Nervous Tissue Homeostatic Control Nervous system and endocrine system are basis of homeostasis Nervous system responds rapidly (in msec) Endocrine system responds slowly Three major components of control Sensing internal or external levels Interpreting and integrating Reacting (motor) via muscle or glandular (effectors) stimulation General Organization of NS Central vs. peripheral Central: brain & spinal cord Peripheral: cranial and spinal nerves Sensory (afferent) vs. motor (efferent) Somatic, autonomic & enteric Somatic (voluntary): sensory neurons from cutaneous and special sense receptors and motor neurons to skeletal muscle Autonomic (involuntary): sensory neurons from visceral organs and motor neurons to smooth & cardiac muscle and glands Enteric (involuntary): sensory neurons from chemical & stretch receptors in GI tract, enteric plexus, motor neurons to smooth muscle and secretory functions Autonomic connections to CNS Sympathetic vs. parasympathetic Sympathetic: regulates energy expenditure Parasympathetic: regulates energy restoration and conservation Organization of NS (graphic) Histology of Nervous Tissue Major cell types Neurons (conducting cells) and neuroglia (support cells) Neuroglia Glia - glue; but much more 5-50X the number of neurons Can mitotically divide Neuroglia Types Astrocytes: manage interstitial environment - metabolism of neurotransmitters, balance of K + ions, help form blood-brain barrier Microglia: protect CNS from foreign and damaged materials through phagocytosis (derived from mesodermal cells that also give rise to monocytes & macrophages) 1
Ependymal cells: epithelial cells that line ventricles of brain & central canal of spinal cord, produce CSF and promote its circulation (many are ciliated) Oligodendrocytes: most common glial cell in CNS, form myelin (w/o neurolemma) Neurolemmocytes (Schwaan cells): form neurolemma and myelin sheath around neurons in PNS Satellite cells: support cell bodies in PNS ganglia Types of Neuroglia (graphic) Myelin Composed of lipid & protein concentrically laid membrane (up to 100 layers) Enhances rate of conduction of excitation and insulates Myelination different between CNS and PNS Presence of neurolemma increases probability of neuron regrowth Myelination increases during early childhood increasing rapidity and coordination of response Multiple sclerosis Myelin produced by oligodendrocytes deteriorates Auto-immune response Slows conduction and short-circuits excitation Formation of Myelin (graphic) Gray and White Matter In CNS, clear difference between myelinated and unmyelinated tissue Gray - areas w/o myelin including unmyelinated regions of myelinated neurons, unmyelinated neurons and neuroglia Brain: gray matter on outside of cerebrum and cerebellum and inner nuclei (groupings of cell bodies and dendrites) Spinal cord: H-shaped gray matter inside Gray vs. White (graphic) Neuronal Structure Size Varying length: <1mm in CNS to >1.5 m in PNS Varying diameter: 5-135µm which along with myelin affect conduction rates (1-280mph) Major parts Dendrites (afferent) usually not myelinated, include rough ER (Nissl bodies), mitochondria, and other cell organelles Cell body (or soma) include nucleus, Golgi, mitochondria, Nissl bodies, and other cell organelles Clustered cell bodies in PNS form ganglia Axon (efferent) plus axon hillock, initial segment, axon terminal Nerve: in PNS, both sensory and motor neurons arranged in bundles surrounded by connective tissue 2
Tract: in CNS, bundled neurons w/o connective tissue Synapse including synaptic end bulbs or varicosities with synaptic vesicles Microanatomyof Neuron (graphic) Tissue Cultured Neurons (graphic) Relational Structure Multipolar - multiple dendrites and one axon Typical of brain and spinal cord Bipolar - one dendrite and one axon Typical of many sensory neurons including retina, inner ear and olfactory Unipolar - dendrite leads directly to axon Typical of sensory neurons for touch and pain Sample Shapes (graphic) Axonal Transport Slow axonal transport Similar to cytoplasmic movement in other cells but usually only toward axon 1-5 mm per day Fast axonal transport Organelle or molecular movement by protein motor, bi-directional 200-400 mm per day Important for long axonal lengths Various viruses and toxins transported this way Herpes & rabies virus, toxin from tetanus bacteria Physiology of Excitable Cells Membrane potential: voltage difference between inside and outside of cell due to ionic concentration differences (e.g. Na +, K +, Cl - and others) Resting potential - little current (ionic) flow Graded potential - varying current flow over a short distance Action potential - predictable current flow over a long distance Current flow due to combined ion movement through channels and pumps Ion Channels Leakage (non-gated) channels (some always open) Gated channels (either opened or closed) Voltage gated - respond directly to changes in membrane potential Ligand (chemically) gated - respond to neurotransmitters, hormones, H + and Ca 2+ Direct or G protein/2 nd messenger mediated Mechanically gated - respond to vibration, pressure or stretch Ion Channels (graphic) Resting Potential Polarization due to separation of charge across cell membrane Ranges from -40mV to -90mv in neurons (typical ~-70 mv) 3
