Lectures 1-3 NROSCI 1011
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This 23 page Class Notes was uploaded by Alexis Gray on Wednesday September 9, 2015. The Class Notes belongs to NROSCI 1011 at University of Pittsburgh taught by Susan Sesack in Summer 2015. Since its upload, it has received 85 views. For similar materials see Functional Neuroanatomy in Neuroscience at University of Pittsburgh.
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Date Created: 09/09/15
Review of Standard Neurotransmission propagation of the AP down the axon making it depolarized W l if opening of voltagesensitive gated calcium channels at synapse a iPreaynantie 39 aetien petvential i Ca2stimulated vesicle fusion and exocytosis E l inegeaaed preeynaptie quot Ca t ermeabilit release and d1ffus1on of transmitter across synaptic cleft 332 aim 3quot 1 binding to postsynaptic receptors 1 opening or clos1ng of transmittergated ion channels Release m Hammer 1 by emeyteeia at vesiclee alteration of postsynaptic membrane potential depolarization more positive inside excitatory postsynaptic potential EPSP hyperpolarization more negative inside inhibitory postsynaptic potential IPSP spread of membrane potential through dendrite toward soma l alteration of membrane potential at the axon initial segment Heaetien ei transmitter with peeteyneptie recapture E i Activation at synaptic engannele Synaptic current gpredueea quot pastamantis petentiai Leaky Membrane gt Electrical impulses undergo passive spread in some neurons The membrane acts as an imperfect resistor with DSEHEFWE some ions leaking out across the membrane and reducing the amplitude of the membrane potential with distance Stimulate a K quot a Stimulate Hence synapses closest to the soma produce a greater it 39 V 7 change in voltage than those further away In other neurons mechanisms eXist to boost distal signals Excitatery inhibitairy iatt39iwaIur pathway Membrane potential decays over Meterneuren distance EPSP IPSP wattage tritier 39iiime ms 1 S i 55 i 1i 5 ao 2 a a 55 i r i i i E 2 4 s e WISEC FIGURE 31 A Schematic diagram of hypotheticai dendriiic tree with a simplified branching pattern A recording site on the some is indicated by the electrode B Recordings of EPSPs are based on computer simulations The numbers correspond with the numbered la utnns The model calculated the resulting EP SP from a brief hypopularizing event at the boutons indicated Note that the amplitude and time course oi the EPSP as recorded in the some vary considerably depending on the location of the active synapse Boosting distal signals 1 Voltage gated ion channels along the dendritic membrane create patches of active conduction that boost the level of depolarization and counteract the effects of resistance 2 Some distal synapses create higher amplitude synaptic potentials e g more transmitter release or more receptors so that the signal arrives at the initial segment with greater amplitude despite passive decay E E Excitatory synapses tend to be more numerous and distal Inhibitory synapses tend to be less numerous and proximal E inhibitory synapse O excitotory synapse Cells usually must integrate many excitatory inputs each being insuf cient to activate the neuron alone Although mechanisms to boost distal signals help to ensure that these signals are heard they still typically require summation to produce action potentials see below Conversely based on their proximal location only one or a few inhibitory synapses can often prevent activation To discharge a neuron depolarization must exceed the threshold for generation of an AP This is typically achieved by spatial and temporal summation of membrane potentials Hyperpolarizations are also summated and can prevent threshold from being reached E Voltagegated Na channels are concentrated at the axon initial segment giving this region the lowest threshold for AP generation If threshold is reached these channels open creating a signi cant in ux of Na along its concentration and electrical gradients If depolarization is not suf cient to open the channels it decays passively Hence the AP is said to be allornone Figure 1111 Spatial decay of a synaptic potential initiated by an input onto a dendrite Adapted from Eckart and Randall 1989 An excitatory synaptic E potential originating in the dendrites decreases With distance as it propagates passively in the cell E PS P Nevertheless an action potential is