NeuroscienceCrystal SigulinskyNeuroscience Graduate ProgramUniversity of Utahcrystal.cornett@utah.edu

Housekeeping NotesPosting lectures online Writing AssignmentListed as #4 due Monday July 7th July 6th = MondayOffice hoursFriday, July 3rd, 5-6 pm, Moran Eye Center 3rd floor lobbyBy appointmentTest Friday, July 10th

Physics in Visual ProcessesImaging in the eyeOpticsAbsorption of light in the eyeQuantum mechanicsNerve conduction Visual Information Processinghttp://en.wikipedia.org/wiki/File:Gray722.pngGray's Anatomy of the Human Body, 1918

NeuroscienceScientific study of the nervous systemHighly interdisciplinaryStructure/functionDevelopment/EvolutionGeneticsBiochemistryPhysicsPhysiologyPathologyInformatics/Computational

http://en.wikipedia.org/wiki/Image:Sagittal_brain_MRI.JPG

ObjectivesBasic Anatomy of the Nervous SystemOrganizationCellsNeuronsStructureMechanism of functionModeling neuronsNeurodegenerative Diseases

Nervous SystemMulticellular organismsSpecialized cellsComplex information processing systemInnervates the entire bodySubstrate for thought and functionGathers informationExternal = Organisms environmentInternal = Organisms selfProcessingResponse initiatedPerceptionMuscle activityHormonal change

Nervous System Anatomy: Gross OrganizationCentral Nervous System (CNS)Brain Spinal cordPeripheral Nervous System (PNS)Cranial and spinal nervesMotor and sensorySomatic NSConscious controlAutonomic NSUnconscious controlhttp://en.wikipedia.org/wiki/File:Nervous_system_diagram.png

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

Nervous System Anatomy: CellsNeurons (Nerve Cells)Receive, process, and transmit information

GliaNot specialized for information transferPrimarily a supportive role for neurons

Neuronshttp://en.wikipedia.org/wiki/NeuronWei-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

NeuronsNeuron DoctrineSantiago Ramon y Cajal, 1891The neuron is the functional unit of the nervous systemSpecialized cell typeVery diverse in structure and functionSensory, interneurons, and motor neuronshttp://en.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_CajalAbove: sparrow optic tectumBelow: chick cerebellum

Neuron: StructureAxon hillock Axonhttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

Neuron: Structure/FunctionSpecially designed to receive, process, and transmit informationDendrites: receive information from other neuronsSoma: cell body, contains necessary cellular machinery, signals integrated prior to axon hillockAxon: transmits information to other cells (neurons, muscles, glands)Polarized Information travels in one directionDendrite soma axonAxon hillockhttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

GliaMajor cell type of the Nervous System~10X as many glia as neuronsNot designed to receive and transmit informationDo influence information transfer by neuronsGlia = Glue (Greek)Support neuronsMaintain a proper environmentSupply oxygen and nutrientsClear debris and pathogensGuide developmentModulate neurotransmissionMyelination

Glia: TypesMacrogliaAstrocytesRegulate microenvironment in CNSForm Blood-Brain BarrierOligodendrocytesMyelinate axons of the CNSSchwann CellsMyelinate axons of the PNSMicrogliaClean up in the CNShttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

How do neurons work?Function Receive, process, and transmit informationSignalsChemical Electrical

BioelectricityElectric current generated by living tissueHistoryhttp://en.wikipedia.org/wiki/File:Electric-eel2.jpghttp://en.wikipedia.org/wiki/File:Torpedo_fuscomaculata2.jpgElectric Rays (Torpedos) Electric Eels

BioelectricityElectric current generated by living tissueHistoryElectric fish"Animal electricityLuigi Galvani, 1786Role in muscle activityInspiration behind Voltas development of the batteryhttp://en.wikipedia.org/wiki/File:Galvani-frog-legs.PNG

BioelectricityElectric current generated by living tissuesMotion of positive and negative ions in the bodyEssential for cellular and bodily functionsStorage of metabolic energyPerforming workCell-cell signalingSensationMuscle control Hormonal balanceCognitionImportant Diagnostic Tool

How do neurons work?Function Receive, process, and transmit informationUnidirectional information transferSignalsChemical Electrical

What is the electrical state of a cell?