Due to concentration gradients of ions across membrane and relative permeability of the ions through the membrane Na + and C - outside, K + inside Permeability of K + 50-100 > than Na + (leakage channels) K + equilibrium potential (-90 mv) has greatest influence over resting potential Membrane permeability greater for K + than Na + or Cl - Na/K electrogenic pump moves ions in 3:2 ratio Anions (Cl - ) have little effect Ions Across Membrane (graphic) Graded Potentials Voltage change due to ion flow through chemically (ligand) or mechanically gated channels Amount of voltage change (graded) dependent on # of gates open at one time and how long Change is localized (not conducted) Change may be depolarization or hyperpolarization Usually limited to dendrites and cell body of neurons, and many sensory cells Synapse - postsynaptic potential, Sensory receptor - receptor potential, Sensory neuron - generator potential Graded Potentials (graphic) Action Potential An all or none voltage change that starts when the neuron is depolarized to a threshold level by graded potential(s) Carried (or conducted) over long distances Amplitude, period (about 1 msec) and conducting rate are dependent on nature of neuron Primary carrier of information in nervous system either alone, in sequence or spatially Phases of AP (graphic) AP Depolarization Caused by rapid opening of voltage-gated Na + channels to where polarization is reversed Channels open at a threshold level (neuron specific) - ~-55mv Initially Na + is driven by both concentration & electrical gradients Voltage-gated Na + channels have an activation & inactivation gate Activation gates opened by super-threshold voltage Inactivation gates closed after specific period of time (a few 10,000 th of a sec) Number of Na + ions that move are small relative to total concentration outside cell thus little change in gradient (important for next AP) Electrogenic pump return the Na + ions to exterior 4
Local anesthetics frequently prevent opening of Na + channels (e.g. Novocaine or Lidocaine), also tetrodotoxin AP Gate Action (graphic) AP Repolarization Voltage-gated K + channels also open at threshold, but slowly K + ion movement more evident (repolarization) as Na + channels close Voltage current is reversed bringing neuron back to resting potential (usually some hyperpolarization prior to all K + channels closing) Refractory Period Absolute refractory period - neuron cannot be re-stimulated (Na + channels are inactivated with both gates closed) Relative refractory period - neuron can be stimulated by suprathreshold level (K + channels are still open) Refractory period determines rate of AP generation (frequency) large diameter cells - ARP about 0.4 msec (2500 APs per sec) small diameter cells - ARP about 4 msec (250 APs per sec) AP Conduction Or propagation In unmyelinated neuron, current flow in one membrane region affects voltage in adjacent region - continuous conduction If Na + channels are in resting state, they are activated If Na + channels are in inactive state, there is no effect Thus APs are conducted in one direction In myelinated neuron, current flow is through nodes of Ranvier only - saltatory conduction Na + and K + channels open in nodal regions only Thus AP jumps from node to node increase rate of conductance Fewer membrane channels open per unit length of neuron decreasing the required work of the electrogenic pump AP Conduction (graphic) Conduction Rates Conduction rate is dependent on neuron diameter as well as presence of myelin A fibers - diameter of 5-20 µm, short absolute refractory period, with conduction rates 12-130 m/sec Typical of sensory and motor neurons needed for quick response B fibers - diameter of 2-3 µm, longer absolute refractory period, with conduction rates 15 m/sec Typical of visceral sensory and ANS motor neurons to autonomic ganglia C fibers - diameter of 0.5-1.5 µm, longest absolute refractory period, with conduction rates 0.5-2 m/sec 5
