Neuroscience Chapter Notes PDF

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Chapter 1 NotesGenetics, Genomics and the Brain  Gene: hereditary unit located on the chromosomes; genetic information is carried by linear sequences of nucleotides in DNA that code for corresponding sequences of amino acids o Comprises of both coding DNA sequences (exons) - Templates for messenger...

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Chapter 1 Notes Genetics, Genomics and the Brain  Gene: hereditary unit located on the chromosomes; genetic information is carried by linear sequences of nucleotides in DNA that code for corresponding sequences of amino acids o Comprises of both coding DNA sequences (exons) - Templates for messenger RNA (mRNA) to be translated into protein o Regulatory DNA sequences (promoters and introns) - Controls whether and in what quantities a gene is expressed (i.e. transcribed into mRNA and translated into fully functioning protein)  Genomics: scientific field focusing on the analysis of DNA sequences, including both protein-coding DNA (genes) and non-coding DNA (regulatory) o Has provided insight into how nuclear DNA provides instructions for the assembly & operation of the brain  Based on current estimates, the human genome contains 20,000 genes  14,000 expressed in developing and/or mature brain o Out of this 14,000, about 8000 are expressed in all cells and tissues o 6000 “brain specific” genes reside in introns & regulatory sequences that control timing, quantity, variability and cellular specificity of gene expression  How the gene varies in level and location (the differences) are the foundation of diversity & complexity of brain functions  Despite the number of genes shared among the brain and other tissues, individual genes vary in the level and location of expression in specific brain regions & cells (i.e., the amount of mRNA expressed from region to region)  these differences are the foundation of the diversity and complexity of brain functions  When one/few genes are altered/mutated, can explain at least some of the pathology of important neurological and psychiatric diseases o Single-celled mutations have been found that, although rare, results in devastating changes in brain development and function  eg. mutation in a single gene that regulates mitosis can result in microcephaly o Mutant genes have been found that can cause disorders eg. Parkinson’s  Relationship between genotype & phenotype isn’t just the result of following genetic instructions, and genomic information alone cannot explain how the brain operates in normal individuals, or how disease processes disrupt normal brain functions The Cellular Component of the Nervous System  Not until well into 20th century that neuroscientists agreed that nervous tissue, like all other organs, is made up of the fundamental units of all living organisms  First generation of neuroscientists in 19th century had difficulty resolving the unitary nature of nerve cells with the microscopes & cell staining techniques then available o Extraordinarily complex shapes & extensive branches of individual nerve cells – difficult to distinguish from one another since they’re all packed together –

further obscured their resemblance to the geometrically simpler cells of other tissues

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Golgi’s “reticular theory” (idea that each nerve cell was connected to its neighbour by protoplasmic links, forming a continuous nerve cell network, or reticulum) was replaced by the “neuron doctrine” (Cajal argued that nerve cells are discrete entities, and Sherrington came up with specialised cell contacts called synapses as a method of electrical signal transfer at synaptic junctions) o Any lingering doubts about the neuron doctrine were resolved with the arrival of electron microscopes in 1950s o Electron microscopes also demonstrated specialised (albeit relatively rare) intercellular continuities between some neurons – gap junctions – which allow for cytoplasmic continuity and the direct transfer of electrical & chemical signals between cells in the nervous system Studies of Cajal, Golgi and others led to consensus that cells of the nervous system can be divided into 2 broad categories – nerve cells/neurons + supporting glial cells o Nerve cells/neurons: cells specialised for the conduction & transmission of electrical signals over long distances in the nervous system o Glial cells: (also called neuroglia or glia) support cells associated with neurons - Support rather than generate electrical signals - Essential contributors to repair of damaged nervous system acting as stem cells in some brain regions, promoting regrowth of damaged neurons in regions where regeneration can usefully occur, and