Membrane PotentialDifference in electrical potential across cell membraneGenerated in all cellsProduced by separation of charges across cell membraneIon solutionsExtracellular fluidCytoplasmCell membrane Impermeable barrierIon channelsPermit passage of ions through cell membranePassive (leaky channels) = with gradientActive = against gradientResting membrane potentialKCl Simple Model

Driving ForcesChemical driving forceFicks First Law of Diffusion Species move from region of high concentration to low concentration until equilibriumPassive mechanismElectrical driving forceCharged species in an electric field move according to chargePassive mechanism

Nernst EquationCalculates the equilibrium potential for each ion

R = gas constant, T = temperature, F = Faraday constant, z = charge of the ionAssumptions:Membrane is permeable to ion Ion is present on both sides of membrane

Ion Distributions[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 mMCytoplasmExtracellular FluidCell Membrane--------++++++++

Driving ForcesChemical driving forceFicks First Law of Diffusion Species move from region of high concentration to low concentration until equilibriumPassive mechanismElectrical driving forceCharged species in an electric field move according to chargePassive mechanismNa+/K+ pumpActive transport pump3Na+ out of cell2 K+ into cell Aids to set up and maintain initial concentration gradients

Resting Membrane PotentialActually 4 ions (K+, Na+,Cl-, Ca2+) that strongly influence potentialGoldman-Hodgkin-Katz Equation Takes into account all ionic species and calculates the membrane potential

P = permeabilityProportional to number of ion channels allowing passage of the ionNot specific to the resting membrane potential Can replace p with conductance (G) and [ion]in/[ion]out with EionGreater the membrane permeability = greater influence on membrane potentialPermeability: PK: PNa: PCl = 1 : 0.04 : 0.45 Cl- typically not pumped, so at equilibriumK+ dominates because greatest conductance Resting membrane potential usually very negative -70 mV

Electric SignalsDeviation in the membrane potential of the cellDepolarizationReduction of charge separation across membraneLess negative membrane potentialHyperpolarizationIncrease in charge separation across membraneMore negative membrane potentialCause: Ion channels open/closeLarge change in permeability of ions relative to each otherNegligible change in bulk ion concentrations!Induce changes in net separation of charge across cell membrane

Goldman equation only applies to steady state

Electric SignalsInitiated by discrete eventsSensory neuronsExamples:Vision: photoreceptors - absorb light triggering a chemical signaling cascade that opens voltage-gated ion channelsTouch: mechanoreceptors - mechanical pressure or distortion opens stress-gated voltage channelsNeuron-neuron, neuron-muscle, neuron-glandChemical signals open ligand-gated ion channels at the Synapse

SynapseFunctional connections between neuronsMediates transfer of informationAllows for information processingAxon terminal talks to dendrite of another neuronNeurotransmitters activate ligand-gated ion channelshttp://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg

Electric SignalsDeviation in the membrane potential of the cellSpread according to different mechanismsElectrotonic conductionDendrites Action PotentialAxons

Neuron: StructureAxon hillock Axonhttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

Electrotonic ConductionPassive spread of electrical potentialInduced point increase in ion concentrationNa+ channels openedNa+ flows into cellMembrane potential shifts toward Na+ equilibrium potential (positive)Depolarization Diffusion of ionsChemical gradientCharge (electrical) gradient Potential dissipates as distance from source increasesNa+

Electrotonic ConductionPotential dissipates as distance from source increasesGraded PotentialsSummation Spatially Multiple sources of ion flux at different locationsTemporallyRepeated instances of ion flux at same locationAllows for information processing

ProcessingA single neuron receives inputs from many other neuronsInput locationsDendrites principle siteSoma low occuranceInputs converge as they travel through the neuronChanges in membrane potential sum temporally and spatiallyhttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

Transmitting InformationSignal inputs do not always elicit an output signalChange in membrane potential must exceed the threshold potential for an action potential to be producedMylenated axons Axon hillock = trigger zone for axon potentialUnmyelenated axonsAction potentials can be triggered anywhere along axonhttp://en.wikipedia.org/wiki/File:Action_potential_vert.pnghttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

Action PotentialsAll-or-none principleSufficient increase in membrane potential at the axon hillock opens voltage-gated Na+ channelsNa+ influx further increases membrane potential, opening more Na+ channelsEstablishes a positive feedback loop Ensures that all action potentials are the SAME sizeAlso, complete potential is regenerated each time, so does not fade outTurned off by opening of voltage gated K+ channelshttp://faculty.washington.edu/chudler/ap.htmlhttp://en.wikipedia.org/wiki/File:Action_potential_vert.pngFigure: Ion channel openings during action potential

Action Potential PropagationVelocityAction potential in one region of axon provides depolarization current for adjacent regionPassive spread of depolarization is not instantaneousElectrotonic conduction is rate-limiting factorUnidirectional Voltage gated channels take time to recoverCannot reopen for a set amount of time, ensuring signal travels in one direction