Typically unmylenated neurons, many peripheral neurons associated with pain, and post-ganglionic ANS motor neurons Synapse Functional junction between neurons and between neuron and effector Gap junctions are a form of electrical synapse (e.g. intercalated discs of heart muscle, also CNS) - two way flow & fast Chemical synapses (e.g. NMJ) - one way flow & slower Review components Synaptic delay about 0.5 msec Synaptic Action AP arrives at presynaptic region of axon Voltage-gated Na + and Ca 2+ channels open Ca 2+ moves inward Ca 2+ initiates exocytosis of synaptic vesicles Neurotransmitter diffuses across synaptic cleft (20-50nm) and bind to receptors Neurotransmitter receptors on postsynaptic membrane open ligand- gated ion channels Na +, Ca 2+ inflow - excitatory K + outflow or Cl - inflow - inhibitory Synaptic Action (graphic) Postsynaptic Potentials Excitatory or inhibitory potentials depend on the neurotransmitter, receptor, and channels opened (EPSP or IPSP) They are graded potentials (not propagated, varying amplitude, no refractory period) Excitatory - opening of cation channels allowing flow of Na +, Ca 2+, and K + Since Na + furthest away from its equilibrium potential, more Na + flow Inhibitory - opening of Cl - or K + channels Excitatory Synapse (graphic) Removal of Neurotransmitter Diffusion Enzymatic breakdown e.g. acetycholinesterase Recycling uptake By presynaptic neuron or neuroglia Involves neurotransmitter transporters in membrane Cocaine blocks transporters of dopamine (brain NT) causing heightened stimulation Prozac (anti-depressant) inhibits uptake of serotonin 6
Postsynaptic Summation CNS neurons may have 1000s of synapses Spatial summation Temporal summation Summed effect on postsynaptic cell Excitatory PSP Action potential (sufficient EPSP at initial segment) Inhibitory PSP Examples of Summation (graphic) Neurotransmitters 100 or so possible substances Modulation Rate of synthesis Blocked or enhanced release Botulinum toxin inhibits release of ACh Inhibited or enhanced removal Blocked or enhanced active site Curare blocks ACh receptors Agonist vs. Antagonist Therapeutic/drug related Acetylcholine PNS neurons and some CNS neurons Excitatory in NMJ Inhibitory at heart via G protein/2 nd messenger (parasympathetic vagus) Amino Acids Glutamate and aspartate Excitatory in CNS (some w/ca + gates) Glutamate ~half of brain synapses and removed by transporters Gamma aminobutyric acid (GABA) and glycine Inhibitory via Cl - channels GABA most prevalent inhibitory transmitter in brain Valium (diazepam) is an agonist for GABA In spinal cord, both about equally found Biogenic Amines Catecholamines including nor-epi, epi and dopamine Derived from tyrosine Can be either excitatory or inhibitory Removed by transporters to pre-syn. membrane Rigidity of skeletal muscle in Parkinson s disease due to relatively low dopamine production (inhibitory in brain) 7
Serotonin (5-hydroxytryptamine) Adenosine Derivatives Adenosine, ATP, ADP, AMP Excitatory in CNS & PNS Frequently co-released with other transmitters Nitric Oxide Gas Derived from arginine Not packaged, but enzymatically formed as released Short-lived (10 sec) Lipid soluble (diffuses through membrane) - no vesicles, no receptor channels; 2 nd messenger (GMP) in post-synaptic cell Produced by endothelial cells of vessels to relax smooth muscle ( BP); Viagra NO effect Transmitter in brain and ANS Neuropeptides CNS & PNS Excitatory & inhibitory Manufactured in cell body First found when looking for effects of opiates Include enkephalins, endorphins, dynorphins Bodies natural painkillers? Effects of acupuncture? Substance P for communication of pain (PNS to CNS) Inhibited by enkephalins Others: Angiotensinogen II, CCK, releasing and inhibiting hormones from hypothalamus Neural Circuits Simple series - no integration Diverging Increased number of terminal neurons; distribution to multiple regions Converging Increases likelihood of excitation or inhibition of terminal neuron or effector Reverberating Causes repetitive stimulation in terminal neuron Inhibition required to stop May be important for breathing, muscle coordination, short-term memory Parallel after-discharge Causes extra EPSP or IPSP in terminal neuron Integrating Circuits (graphic) Regeneration 8
Plasticity - new dendrites, synapses In PNS, dendrite or axon w/o neurolemma damage may repair Chromatolysis (breakdown of Nissl bodies), Wallerian (distal) degeneration, mitotic division of neurolemmocytes and formation of regeneration tube In CNS, neither unmylenated or mylenated (by oligodendrocytes) neurons regenerate Astrocytes fill space Research - stem cells & epidermal growth factor Regeneration (graphic) Epilepsy READ 9