preventing regeneration in other regions where uncontrolled regrowth might do more harm than good Neurons  Distinguished by their specialisation for intercellular communication & moment-tomoment electrical signalling  seen in their overall morphology, organisation of their membrane components for long-distance signalling, and in the structural & functional intricacies of the synaptic contacts between neurons o Most obvious morphological sign of neural specialisation for communication is the extensive branching of neurons  2 aspects for typical nerve cells = presence of an axon + the elaborate arborisation of dendrites (arise from the neuronal cell body in the form of dendritic branches/dendritic processes) - Axon: neuronal process that carries the action potential from the nerve cell body to the target - Dendrite: neuronal process arising from the axon terminals of other nerve cell bodies that receives synaptic input  Distinguished by their high content of ribosomes + specific cytoskeletal proteins  Number of inputs a particular neuron receives depends on the complexity of its dendritic arbor o Number of inputs to a single neuron reflects the degree of convergence, while the number of targets innervated by any one neuron represents its divergence  Axon terminal of the presynaptic neuron is immediately adjacent to a specialised region of postsynaptic receptors on the target cell o Presynaptic: the component of a synapse specialised for transmitter release; upstream at a synapse o Postsynaptic: the component of a synapse specialised for transmitter reception; downstream at a synapse o Pre- and postsynaptic components communicate via the secretion of molecules from the presynaptic terminal that bind to receptors in the postsynaptic terminal o Synaptic cleft: interval of extracellular space between pre- and postsynaptic elements  i.e. space that separates pre- and postsynaptic neurons at chemical synapses - Site of extracellular proteins that influence the diffusion, binding and degradation of the molecules secreted by the presynaptic terminal  Number of synaptic inputs received by each nerve cell in human nervous system varies from 1-100,000  range reflects a fundamental purpose of nerve cells – to relay & integrate information from other neurons in a neural circuit  Information conveyed by synapses on neuronal dendrites is integrated & “read out” at the origin of the axon (portion of the nerve cell specialised for relaying electrical signals) o Axon is a unique extension from neuronal cell body that may travel a few hundred micrometres (μm) or much farther, depending on type of neuron and size of animal

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Relatively short axons are a feature of local circuit neurons/interneurons (neurons whose activity mediates interactions between sensory systems and motor systems) throughout the brain  Axons of projection neurons (neurons with long axons that) extend to distant targets  Action potential: an all-or-nothing change in the electrical potential (voltage) across the nerve cell membrane that conveys information from one point to another in the nervous system; a self-regenerating wave of electrical activity that carries signals over distances o Propagates from its point of initiation at the cell body (the axon hillock) to the terminus of the axon, where synaptic contacts are made  Synaptic transmission: the chemical and electrical processes by which the information encoded by action potentials is passed on at synaptic contacts to a target cell  Presynaptic terminals and their postsynaptic specialisations are typically chemical synapses, the most abundant type of synapse in the nervous system  The electrical synapse (facilitated by gap junctions) is relatively rare and has special functions  Synaptic vesicles: secretory organelles in the presynaptic terminal of chemical synapses; spherical structures filled with neurotransmitter molecules (i.e. neurotransmitters)  The intricate and concerted activity of neurotransmitters, receptors, related cytoskeletal elements, and signal transduction molecules are the basis for nerve cells communicating with one another, and with effector cells in muscles and glands Glial Cells  …

Chapter 2 Notes Electrical Signals of Nerve Cells  Neurons employ different types of electrical signals to encode and transfer information  Best way to observe them are though intracellular microelectrodes to measure the electrical potential across the neuronal plasma membrane  When the microelectrode enters the cell, it reports a negative potential  neurons have a means of generating constant voltage across membrane at rest  called resting membrane potential  Electrical signals in neurons caused by a reaction to stimuli (eg. light)  change in resting membrane potential  Receptor potential caused by activation of sensory neurons by external stimuli  Another electrical signal is though communication between neurons at synaptic contacts  synaptic potentials o Allows transmission of information from one neuron to another o Serve as means of exchanging info I complex neural circuits in CNS & PNS  Neurons create special electrical signal that travels along their long axons  axon potentials  responsible for long-range transmission of info within neurons system and allow nervous systems to transmit info to target organs  To elicit an action potential, pass an electrical current through the neuron’s membrane  normal circumstances, done by receptor/synaptic potentials  Can be done by inserting a second microelectrode and connecting to battery o If membrane potential is more negative (hyperpolarisation), it simply changes in proportion to the magnitude of the current passive electrical response o When membrane potential becomes more positive (depolarisation)  at a certain level called the threshold potential, action potential occurs  Action potential is an active response created by the change from – to + in a transmembrane potential o Amplitude is independent of the magnitude of the current - Immensity of stimulus in frequency  Receptor potentials  amplitude in proportion to the magnitude of sensory stimulus  Synaptic potentials  amplitudes vary according to amount of synapses activated + strength of synapse + previous amount of activity Long Distance Transmission of Electrical Signals  Problem for neurons is that their axons are not good electrical conductors o If pulse < threshold of generating action potential = magnitude of potential change decays over distance o Caused by current leaks across axonal membrane  prevents effective passive conduction of electrical signals  Action potentials act as “booster system” to allow neurons to conduct over great distances o Conduction of electrical signals via action potentials occurs without decrement How Ion Movements Produce Electrical Signals

