Academic year 2017/2018 Physiology 2 nd year Semester 1 Curricula Nervous system physiology Blood physiology Acid-base equilibrium Bibliography: Boron & Boulpaep Medical Physiology, 3 rd edition Physiology Lecture: Wednesdays, 10:00-12:00, G.E. Palade Amphitheatre, Faculty of Medicine Neuroscience Optional Lecture October, 12 - November 23, 2017 Thursdays, 18:00-20:00, Clinical (SUUB) Amphitheatre (Neuroscience Lecture starts on October 12) Assoc. Prof. Ana-Maria Zagrean Coordinator for Physiology and Neuroscience, 2 nd Year, English Module Discipline of Physiology and Neuroscience E-mail: physiology.caroldavila@gmail.com Info at www.fiziologie.ro
NERVOUS SYSTEM PHYSIOLOGY LECTURE 1 Organization of the Nervous System. Excitability and ionic transport
BIBLIOGRAPHY FOR PHYSIOLOGY - MEDICAL PHYSIOLOGY BORON & BOULPAEP, 3 rd Ed. Lecture Bibliography for the exam Supplementary bibliography Lecture 1 Organization of the Nervous System. Excitability and ionic transport Chapter 5: p. 105 to p. 118: Solute transport across cell membranes p. 125 to p. 128: Regulation of intracellular ion concentrations + Water transport is driven by osmotic and hydrostatic pressure differences across membranes Chapter 6: p. 141 to p. 149: Electrophysiology of the cell membrane - Ionic basis of membrane potentials p. 157 to p. 159: Molecular physiology of ion channels Chapter 7: p. 173 to p. 203: Electrical excitability and action potentials Chapter 10: p. 254 to p. 261: Organization of the Nervous System p. 269 to p. 274: Subdivisions of the Nervous System Chapter 5: p. 102-105: The intracellular and extracellular fluids p. 118-125: ATPases transport..., Cotransporters..., Exchangers... Chapter 6: p. 149-157: Electrical model of a cell membrane
Physiology pathway dynamic study of life, describing the vital functions of living organisms and their organs, cells, molecules... integrative discipline, from general physiology (cellular & molecular physiology) to medical physiology (integrated understanding of events at the level of molecules, cells, organs and whole body all in an interdependent action) genome with its epigenetic modifications: Physiological genomics - new branch of physiology devoted to the understanding of the genes function
Organization of the Nervous System (NS) How NS is organized, how it develops and functions to generate behaviour these questions can be explored using the tools of genetics and genomics, molecular & cellular biology, anatomy and systems physiology, behavioural observations and psychology.
Nervous system At cellular level neurons & glia neural circuits Neural circuits primary components of neural systems that process specific types of information Neural systems serve one of three general functions: 1. sensory systems (inform about the state of the organism and its environment) 2. motor systems (organize and generate actions) 3. association systems - link sensory & motor components provide the basis for higher order brain functions: perception, attention, cognition, emotion, language, rational thinking, creativity
Challenge: to understand the physiological role of the neural circuits and systems in behaviorally meaningful contexts.
Different perspectives on the brain Anatomical aspects Connectivity and function (http://www.sciencemag.org/content/335/6076/1628).
Genetics and the Brain Human genome: about 20,000 genes (coding & regulatory DNA) 14,000 genes expressed in the developing/mature brain about 8,000 genes are expressed in all cells and tissues a great deal of brain specific genetic information resides in the regulatory DNA sequences that control timing, quantity, variability, and cellular specificity of gene expression individual genes vary in the level of expression in specific brain regions and cells (i.e. the amount of mrna expressed) relationship between genotype and phenotype, epigenetics foundation of the diversity & complexity of brain functions! Gene mutations associated with brain pathology (Huntington D, Alzheimer D, Parkinson D )
Nervous System Subdivisions! All elements of the nervous system work closely together in a way that has no clear boundaries.
Nervous System: structure 1) CENTRAL NERVOUS SYSTEM (CNS): brain spinal cord Covered by meninges 2) PERIPHERAL NERVOUS SYSTEM (PNS): cranial nerves spinal nerves 2 types of nervous tissue cells: neurons: sensory, motor, interneurones/association neurons non-neuronal/neuroglial cells: astrocytes, microglia, ependymal cells, oligodendocytes / Schwann cells Spinal cord
Cellular diversity of the brain Nerve cells: neurons and neuroglial cells. ~10 11 neurons in the human brain and 10 x more neuroglia Neurons have special shapes, physiological properties, and connections (~1000 synapses/each neuron & other connecting mechanisms!) responsible for information transmission throughout the nervous system unique patterns of connectivity & regional specialization tremendous complexity of NS Neuroglial cells variable structures that are suited for their diverse functions provide a physiological environment for neurons can function as signaling cells!