Decay likely to be initiated at the axon hillock because the density of the Na N J channels in this region is high and thus the threshold is low The density of Na channels in the cell is indicated by the density of the stippling Dendrites Initial segment Axon Myelln Ce body hillock sheath 30 an 71 g in 10 E U are 10 Aeltiian E 7 potential 15 3I r 3 U a g 50 so quot39 Threshold quot hrshnld a ru IJ s s W r l i H l u lllnhibiterv39 Essiteterv sig39iiiisl 9Egreiitsltenit 2nd excitatory signal arrives adds in signal signal arrives arrives 1st signal arrives summed patentisls pass threshold At the peak of the AP Na channels inactivate and remain closed for several msec during which the cell is 50 refractory and unable to support 5 another AP E 5 Ea Slightly later depolarization opens K channels that conduct more slowly than Na channels K ions efflux along concentration and electrical gradients and this repolarizes the membrane toward rest and sometimes a little beyond after hyperpolarization The NaK ATPase then restores the resting membrane potential 393 Membrane lnaicle r 39 Time h i l 1 millisecond le a Figure 39 When the action potential develops and the membrane patential Shifts 39ralziidlir from all tnilliv ults tuwartl 50 millivnlts the closed sodium channels mp open brie y and then clear again Meartwhllei the many fewer closed parasslum channels pap pEIt and then elm5e more slnwla pmdueing the alterpnrential at 6 quot al 170 rnillivnlt potential mugh positively charged Na aceu mulates to tagger ripening at gate to reach threaheld of till millimlts Figure 3112 Whit sodium channels pup UJlii39ll39l as the action pntentinl Clevelnpa Their elnsetl gates are voltage controlled and have a threshold a few millivnlts less negative than the resting potential In the figure an Na gate just to the left of a elmed Na gate opens Na rushes ln anti because it earner positive Charge makes the voltage at the inaitle at the membrane at the WEEt chased Naif channel leaa negar tire until the threshnld is reached The closed channel pops open and so on along the membrane we Ftppentllxlu The entire axon contains voltagegated Na channels that are opened by membrane depolarization As Na in ux is itself depolarizing this sets off a wave of depolarization that makes the AP active or regenerative ie no loss of amplitude with distance E E E Myelination The speed of AP conduction is proportional to axon diameter But myelination is a more space ef cient mechanism for speeding AP conduction Axons with diameter 1 pm or greater are insulated in myelin a continuous wrapping of plasma membrane from a glial cell The largest axons typically have the thickest myelin Myelinated amna Node m Ranvier Eoma of oligndendroeyte oligodendrocytes in CNS Schwann cells in PNS Peripheral O O I h Mfga a Mi r tUbUIE Whlte matter myelinrich 1e fatty WWW me quot In moplaam 3 axon regions traCtS in thC CNS Mode at Harwiie rv a nerves in the PNS gray matter myelin poor cell regions Multiple glial cells supply the wrapping for a single axonuThe break that occurs where plasma membranes from neighboring glial cells are not continuous is called the node of Ranvier Myelinated divisions between nodes are called internodes Naked Axons Myelin prevents the ow of ions across the membrane so that they travel through the interior of the internodes passive conduction via charge transfer and depolarize the nodes of Ranvier where Na channels are packed and the threshold for AP quotregenerationquot is always reached active conduction This is known as saltatory conduction saltare L to leap or dance which greatly increases the speed of AP transmission and minimizes the use of ion channels and pumps that require energy Site of present action potential unmyelinated axon Outside amp A TE 33E fa Lt Z I V a The smallest unmyelinated Inside axons conduct around 05 msec l milehour and the largest most heavily myelinated axon Outside myelinated axons conduct M elin around 120 msec 268 IA mileshour 9 17 Inside V 1 Multiple sclerosis is an myelinated axon autormmune demyelinating disorder characterized by weakness loss of sensation loss of motor control and blindness Outside Inside 3 CF lin ii iii iiT 3F ii3 ii ll 9 43 ltFjgt 3 1 gt5 W E GE Take up space around neurons Neurog nerve glue VirchowThe brain contains 10X as many glia as neurons CNS PNS astrocytes microglia oligodendrocytes myelination ependymal cells ventricle lining Schwann cells