Transmitting Information Presynaptic action potential causes a change in membrane polarization at the axon terminalsVotage-modulated Ca2+ channels open Neurotransmitter is releasedActivates ligand-gated ion channels on dendrites of next cellhttp://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svgThe Synapse

Modeling NeuronsNeurons are electrically activeModel as an electrical circuitBattery Current (i) generatorResistorCapacitor

Membranes as CapacitorsCapacitorTwo conductors separated by an insulatorCauses a separation of chargePositive charges accumulate on one side and negative charges on the otherPlasma MembraneLipid bilayer = insulatorSeparates electrolyte solutions = conductors

http://en.wikipedia.org/wiki/File:NeuronCapacitanceRev.jpg

Ionic Gradients as BatteriesConcentration of ions differ between inside the neuron and outside the neuronAdditionally, Na+/K+ pump keeps these ions out of equilibriumIon channels permeate the membraneSelective for passage of certain ions Vary in their permeability Always open to some degree = leakyNet Result: each ionic gradient acts as a batteryBattery Source of electric potential An electromotive force generated by differences in chemical potentialsIonic batteryVoltage 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 neuronEstablish the resting membrane potential of the neuron

Ion Channels as ResistorsResistor Device that impedes current flowGenerates resistance (R)Ion channels vary in their permeability LeakyAlways permeable to some degreePermeability is proportional to conductivityConductance (g) = 1/RIon channels modeled as a battery plus a resistorLeak channelsLinear conductance relationship, gL Voltage-gated channelsNon-linear conductance relationship, gn(t,V)

Neuron modeled as an Electrical CircuitIon pumpCreated by Behrang Amini http://en.wikipedia.org/wiki/File:Hodgkin-Huxley.jpg

Cable EquationDescribes the passive spread of voltage change in the membrane of dendrites and axons

Time constant ()Capacitor takes time to rearrange chargesLength constant ()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

Hodgkin-Huxley ModelDescribes how action potentials in neurons are initiated and propagatedNrets at en.wikipediahttp://en.wikipedia.org/wiki/File:MembraneCircuit.jpg

Neuron Design ObjectivesMaximize computing powerIncrease neuron densityRequires neurons be smallMaximize response abilityMinimize response time to changes in environmentRequires fast conduction velocities

Passive Electrical PropertiesLimitations to the design objectivesAction potential generated in one segment provides depolarization current for adjacent segmentMembrane is a capacitorTakes time to move chargesRate of passive spread varies inversely with the product of axial resistance and capacitance= raCm

Passive Electrical PropertiesMembrane Capacitance (C)Limits the conduction velocityV = Ic x t / C, where Ic = current flow across capacitor, t = time, and C = capacitanceTakes 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 ()

Lipid bilayer = great insulator properties and very thin = high capacitanceSmaller neuron = smaller area = shorter time to change membrane potential = faster conduction velocity

Passive Electrical PropertiesAxial resistance (ra)Limits conduction velocityOhms Law: V = I x ra ra = /a2 = resistance of cytoplasm, a = cross-sectional area of processIncreases with decreasing axonal radiusLarger axon = smaller axial resistance = larger current flow = shorter time to discharge the capacitor around axon = faster conduction velocity

Passive Electrical PropertiesInput resistance (Rin)Limits the change in membrane potentialOhms Law: V = I x Rin Rin = Rm/4a2Rm = specific membrane resistanceFunction of ion channel density and their conductanceRin = function of Rm and cross sectional area of processSmaller axon = fewer channels and smaller area = greater resistance = smaller current for a given membrane potential = longer time to discharge capacitor = slower conduction velocities

Increasing Conduction VelocityIncrease axon diameterAxial resistance decreases in proportion to square of axon diameterCapacitance increases in direct proportion to diameterNet effect Increased diameter reduces raCm Increases rate of passive spreadGiant axon of squidAxon diameter = 1 mmLimitations:Need to keep neurons small so can increase their numbersEnergy cost also increases with larger axon diameter

Increasing Conduction VelocityMyelination of axonsWrapping of glial membranes around axonsIncreases the functional thickness of the axonal membrane100x thickness increaseDecreases capacitance of the membrane

Same increase in axonal diameter by myelination produces larger decrease in raCmMore effective increase of conduction velocity

MyelinLipid-rich substanceProduced by Schwann cells and Oligodendrocytes that wrap around axonsGaps between = Nodes of Ranvierhttp://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

