Chapter 12 Lecture Outline 12 1 Copyright c

Chapter 12 Lecture Outline 12 -1 Copyright (c) The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display.

Nervous Tissue Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. • overview of the nervous system • properties of neurons • supportive cells (neuroglia) • electrophysiology of neurons • synapses Neurofibrils • neural integration (d) Figure 12. 4 d Axon 12 -2

Overview of Nervous System • endocrine and nervous system maintain internal coordination – endocrine system - communicates by means of chemical messengers (hormones) secreted into to the blood – nervous system - employs electrical and chemical means to send messages from cell to cell • nervous system carries out its task in three basic steps: • sense organs receive information about changes in the body and the external environment, and transmits coded messages to the spinal cord and the brain • brain and spinal cord processes this information, relates it to past experiences, and determine what response is appropriate to the circumstances • brain and spinal cord issue commands to muscles and gland cells to carry out such a response 12 -3

Two Major Anatomical Subdivisions of Nervous System • central nervous system (CNS) – brain and spinal cord enclosed in bony coverings • enclosed by cranium and vertebral column • peripheral nervous system (PNS) – all the nervous system except the brain and spinal cord – composed of nerves and ganglia • nerve – a bundle of nerve fibers (axons) wrapped in fibrous connective tissue • ganglion – a knot-like swelling in a nerve where neuron cell bodies are concentrated 12 -4

Subdivisions of Nervous System Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Central nervous system (CNS) Peripheral nervous system (PNS) Brain Spinal cord Nerves Ganglia Figure 12. 1 12 -5

Sensory Divisions of PNS • sensory (afferent) division – carries sensory signals from various receptors to the CNS – informs the CNS of stimuli within or around the body – somatic sensory division – carries signals from receptors in the skin, muscles, bones, and joints – visceral sensory division – carries signals from the viscera of the thoracic and abdominal cavities • heart, lungs, stomach, and urinary bladder 12 -6

Motor Divisions of PNS • motor (efferent) division – carries signals from the CNS to gland muscle cells that carry out the body’s response • effectors – cells and organs that respond to commands from the CNS – somatic motor division – carries signals to skeletal muscles • output produces muscular contraction as well as somatic reflexes – involuntary muscle contractions – visceral motor division (autonomic nervous system) - carries signals to glands, cardiac muscle, and smooth muscle • involuntary, and responses of this system and its receptors are visceral reflexes • sympathetic division – tends to arouse body for action – accelerating heart beat and respiration, while inhibiting digestive and urinary systems • parasympathetic division – tends to have calming effect – slows heart rate and breathing – stimulates digestive and urinary systems 12 -7

Subdivisions of Nervous System Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Central nervous system Brain Peripheral nervous system Spinal cord Visceral sensory division Figure 12. 2 Sensory division Somatic sensory division Motor division Visceral motor division Sympathetic division Somatic motor division Parasympathetic division 12 -8

Universal Properties of Neurons • excitability (irritability) – respond to environmental changes called stimuli • conductivity – neurons respond to stimuli by producing electrical signals that are quickly conducted to other cells at distant locations • secretion – when electrical signal reaches end of nerve fiber, a chemical neurotransmitter is secreted that crosses the gap and stimulates the next cell 12 -9

Functional Types of Neurons • sensory (afferent) neurons – specialized to detect stimuli – transmit information about them to the CNS • begin in almost every organ in the body and end in CNS • afferent – conducting signals toward CNS • interneurons (association) neurons – lie entirely within the CNS – receive signals from many neurons and carry out the integrative function • process, store, and retrieve information and ‘make decisions’ that determine how the body will respond to stimuli – 90% of all neurons are interneurons – lie between, and interconnect the incoming sensory pathways, and the outgoing motor pathways of the CNS • motor (efferent) neuron – send signals out to muscles and gland cells (the effectors) • motor because most of them lead to muscles • efferent neurons conduct signals away from the CNS 12 -10