Astrocytes starshaped cells are the major glial type in the CNS They are called protoplasmic in gray matter and brous in White matter Their many functions include structure and support by lling in the extraneuronal space segregation of neuropil constituents development as radial glial cells bufferingnutrient support Ependymra Microglia Oligodendrocytes Blood vessel Bloodvessel quot CB39 395 Astra cyte and feet l39 Kl J Astrocytic end feet contact blood vessel endothelial cells When neuronal activity is high extracellular K builds up and is absorbed by astrocytes Astrocytes then release K onto blood vessels causing them to dilate This increases blood ow to areas of high neuronal activity A51 meme Myal39inated quot BEENquot Simple Circuits grammar or Genmw A circuit is a functional collection of 3km a mmm umn 39i quot l e receptors neurons and effectors that 7 does something The simplest circuit is n a re ex arc between a sensory neuron 739 and a motor neuron The presence of one or more interneurons in the re ex circuit provides opportunities for complex processing and increases variability and exibility Most circuits are more complex than the re ex arc Cell body I of a e rent neuron Hot object i 7 9 Spinal cord Cell body of efferent new FOII I Axon of affan nl neuron efferent neuron im pulse quot Muscle contracts and wilhdraws pant being simulated Central Nervous Peripheral Nervous System Sensory neurons 5 X 106 are bipolar or system pseudounipolar They receive input at a P specialized receptor in the PNS and Q g quot 39 39 39 39 39 39 transmit information in toward the CNS Sensory Afferent Neuron receptor 1 they are afferent E Motor neurons 23 X 105 are multipolar a neurons They transmit information T effector from the CNS out toward an effector in V Motor Efferent Neuron the PNS primarily skeletal or smooth 0 0 muscle they are efferent E I I Interneurons 1011 cells are typically multipolarJThey are neither sensory nor motor neuronsJA11 1of their structure lies within the CNS Note Within nuclei of the CNS the word interneuron is also used to denote a local circuit neuron whose axon does not leave the nucleus This contrasts with projection neurons whose axons travel to other nuclei Convergence In more complex olrcu1ts convergence allows gt for the integration of multiple inputs and EJ increases the probability that a postsynaptic neuron will reach threshold for ring an action potential This is true only if the inputs are active close in time temporal summation GO 00 L 39 Divergence occurs when single neurons form gt axon collaterals that travel to different nuclei and helps to coordinate functions in separate gt target areas 395 Divergence GO GO Lateral inhibition occurs speci cally within sensory systems and this term is generally not used for other systems It occurs when a neuron in one sensory circuit inhibits a neuron in an adjacent EJ sensory circuit Lateral inhibition sharpens sensory signals and blocks out irrelevant stimuli by inhibiting weakly activated neighboring cells Lateral Inhibition O gt O O gt Disinhibition occurs when a neuron is excited by inhibition of an inhibitory input If a neuron is excited by one input and inhibited by another input increased activity in the postsynaptic neuron can be achieved by 1 increasing excitatory drive or 2 decreasing inhibitory drive ie disinhibition Disinhibition TractTracing Methods Which neurons are connected to each other observation by LM and EM retrograde tracing E collateralization anterograde tracing E nonselective tracing transneuronal tracing E horseradish peroxidase E determining the afferents inputs to a region by injecting a tracer that selectively binds to surface glycoproteins on axons is taken up by endocytosis and is transported back to the soma axonal branching patterns determining the efferents outputs from a region by injecting a tracer that selectively binds to surface glycoproteins on soma and dendrites is taken up by endocytosis and is transported out the axons determining a region s efferents and afferents by injecting a tracer that is passively endocytosed Without binding to glycoproteins at either soma dendrites or axons and transported respectively to axons or soma HRP is such a tracer determining the multisynaptic connections of a region by injecting a tracer e g herpespseudorabies virus glradioactive amino acids that is taken up by first order neurons transported released at synapses