron.jpg http://en.wikipedia.org/wiki/Neuron

  11. Neurons • Neuron Doctrine • Santiago Ramon y Cajal, 1891 • The neuron is the functional unit of the nervous system • Specialized cell type • Very diverse in structure and function • Sensory, interneurons, and motor neurons Above: sparrow optic tectum Below: chick cerebellum http://en.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_Cajal

  12. Neuron: Structure Axon Axon hillock http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

  13. Neuron: Structure/Function • Specially designed to receive, process, and transmit information • Dendrites: receive information from other neurons • Soma: “cell body,” contains necessary cellular machinery, signals integrated prior to axon hillock • Axon: transmits information to other cells (neurons, muscles, glands) • Polarized • Information travels in one direction • Dendrite → soma → axon Axon hillock http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

  14. Glia • Major cell type of the Nervous System • ~10X as many glia as neurons • Not designed to receive and transmit information • Do influence information transfer by neurons • Glia = “Glue” (Greek) • Support neurons • Maintain a proper environment • Supply oxygen and nutrients • Clear debris and pathogens • Guide development • Modulate neurotransmission • Myelination

  15. Glia: Types • Macroglia • Astrocytes • Regulate microenvironment in CNS • Form Blood-Brain Barrier • Oligodendrocytes • Myelinate axons of the CNS • Schwann Cells • Myelinate axons of the PNS • Microglia • Clean up in the CNS http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

  16. How do neurons work? • Function • Receive, process, and transmit information • Signals • Chemical • Electrical

  17. Bioelectricity • Electric current generated by living tissue • History Electric Rays (Torpedos) Electric Eels http://en.wikipedia.org/wiki/File:Torpedo_fuscomaculata2.jpg http://en.wikipedia.org/wiki/File:Electric-eel2.jpg

  18. Bioelectricity • Electric current generated by living tissue • History • Electric fish • "Animal electricity” • Luigi Galvani, 1786 • Role in muscle activity • Inspiration behind Volta’s development of the battery http://en.wikipedia.org/wiki/File:Galvani-frog-legs.PNG

  19. Bioelectricity • Electric current generated by living tissues • Motion of positive and negative ions in the body • Essential for cellular and bodily functions • Storage of metabolic energy • Performing work • Cell-cell signaling • Sensation • Muscle control • Hormonal balance • Cognition • Important Diagnostic Tool

  20. How do neurons work? • Function • Receive, process, and transmit information • Unidirectional information transfer • Signals • Chemical • Electrical • What is the electrical state of a cell?

  21. Membrane Potential • Difference in electrical potential across cell membrane • Generated in all cells • Produced by separation of charges across cell membrane • Ion solutions • Extracellular fluid • Cytoplasm • Cell membrane • Impermeable barrier • Ion channels • Permit passage of ions through cell membrane • Passive (leaky channels) = with gradient • Active = against gradient • Resting membrane potential • KCl Simple Model

  22. Driving Forces • Chemical driving force • Fick’s First Law of Diffusion • Species move from region of high concentration to low concentration until equilibrium • Passive mechanism • Electrical driving force • Charged species in an electric field move according to charge • Passive mechanism

  23. Nernst Equation • Calculates the equilibrium potential for each ion • R = gas constant, T = temperature, F = Faraday constant, z = charge of the ion • Assumptions: • Membrane is permeable to ion • Ion is present on both sides of membrane

  24. [Na+] = 15 mM [K+] = 150 mM [Cl-] = 9 mM [A-] = 156 mM [Na+] = 145 mM [K+] = 5 mM [A+] = 5 mM [Cl-] = 125 mM [A-] = 30 mM Ion Distributions Cell Membrane Cytoplasm Extracellular Fluid - - - - - - - - + + + + + + + +

  25. Driving Forces • Chemical driving force • Fick’s First Law of Diffusion • Species move from region of high concentration to low concentration until equilibrium • Passive mechanism • Electrical driving force • Charged species in an electric field move according to charge • Passive mechanism • Na+/K+ pump • Active transport pump • 3Na+ out of cell • 2 K+ into cell • Aids to set up and maintain initial concentration gradients