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Characteristics of Neurons 1) excitable - respond to stimuli - produce & conduct electrical impulses - release chemical regulators 2) long-lived 3) high metabolic rate 4) amitotic - cannot divide by mitosis! Most human neurons arise in about the first 4 months of intrauterine life. After birth, neurons do not divide, and if a neuron is lost for any reason, it is generally not replaced, which is the main reason for the relatively limited recovery from serious brain and spinal cord injuries (possible preserving learned behavior and memories in stable populations of neurons throughout life). Exception: olfactory bulb neurons, which are continually renewed throughout adult life by a population of stem cells or neuronal progenitor cells.
Typical neuron has 4 regions: cell body, dendrites, axon, presynaptic terminals each region is specialized for its particular function information flows in a single direction Neuron Cell Body Location In the central nervous system Gray matter cell bodies and unmyelinated fibers Nuclei clusters of cell bodies within the white matter of the central nervous system In the peripheral nervous system: Ganglia collections of cell bodies
The structure of a typical neuron (1) cell body/ soma /perikaryon -nucleus, ER, Golgi complex, mitochondria -cytoskeleton: neurofilaments, microtubules, thin filaments (dynamic features plasticity ) (2) dendrites: limited length, contain microtubules and ER; membrane receptors for neurotransmitters; dendritic spines amplify the receiving/postsynaptic area The dendrites & cell body are the main areas for receiving information through the membrane receptors that bind and respond to neurotransmitters released by neighboring cells
The structure of a typical neuron (3) the axon: - axon hillock, a cone-shaped initial segment = the spike initiation zone (unmyelinated region where AP initiates) - axon can extend >1 m, can be myelinated (electrical insulation, fast impulse spread salutatory conduction), high density Na + channels - contain axoplasm (more than does the cell body - up to 1000x), microtubules and microfilaments that confer structural stability and axonal transport. - are self-reliant in energy metabolism, taking up glucose and oxygen from their immediate environment to produce ATP (4) the presynaptic terminals: rapid conversion of the neuron's electrical signal into a chemical signal or another kind of signal.
Neuronal compartmentalization Neurons are polarized cells and have distinct membrane protein at each of the distinct domains of the plasma membrane. Axoplasmic transport of molecules in vesicles along microtubules is mediated by microtubule-associated proteins 1. kinesin for anterograde transport: toward the (+) end of microtubules 2. dynein for retrograde transport: provides a mechanism for target-derived growth factors (NGF), to reach the nucleus of a neuron where it can influence survival!
Neurons classification: great structural diversity, correlated with their functions -axonal projection long axons: Axonal Projection Neurons = principal neurons or Golgi type I cells short axons: restricted to one region of the brain = interneurons/intrinsic neurons or Golgi type II cells
Neurons classification: great structural diversity, correlated with their functions - dendrites geometry pyramid-shaped dendritic branches - pyramidal cells radial pattern of dendritic branches - stellate cells presence of dendritic spines - spiny cells (pyramidal and stellate cells)
Neurons classification: great structural diversity, correlated with their functions - number of processes originating from the cell body: unipolar neuron: dorsal root ganglion (DRG) cell - primary sensory neuron bipolar neurons: retinal bipolar cell multipolar neurons (most neurons); neurons with many dendritic processes receive large numbers of synaptic inputs.
Classification of Neurons based on their function Sensory (afferent) neurons Carry impulses from the sensory receptors -Cutaneous sense organs -Proprioceptors detect stretch or tension Motor (efferent) neurons -Carry impulses from the central nervous system Interneurons (association neurons) -Found in neural pathways only in the CNS -Connect sensory and motor neurons
Neuron Classification
Non-neuronal cells: glial cells smaller & more numerous than the neurons they lack: axons, action potentials, and synaptic potentials
Glial Cell Functions: Glial cells have a major impact on the composition of the extracellular fluid, which in turn has a major impact on brain function: Glia fills in almost all the space around neurons: extracellular space between neurons and glial cells ~0.02 μm Clear transmitters from synapse, ion homeostasis, role in cell volume control, volume transmission K+ and H+ uptake vs. spatial buffering; Ca waves
Glial cells - Astrocytes The no. of astrocytes increases with an increase in brain size: The glia/neurons ratio - in the rat cerebral cortex ~0.4 - in the human cerebelar cortex ~1.65
Neuron-glia connections Amzica, 2000 Synchronous Firing Groups: Astrocytic regulation of neural networks
Glial cells: Schwann cells and oligodendrocytes (PNS) (CNS)
Excitability and ionic transport
Selective membrane permeability: The lipid barrier of the cell membrane and cell membrane transport proteins Chemical compositions of extracellular and intracellular fluids.