taken up by second order neurons etc different viral strains are used for either anterograde or retrograde tracing HRP is an enzyme that catalyzes oxidative reactions using hydrogen peroxide as a cofactor Upon oxidation the substrate chromogen forms a colored product HRP is used for either anterograde or retrograde transport and is also used as a marker for immunocytochemistry Injection B A quot C O somaQtC 39 O O ermlna 39 U T2 23353 al Retrograde Axoplasmio Transport Transport lnjection B A squot C O O Q or Q Antero rade soma termlnal g 4 Transneuronal Antemgrade Transport Axoplasmic Transport Axonal Transport 1 I x l I retrograde anterograde injection I o gtQgt gtgtgt7gtgtgtgtQgtgtgtX I I I 1 tracer P endocytosis lt ltlt ltlt lt lt lt lt 6 transport R d etro ra e Transgport i 0 Most tracttracing agents are taken up into cells by endocytosis C l l X Some tracers bind to speci c surface glycoproteins and a trigger internalization see earlier Other tracers do not bind to glycoproteins but are taken up passively from the We Inspect extracellular space by ongoing endocytosis Either way the tracer typically ends up in endocytotic vesicles and is 333 transported l5 5 O 3951 Inject Inspect For correct application of tracing techniques substances must be injected precisely into the desired Brooms 28 The atlas indicates that the amygdaia target site is 28 mm posterior to bregma 45mm brain region The stereotaxm lateral and 85mm ventral apparatus assists in accurate drawn from Paxrnos amp Watson 1982 placement of tracers having metrically graded coordinates in all dimensions Correct coordinates are determined from a brain atlas Animals are anesthetized and mounted into the stereotaXic apparatus A hole is drilled in the skull and a glass pipette containing the tracer is lowered down to the desired site Rub A hole is drilled 28mm posterior to bregma and 45 lateral to it Then the electrode holder is positioned over the hole and the electrode is lowered 85mm through the hole To visualize tracers an appropriate survival time must pass to allow for axonal transport The animal is then anesthetized and perfused with aldehyde fixativesithat harden the brain The brain is then cut into sections on a vibratome or freezing microtome The presence of the tracer in brain tissue must be revealed through some kind of visualization procedure Some compounds e g many retrograde tracers are inherently uorescent and can be revealed by exposing brain sections to uorescent light of an appropriate wavelength Find using fluorescent microscope Tracers that uoresce at different wavelengths allow for experiments to determine the degree of divergence in a pathway ie the presence of cells with collateral projections to two regions Other non uorescent tracers can also be used for this purpose as long as their respective visualization products can be easily distinguished from each other when occurring within soma When HRP is used as a tracer its presence is revealed by providing the enzyme with a substrate a chromogen and cofactor hydrogen peroxide The resulting oxidization reaction creates a visible colored product wherever HRP is present l5 FIXATIVE PERFUSION Retrograde Transport VIBRATOME SECTIONING m 7 I quotl 1 3V neuron with g branched axon HRP O g 30 330 I chromogen gt in moin H202 H RP E Molecular Methods What are the proteins and other molecules in neurons observation by LM and EM immunocytochemistry utilization of antibodies for detection of proteins and small peptides transmitters enzymes receptors ion channels cytoskeletal proteins etc antibodies bind to antigens in tissue but need to be tagged in order to be detected e g With uorescent markers HRP gold particles etc Inject the protein ie antigen into an animal Whose immune system Will make antibodies to it 39 After a few weeks collect blood and isolate the desired antibodies 39 Section the brain of another animal and expose brain sections to a solution containing the antibodies 39 Antibodies Will bind to sites in the tissue that contain the antigen 39 Wash off unbound antibodies 39 Detect the presence of bound antibodies using a Visible tag 39 Some of these markers are also Visible by EM Typical Products Fluorescence light microscope NOT EM Antibody H RP chemically Brain tagged with tissue visible marker SBCtion Labeled neuron Unlabeled pm containing neuron antigen lnjiect antigen Withdraw specific antibodies Immunocytochemistry This method