  26. Resting Membrane Potential • Actually 4 ions (K+, Na+,Cl-, Ca2+) that strongly influence potential • Goldman-Hodgkin-Katz Equation • Takes into account all ionic species and calculates the membrane potential • P = permeability • Proportional to number of ion channels allowing passage of the ion • Not specific to the resting membrane potential • Can replace p with conductance (G) and [ion]in/[ion]out with Eion • Greater the membrane permeability = greater influence on membrane potential • Permeability: PK: PNa: PCl = 1 : 0.04 : 0.45 • Cl- typically not pumped, so at equilibrium • K+ dominates because greatest conductance • Resting membrane potential usually very negative -70 mV

  27. Electric Signals • Deviation in the membrane potential of the cell • Depolarization • Reduction of charge separation across membrane • Less negative membrane potential • Hyperpolarization • Increase in charge separation across membrane • More negative membrane potential • Cause: Ion channels open/close • Large change in permeability of ions relative to each other • Negligible change in bulk ion concentrations! • Induce changes in net separation of charge across cell membrane • Goldman equation only applies to steady state

  28. Electric Signals • Initiated by discrete events • Sensory neurons • Examples: • Vision: photoreceptors - absorb light triggering a chemical signaling cascade that opens voltage-gated ion channels • Touch: mechanoreceptors - mechanical pressure or distortion opens stress-gated voltage channels • Neuron-neuron, neuron-muscle, neuron-gland • Chemical signals open ligand-gated ion channels at the Synapse

  29. Synapse • Functional connections between neurons • Mediates transfer of information • Allows for information processing • Axon terminal “talks to” dendrite of another neuron • Neurotransmitters activate ligand-gated ion channels http://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg

  30. Electric Signals • Deviation in the membrane potential of the cell • Spread according to different mechanisms • Electrotonic conduction • Dendrites • Action Potential • Axons

  31. Neuron: Structure Axon Axon hillock http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

  32. x = 0 Change in Potential Distance (x) Electrotonic Conduction • Passive spread of electrical potential • Induced point increase in ion concentration • Na+ channels opened • Na+ flows into cell • Membrane potential shifts toward Na+ equilibrium potential (positive) • Depolarization • Diffusion of ions • Chemical gradient • Charge (electrical) gradient • Potential dissipates as distance from source increases Na+

  33. Electrotonic Conduction • Potential dissipates as distance from source increases • “Graded Potentials” • Summation • Spatially • Multiple sources of ion flux at different locations • Temporally • Repeated instances of ion flux at same location • Allows for information processing

  34. Processing http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png • A single neuron receives inputs from many other neurons • Input locations • Dendrites – principle site • Soma – low occurance • Inputs converge as they travel through the neuron • Changes in membrane potential sum temporally and spatially

  35. Axon hillock Transmitting Information • Signal inputs do not always elicit an output signal • Change in membrane potential must exceed the threshold potential for an action potential to be produced • Mylenated axons • Axon hillock = trigger zone for axon potential • Unmyelenated axons • Action potentials can be triggered anywhere along axon http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png http://en.wikipedia.org/wiki/File:Action_potential_vert.png

  36. Action Potentials • “All-or-none” principle • Sufficient increase in membrane potential at the axon hillock opens voltage-gated Na+ channels • Na+ influx further increases membrane potential, opening more Na+ channels • Establishes a positive feedback loop • Ensures that all action potentials are the SAME size • Also, complete potential is regenerated each time, so does not fade out • Turned off by opening of voltage gated K+ channels http://en.wikipedia.org/wiki/File:Action_potential_vert.png Figure: Ion channel openings during action potential http://faculty.washington.edu/chudler/ap.html

  37. Action Potential Propagation • Velocity • Action potential in one region of axon provides depolarization current for adjacent region • Passive spread of depolarization is not instantaneous • Electrotonic conduction is rate-limiting factor • Unidirectional • Voltage gated channels take time to recover • Cannot reopen for a set amount of time, ensuring signal travels in one direction

  38. Transmitting Information The Synapse • Presynaptic action potential causes a change in membrane polarization at the axon terminals • Votage-modulated Ca2+ channels open • Neurotransmitter is released • Activates ligand-gated ion channels on dendrites of next cell http://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg

  39. + + i Battery Resistor - + - + - + - + Capacitor Modeling Neurons • Neurons are electrically active • Model as an electrical circuit • Battery • Current (i) generator • Resistor • Capacitor

  40. Membranes as Capacitors • Capacitor • Two conductors separated by an insulator • Causes a separation of charge • Positive charges accumulate on one side and negative charges on the other • Plasma Membrane • Lipid bilayer = insulator • Separates electrolyte solutions = conductors http://en.wikipedia.org/wiki/File:NeuronCapacitanceRev.jpg

  41. Ionic Gradients as Batteries • Concentration of ions differ between inside the neuron and outside the neuron • Additionally, Na+/K+ pump keeps these ions out of equilibrium • Ion channels permeate the membrane • Selective for passage of certain ions • Vary in their permeability • Always open to some degree = “leaky” • Net Result: each ionic gradient acts as a battery • Battery • Source of electric potential • An electromotive force generated by differences in chemical potentials • Ionic battery • Voltage created is essentially the electrical potential needed (equal and opposite) to cancel the diffusion potential of the ions so equal number of ions enter and leave the neuron • Establish the resting membrane potential of the neuron

  42. Ion Channels as Resistors • Resistor • Device that impedes current flow • Generates resistance (R) • Ion channels vary in their permeability • “Leaky” • Always permeable to some degree • Permeability is proportional to conductivity • Conductance (g) = 1/R • Ion channels modeled as a battery plus a resistor • Leak channels • Linear conductance relationship, gL • Voltage-gated channels • Non-linear conductance relationship, gn(t,V)

  43. Neuron modeled as an Electrical Circuit Ion pump Created by Behrang Amini http://en.wikipedia.org/wiki/File:Hodgkin-Huxley.jpg

  44. Cable Equation • Describes the passive spread of voltage change in the membrane of dendrites and axons • Time constant (τ) • Capacitor takes time to rearrange charges • Length constant (λ) • Spread of voltage change inhibited by resistance of the cytoplasm (axial resistance) • Spread of voltage limited by membrane resistance (leak channels) http://en.wikipedia.org/wiki/File:NeuronResistanceCapacitanceRev.jpg

  45. Hodgkin-Huxley Model • Describes how action potentials in neurons are initiated and propagated Nrets at en.wikipedia http://en.wikipedia.org/wiki/File:MembraneCircuit.jpg

  46. Neuron Design Objectives • Maximize computing power • Increase neuron density • Requires neurons be small • Maximize response ability • Minimize response time to changes in environment • Requires fast conduction velocities

  47. Passive Electrical Properties • Limitations to the design objectives • Action potential generated in one segment provides depolarization current for adjacent segment • Membrane is a capacitor • Takes time to move charges • Rate of passive spread varies inversely with the product of axial resistance and capacitance • = raCm

  48. Passive Electrical Properties • Membrane Capacitance (C) • Limits the conduction velocity • ΔV = Ic x Δt / C, where Ic = current flow across capacitor, t = time, and C = capacitance • Takes time to unload the charge on a capacitor when changing potential. • Function of surface area of plates (A), distance between plates (d) and insulator properties (ε) • Lipid bilayer = great insulator properties and very thin = high capacitance • Smaller neuron = smaller area = shorter time to change membrane potential = faster conduction velocity

  49. Passive Electrical Properties • Axial resistance (ra) • Limits conduction velocity • Ohm’s Law: ΔV = I x ra • ra = ρ/πa2 • ρ = resistance of cytoplasm, a = cross-sectional area of process • Increases with decreasing axonal radius • Larger axon = smaller axial resistance = larger current flow = shorter time to discharge the capacitor around axon = faster conduction velocity

  50. Passive Electrical Properties • Input resistance (Rin) • Limits the change in membrane potential • Ohm’s Law: ΔV = I x Rin • Rin = Rm/4πa2 • Rm = specific membrane resistance • Function of ion channel density and their conductance • Rin = function of Rm and cross sectional area of process • Smaller axon = fewer channels and smaller area = greater resistance = smaller current for a given membrane potential = longer time to discharge capacitor = slower conduction velocities

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