Cell membrane and its selective permeability TRANSPORT OF SUBSTANCES THROUGH THE CELL MEMBRANE 1.Diffusion -Simple diffusion: - lipid-soluble subst. (O2, CO2, alcohols) through intermolecular spaces of the lipid barrier - through a membrane opening - protein channels (e.g., water, lipid-insoluble molecules that are water-soluble and small enough): selective permeable channels non-gated OR gated (open/closed by gates) voltage-gated ligand-gated (chemical-gated) -Facilitated diffusion = carrier mediated diffusion e.g. transport of most of aminoacids and glucose Driving force of diffusion and net diffusion depends on: -Substance availability, kinetic energy, membrane permeability -Concentration difference/gradient -Membrane electrical potential effect on diffusion of ions 2.Active transport - Primary active (pumps) - Secondary active (co- and counter-transport)
Simple diffusion through protein channels: Pores/channels are integral cell membrane proteins that are always open Pore diameter, its shape and its internal electrical charge/chemical bonds provide selectivity Aquaporins = water channels (13 different types) - protein pores which permit rapid passage of water through cell membranes but exclude other molecules (a narrow pore permits water molecules to diffuse through the membrane in single file). The pore is too narrow to permit passage of any hydrated ions.! Density of aquaporins (e.g., aquaporin-2) in cell membranes is not static but is altered in different physiological conditions.
Membrane ionic transport system (MITS) 1 - Ion channels 2 - Ion pumps 3 - Ion exchangers, carriers, co/counter transporters
1. Ion channels Gated (active) Ion Channels - Voltage gated - Ligand gated - Mechanic gated Non-gated (passive) Ion Channels The diversity of ion channels is significant, especially in excitable cells of nerves and muscles. Of the more than 400 ion channel genes currently identified in the human genome, about 79 encode potassium channels, 38 encode calcium channels, 29 encode sodium channels, 58 encode chloride channels, and 15 encode glutamate receptors. The remaining are genes encoding other channels such as inositol triphosphate (IP3) receptors, transient receptor potential (TRP) channels and others.
Gated (active) Ion Channels
The voltage-gated Na + channel - used in the rapid electrical signaling - components: - ion selectivity filter for Na+: Na+ discard the water molecules associated with them in order to pass in single file through the narrowest portion of the channel - activation gate that can open and close, as controlled by voltage sensors, which respond to the level of the membrane potential - inactivation gate limits the period of time the channel remains open, despite steady stimulation. a subunit: polypeptide chain of >1800 am.ac. embedded in cell membrane. * Nonpolar side chains coil into transmembrane alpha-helices and face outward where they readily interact with the lipids of the membrane. * By contrast, the polar peptide bonds face inward, separated from the lipid environment of the membrane. b subunit: anchor the channel to the plasma membrane - activation: - at resting membrane potential (-90-70 mv) the channel is closed; - the voltage sensor moves outward and the gate opens if any factor depolarize the membrane potential sufficiently (threshold ~ -50 mv).
Voltage-gated Na+ channel
Gated (active) Ion Channels Ligand-gated ion channels : ionotropic vs metabotropic Ionotropic - directly gate ion channels Metabotropic - indirectly gate channels via 2 nd messengers
Ligand-gated ion channels - glutamate receptors: - NMDA & AMPA ionotropic receptors - metabotropic group I & II receptors (G-prot. coupled) PCP- phenylciclidine
extracellular Gated (active) Ion Channels Mechanic gating ion channel Anchoring situs Cell membrane intracellular Fibrillary protein gate
Non-gated (passive) Ion Channels K + leak channels
2. Ion Pumps Functional particularities: -active transport of ions and organic molecules against concentration gradient - involve enzymatic reactions, ATP consume -decreased transport rate Ex: Na + /K + pump, H + pump, Ca 2+ pump...
3. Ion Exchangers/ Carriers/Cotransporters - Na/Ca - Na/H - Na/HCO 3 - Na/ aa, Na/G - Cl/HCO 3 - - Na/K/2Cl - K/Cl, etc
Ion gradients, channels, and transporters in a typical cell (Boron, 2009)
Factors that influence the resting membrane potential The Na + /K + pump contributes to resting membrane potential in 2 ways: Pumping Na + & K + ions in a 3:2 ratio contribute to internal electronegativity Maintaining a high K + concentration in the cell s interior The membrane conductance to K + far exceeds that to Na + : K + leakage results in internal electronegativity
When the neuron is inactive, the membrane is said to be at rest and has a resting membrane potential When the neuron is active, the flow of information is from soma to axon terminal action potentials (AP). A Motor Neuron
Membrane responses to stimulus current Hyperpolarizing currents produce responses 1 and 2. A small depolarizing current produces response 3. These are all graded local responses which dissipate locally. A sufficiently large current (threshold) produces an action potential (4), which can be propagated along the axon. Animation at http://www.sumanasinc.com/webcontent/animations/neurobiology.html
-A stimulus initiates a membrane electrical change that depend on the passive properties of the neuronal membrane -Electrical signal /potentials are initiated by local current flow -Local potentials then spread electrotonically over short distances, and decay with distance from their site of initiation (as some of the ions leak back out across the cell membrane and less charge reaches more distant sites); Considering the Ohms law and a stable membrane resistance, the diminished current with distance away from the source results in a diminished voltage change.