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Electrical potentials generated across membranes of neurons because: o Differences in the concentrations specific ions o Membranes are selectively permeable to some ions Ion concentration gradients established by proteins called active transporters  actively move ions in/out of cells against their concentration gradient Selective permeability because of ion channels  proteins that allow only some kinds of ions to cross membrane in direction of concentration gradient Transporters and channels work against each other to create resting membrane potential, action potentials & synaptic potentials If the concentration of an ion is equal on both sides of the membrane  no electrical potential is created But if concentration is not equal, electrical potential is created o Difference in electrical potential is created because of K+ ions flowing down concentration gradient and taking K+ ions with them o Continual resting efflux of K+ creates resting membrane potential

When the ion (K+) movies from left to right, potential is generated  impedes flow of K+ o Creates potential gradient across membrane repels (K+) ions o Right becomes positive relative to left, increasing positivity makes right less attractive to positively charged ions  The net movement (flux) will stop at the point where potential change offsets concentration gradient  electrical equilibrium o Exact balance between 2 opposing forces: (i) Concentration gradient that causes ion to move from left to right (i.e. positive to negative) taking the positive charge with it (ii) Opposing electrical gradient that opposes the flow of the positive ions  Number of ions that needs to flow to generate electrical potential is very small o Concentration of permeable ions on each side remains constant, even after flow of ions has generated the potential o Fluxes of ions required to establish membrane potential doesn’t disrupt chemical electroneutrality because each ion has an oppositely charged counter-ion to maintain neutrality of solutions on each side of the membrane Forces That Create Membrane Potentials

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Electrical potential generated across membrane at electrochemical equilibrium (equilibrium potential) can be predicted by Nernst Equation, expressed as: RT [ X ] out EX= ln [ X ]¿ zF o Ex = equilibrium potential o R = gas constant o T = absolute temperature (in degrees on Kelvin scale) o z = valence (electrical charge) o F = Faraday constant (the amount of electrical charge contained in one mole of a univalent ion) o [X] = concentrations of ion X on each side of the membrane; “in” = inside, “out” = outside o ln = natural logarithm of concentration gradient Because it is easier to perform calculations using base 10 and experiments using room temperature, the formula gets simplified down to: [ X ]out 58 E X = log z [ X ]¿ The equilibrium potential is conventionally defined in terms of the potential difference between inside and outside compartments (i.e. left to right) Balance of chemical and electrical forces at equilibrium means that the electrical potential can determine ion fluxes across the membrane, just as the ionic gradient can determine the membrane potential

Electrochemical Equilibrium in an Environment with More Than One Permeant Ion  A more elaborate equation is needed, however, one that takes into account both the concentration gradients of the permeant ions and the relative permeability of the membrane to each permeant ion  The Goldman Equation, using the cause most relevant to neurons, is written as: +¿¿ K ¿ +¿ Na¿ ¿ Cl ¿ −¿ ¿¿ ¿ ¿¿ ¿ +¿ ¿ K ¿ +¿ ¿ Na ¿ Cl ¿ −¿ ¿¿ ¿ ¿ ¿ ¿ ¿ ¿ ¿ PK ¿ V =58 log¿ o V = voltage across the membrane o P = permeability of the membrane to each ion of interest  Note: valence factor (z) has been eliminated  negatively charged ions inverted relative to the concentrations of positively charged ions The Ionic Basis of the Resting Membrane Potential  Action of ion transporters creates substantial transmembrane gradients for most ions o Transporter-dependent concentration gradients are the source of resting neuronal membrane potential  Alan Hodgkin & Bernard Katz in 1949 showed that the negative membrane potential on the inside of the neuron varies because:

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The membrane of the resting neuron is more permeable to K+ than any other ion present ii. There is more K+ inside the neuron than outside o Selective permeability to K+ is caused by K+-permeable channels that are open in resting neurons o Large K+ concentration gradient producing membrane transporters The Ionic Basis of Action Potentials  The membrane potential of a neuron depolarises during an action potential due to an increased permeability to Na+  If membrane becomes highly permeable to Na+, the membrane potential approaches ENa o Action potential arises because neuronal membrane becomes temporarily permeable to Na+  Hodgkin and Katz tested out the role of Na+ by removing it from the external medium o Lowering Na+ concentration externally reduced both the rate of rise of the action potential & peak amplitude o Linear relationship between amplitude of action potentials & logarithm of external Na+ concentration o Resting membrane potential only slightly permeably to Na+, becomes extraordinarily permeable to Na+ during rising phase and the overshoot phase of action potential

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It is resulted from the opening of Na+ selective channels that are closed during resting state When Na+ channels open, Na+ flows into neuron  membrane potential depolarises and approaches ENa o Time it lingers near ENa (+58mV) during overshoot phase is brief

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Membrane potential rapidly repolarises to resting levels and is followed by a brief undershoot phase o It is an inactivation of Na+ permeability and increase in K+ permeability o During undershoot, membrane potential is hyperpolarised due to an even greater K+ permeability than at rest Action potential ends when this phase of enhanced K+ permeability subsides  returns to normal resting level Hodgkin and Katz experiments provided evidence: i. Resting membrane potential results from a high resting membrane permeability to K+ ii. Depolarisation during an action potential results from a transient rise in membrane Na+ permeability

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Action potentials are only initiated when the neuronal membrane potential becomes more positive than the threshold potential  mechanism responsible for increase in NA+ permeability is sensitive to membrane potential Voltage clamp method allows experimenters to control the membrane potential & simultaneously measure the permeability changes Alan Hodgkin and Andrew Huxley used this technique on the squid neuron  first experimenters to test how permeability catalyses action potentials The current produced by a squid axon when its membrane potential is hyperpolarised from resting level (-65mV) to -130mV initially is a redistribution of charge across the membrane  known as capacitive current  lasts a millisecond and the current is very little o Membrane potential is depolarised from -65mV to 0mV  following capacitive current, axon produces rapidly rising inward ionic current (positive charge entering the cell)  more slowly rising, delayed outward current o Membrane permeability at axons is voltage-dependent No ionic currents flow at membrane potential more negative than resting potential  more positive potentials, the currents not only flow but change in magnitude The early current has a u-shaped dependence on membrane potential  increasing in a range of depolarisation up to -mV but decreasing as the potential is depolarised further Late current increases monotonically with increasingly positive membrane potentials In the experiment, external Na+ > internal Na+ concentration  at the Na+ equilibrium potential, there is no net flux of Na+ across membrane, even if the membrane is highly permeable to Na+ o No early current at membrane potential where Na+ cannot flow  current is carried by entry of Na+ into the axon By removing Na+ outside the axon, ENa becomes negative; if permeability is increased, current should flow outwards as electrochemical gradient is reversed o Proven by Hodgkin & Huxley  by removing Na+ externally, the early current’s polarity reversed & became an outward current o Proves the early inward current occurs due to Na+ entering the neuron

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Late, outward current is caused by K+ exiting the neuron  amount of efflux from the neuron is closely correlated with the magnitude of the late, outward current Early influx of Na+ causes a transient inward current; delayed efflux of K+ produces sustained outward current Na+ & K+ flow through independent permeable pathways  ion channels Ionic currents are due to a change in membrane conductance  reciprocal of ...