Action Potential PropagationMyelin decreases capacitanceDepolarization current moves quickly Current flow not sufficient to discharge capacitance along entire length of axon Length > 1 mMyelin sheath interrupted every 1-2 mmNodes of RanvierExposed bare membrane (~2 um)Increases capacitanceDepolarization current slowsHigh density of Na+ channelsIntense depolarizationRegenerates full depolarization of amplitudePrevents action potential from dying outSaltatory ConductionAction potential hops from one node of Ranvier to the next, down the axonFast in myelinated regionsSlow in bare membrane regionsIon flow restricted to nodes of RanvierImproves energy efficiency NS uses >20% of bodys metabolic energy!!High resistance of myelinated membrane reduces current leakLess work by Na+/K+ pump

Demyelination Loss of the myelin sheath that insulates axonsExamples:Multiple sclerosisAcute disseminated encephalomyelitisAlexanders DiseaseTransverse myelitisChronic inflammatory demyelinating neuropathyCentral pontine myelinosisGuillain-Barre SyndromeResult:Impaired or lost conductionNeuronal deathSymptoms vary widely and depend on the collection of neurons affected

Multiple Sclerosismultiple scarsAutoimmune conditionImmune system attacks CNSKills oligodendrocytes2-150 affected in 100,000 peopleMore prevalent in womenOnset in young adults Physical and cognitive symptomsArise from loss of myelination impairing axon conductionStart as discrete attacksProgress to chronic problemsSymptoms vary greatlyChanges in sensationNeuropathic painMuscle weakness, spasms, or difficulty movingDifficulty with coordination and balanceSpeech, swallowing or visual problemsFatigueCognitive impairment

Nervous System Anatomy: Gross OrganizationInnervates every part of the bodyHierarchical organization

http://en.wikipedia.org/wiki/File:Nervous_system_diagram.png

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

Nervous System Anatomy: Gross OrganizationInformation processing in the brain is highly parallelLocalization of function Parallel streams of information in separate tracts and nuclei Hierarchical processing schemeInformation is relayed serially from one nucleus to the next Each nucleus performs a specific processing step More and more abstract information is extracted from the sensory inputs

Neuronal DeathOne of few non-regenerating cell populationsAxons can re-grow if cell body survivesTargetderived neurotrophic signalsNecessary for survivalBarriers to re-growthScar tissueAbsence of appropriate developmental guidance signalsLoss of signalSwitch in response to signal

Neurodegenerative DiseasesAtaxiaConditions causing problems with movementsCerebellar ataxiaCerebellum affected coordination of movementsSensory ataxiaDorsal columns affected diminished sensitivity to joint and body part positionVestibular ataxia Vestibular system affected disequilibrium and vertigoDimentiaConditions affecting cognitive functionCortical or subcortical areas affected

Alzheimers DiseaseMost common type of dimentiaDegenerative diseaseTerminalSymptoms varyMemory lossParticularly recent memoriesConfusionAngerMood swingsLanguage problemsLong term memory lossSufferer eventually withdraws as senses declineAssociated with plaques and tangles in the brain

Parkinsons DiseaseCommon type of ataxiaDegenerative, chronic and progressiveInsufficient production of the neurotransmitter dopamineReduced stimulation of the motor cortex by the basal ganglia Characteristic symptomsMuscle rigidityTremor Slowing or loss of physical movementEventually high level cognitive and language problemshttp://en.wikipedia.org/wiki/File:Sir_William_Richard_Gowers_Parkinson_Disease_sketch_1886.jpg

Vision - one of key senses for humans in their day-to-day living.Lots of physics involved in vision: we will focus on the first three of these. 1) physics of optics involved in imaging, 2) quantum physics of light absorption by the retina, 3) physics of electrical conduction of nerve impulses, 4) Visual processing in the brain

Cajal = father of NeuroscienceNeuron doctrine = central tenet of modern neurosciencePreviously believed that the nervous system was a connected meshwork, not made of individual cells Anatomy determined by functionStudies on static electricityDissected frog on same table, Frog now dead, using a scalpel, which had picked up a charge, touched sciatic nerve (other end of nerve touching different metal) and dead frogs leg contracted, kicking as if alive. Basically found that if touch two ends of muscle with open ends of two different metals that are connected, muscles would contract on dead animalBasic idea for battery weak electrical current produced by crude battery two metals as electrodes and body fluid as the electrolyteElectrical activity in the body = Motion of positive and negative ions in the body

How do neurons generate electrical signals?[A-] = miscellaneous ions and organic ions (proteins)Without pump, Na and K gradients would be highly variable and eventually run downSo what happens during the different stages of information transfer and processing in the neuronDepolarization b/c Na normally>> outside cell than inIon pump keeps the battery charged