- When the potential is equal/over threshold, it propagates over a long distance - at the axon hillock level, the potential initiates an action potential (AP) that propagates without changing its amplitude - APs depend on a regenerative wave of channel openings and closings in the membrane
Action Potential (AP) nerve impulse = action potential: cycle of depolarization & repolarization needs no direct energy all-or-none principle The action potential is essential to our understanding of nervous system function. Its shape, velocity of conduction, and propagation fidelity are essential to the timing, synchrony, and efficacy of neuronal communication. G. J. Kress and S. Mennerick / Neuroscience 158 (2009) 211 222
Action Potential -The necessary actor in causing both depolarization and repolarization of the nerve membrane during the action potential is the voltage-gated Na+ channel -A voltage-gated K+ channel also plays an important role in increasing the rapidity of repolarization of the membrane. -These two voltage-gated channels are in addition to the Na + -K + pump and the K + -Na + leak channels. Na + permeability increases 500-5000 x
The nerve action potential Profile of a Nerve Action Potential Threshold -Occurs when Na + entering exceeds K + leaving -A rise in potential of 15-30 mv is required The All-or-None principle An action potential will not occur until the initial rise in membrane potential reaches threshold. However any larger stimulus produces no greater response than that produced by the threshold stimulus, i.e., the threshold stimulus produces the maximal effect the action potential.
The nerve action potential Resting Stage Depolarization Stage Repolarization Result of Voltage-gated Na+ channels After-Hyperpolarization Membrane is polarized i.e., a 90 mv membrane resting potential present Membrane becomes very permeable to Na+ ions Influx of Na+ ions Polarized state is neutralized Potential merely approaches in smaller CNS fibres Membrane potentials overshoots beyond zero in large fibres Na+ channels get inactivated Permeability to K+ increases K+ channels remain open after repolarization
Cation conductances during an action potential action potential Ion conductance Na + conductance increases faster and lasts for a shorter duration. K + conductance is delayed, increases slowly and lasts longer
Membrane Refractoriness Refractoriness = non-responsive state Involves Na channel inactivation Absolute refractory period (ARP)- membrane is not responsive to any stimulation Relative refractory period (RRP) - membrane is responsive to supra-threshold stimuli
Na channels distribution and generation of AP in axon hillock The soma membrane has few Na+ channels it is harder to have sufficient Na+ influx to change membrane potential to the threshold potential (-45 mv). A voltage change up to +30 mv is required Axon hillock membrane has 7x more Na+ channels than the soma membrane and the threshold potential is lower (a voltage change of only +10 +20 mv is required to bring the membrane potential to threshold) = trigger zone for AP Action potentials in postsynaptic neurons are initiated at the axon hillock.
AP generation and conductance along the axon - initial depolarization at the axon hillock +f.b. for Na + channels critical membrane potential = threshold (all-or-none response) -AP: depolarization and repolarization, followed by afterhyperpolarization, as Ca2+-dependent K+ channels remain open and membrane permeability for K+ is higher - propagation of AP to the axon terminals synapses - also backpropagation in the soma & dendrites, without regenerating in the somal membrane, as somal membrane has too few Na + channels to regenerate APs; also, inactivation of Na channels at axon hillock (here, refractory period). -Speed of propagation depends on axon diameter & presence of myelin sheath -in unmyelinated axons, Na & K voltage-gated channels are uniformly distributed AP as a traveling wave -large diameter axons allow a grater flow of ions grated length of the axon to be depolarized increase of the conduction velocity -in myelinated axons, myelin sheath insulate the axon membrane generation of AP between the myelinated segments, at the nodes of Ranvier saltatory conduction
Propagation of impulses from the axon hillock Once the action potential begins, the potential travels forward along the axon and usually also backward toward the soma. However it does not regenerate in the soma membrane. Why is regeneration impossible in the soma membrane? EPSPs arrive and an AP is generated at the axon hillock. The AP is regenerated forward to the axon, depolarization spreads backwards to soma and dendrites, but impulse potential decays dies because the somal membrane has too few Na+ channels to regenerate APs.
Saltatory Conduction current flows electronically to the next node action potentials are regenerated only at nodes action potential jumps from node to node
Propagation of an Action Potential
Action Potential travels along the membrane as a wave of depolarization. Directional propagation of an AP