uses labeled antibodies to identify the location of molecules Within cells The molecule of interest for example a transmitter candidate is injected into an animal causing an immune response and the generation of antibodies Blood is Withdrawn from the animal and the antibodies are isolated from the serum The antibodies are tagged With a Visible marker and applied to sections of brain tissue from another animal The antibodies bind to and label cells that contain the antigen ie the transmitter candidate antigencontaining cell typical markers fluorescence antigerl ontaining cell HRP in situ hybridization utilization of complementary cDNA or cRNA strands to detect speci c types omeNA in cells if the strands bind it means that the labeled cell is capable of making that gene product probes are usually radiolabeled for detection the number of silver grains are proportional to the amount of mRNA present Strand of mRNA in neuron Labeled probe with proper sequence of complementary nucleic acids In situ hybridization Strands of mRNA consist of nucleotides arranged in a speci c sequence Each of these nucleotides Will stick to one other complementary nucleotide In the method of in situ hybridization a synthetic probe is constructed Brain that contains a sequence of complementary nucleotides that Will allow it to stick to tissue the mRNA If the probe is labeled the location of cells containing the mRNA will section be revealed enzyme histochemistry providing substrate and cofactor to reveal the presence of speci c enzymes in E tissue e g acetylcholinesterase cytochrome oxidase receptor autoradiography using radiolabeled receptor ligands to reveal the presence of speci c receptors Physiological Methods How can anatomy be used to study function lesion electrical stimulation used to study possible correlations between a brain structure and its physiological or behavioral function 395 39339 interpretational dif culties because the exact extent of damage or current spread is hard to assess and because functionally unrelated processes passing through the area of stimulation or lesion might be disrupted Electrical etimuletien of the motor cortex Hemuueul tie v Stimulating quot electrode elinit5 movements at body parts terresponcliing te the map of the body Movement et bode petite Imaging Methods HoW does What is learned in animals apply to the living human brain 395 computerized tomography positron emission tomography E magnetic resonance imaging E functional MRI E Magnetic Resonance Imaging unstimulated tissue 3 D eoxyhiemoigilobin nyhemoglobin Stimulated tissue CT computer assisted Xray procedure for visualizing the brain in 3D the Xray tube and detector rotate around the head taking short exposure individual measurements that are combined to generate one section PET measurement of metabolic activity by injection of positron emitting isotopes e g C 15O that accumulate in regions of high blood ow the PET detector localizes where the radioactive glucose is concentrated based on the emission of positrons and the gamma rays that result when positrons combine with electrons MRI measurements of waves emitted by hydrogen atoms when activated by radiofrequency pulses in a magnetic eld variation in hydrogen atom concentration in different brain regions creates detailed structural images fMRI measurement of regional cerebral blood ow based on differential proton shifts between oxygenated and deoxygenated forms of hemoglobin and the higher ratio of oxygenated to deoxygenated blood in areas of high neuronal activity Positron emission in the brain iPosiiron annihilation and emission of gamma rays Gamma ray Site of positron annihilation Electron Iimagw point I Unstable O Positron ra dienuciide Gamma ray N detectors I IIIConcentration of Iu Ill iidttlin isigitziti s x A Gamma ray neursil activity I MRI mechanism in brief Hydrogen protons highly charged particles in the hydrogen nucleus spin in random directions When a magnetic eld is applied protons wobble in alignment and the frequency of the wobble is proportional to the strength of the magnetic eld The wobble of certain protons is knocked out of alignment when a brief radio signal is applied whose frequency matches the wobble When the radio signal ceases the protons snap back into alignment with the magnetic eld and emit a radio signal of their own that signi es the composition of the tissue
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