Functional Classes of Neurons Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Peripheral nervous system Central nervous system 1 Sensory (afferent) neurons conduct signals from receptors to the CNS. 3 Motor (efferent) neurons conduct signals from the CNS to effectors such as muscles and glands. 2 Interneurons (association neurons) are confined to the CNS. Figure 12. 3 12 -11

Structure of a Neuron Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. • soma – the control center of the neuron Dendrites – also called neurosoma, cell body, or perikaryon – has a single, centrally located nucleus with large nucleolus – cytoplasm contains mitochondria, lysosomes, a Golgi complex, numerous inclusions, and extensive rough endoplasmic reticulum and cytoskeleton – cytoskeleton consists of dense mesh of microtubules and neurofibrils (bundles of actin filaments) Soma Nucleus Nucleolus Trigger zone: Axon hillock Initial segment Axon collateral Axon Direction of signal transmission • compartmentalizes rough ER into dark staining Nissl bodies Internodes – no centrioles – no further cell division – inclusions – glycogen granules, lipid droplets, melanin, and lipofuscin (golden brown pigment produced when lysosomes digest worn-out organelles) Node of Ranvier Myelin sheath Schwann cell • lipofuscin accumulates with age • wear-and-tear granules • most abundant in old neurons Terminal arborization Figure 12. 4 a Synaptic knobs (a) 12 -12

Structure of a Neuron Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Dendrites Soma Nucleus • dendrites – vast number of branches coming from a few thick branches from the soma Nucleolus Trigger zone: Axon hillock Initial segment – resemble bare branches of a tree in winter – primary site for receiving signals from other neurons – the more dendrites the neuron has, the more information it can receive and incorporate into decision making – provide precise pathway for the reception and processing of neural information Axon collateral Axon Direction of signal transmission Internodes Node of Ranvier Myelin sheath Schwann cell Terminal arborization Figure 12. 4 a Synaptic knobs (a) 12 -13

Structure of a Neuron Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Dendrites • axon (nerve fiber) – originates from a mound on one side of the soma called the axon hillock Soma Nucleus Nucleolus – cylindrical, relatively unbranched for most of its length Trigger zone: • axon collaterals – branches of axon Axon hillock Initial segment – branch extensively on distal end – specialized for rapid conduction of nerve signals to points remote to the soma – axoplasm – cytoplasm of axon – axolemma – plasma membrane of axon – only one axon per neuron – Schwann cells and myelin sheath enclose axon – distal end, axon has terminal arborization – extensive complex of fine branches Axon collateral Axon Direction of signal transmission Internodes Node of Ranvier Myelin sheath Schwann cell • synaptic knob (terminal button) – little swelling that forms a junction (synapse) with the next cell • contains synaptic vesicles full of neurotransmitter Terminal arborization Figure 12. 4 a Synaptic knobs (a) 12 -14

Variation in Neuron Structure Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. • multipolar neuron – one axon and multiple dendrites – most common – most neurons in the brain and spinal cord Dendrites Axon Multipolar neurons • bipolar neuron Dendrites – one axon and one dendrite – olfactory cells, retina, inner ear Axon • unipolar neuron – single process leading away from the soma – sensory from skin and organs to spinal cord • anaxonic neuron – many dendrites but no axon – help in visual processes Bipolar neurons Dendrites Axon Unipolar neuron Dendrites Anaxonic neuron Figure 12. 5 12 -15

Axonal Transport • many proteins made in soma must be transported to axon and axon terminal – to repair axolemma, serve as gated ion channel proteins, as enzymes or neurotransmitters • axonal transport – two-way passage of proteins, organelles, and other material along an axon – anterograde transport – movement down the axon away from soma – retrograde transport – movement up the axon toward the soma • microtubules guide materials along axon – motor proteins (kinesin and dynein) carry materials “on their backs” while they “crawl” along microtubules • kinesin – motor proteins in anterograde transport • dynein – motor proteins in retrograde transport 12 -16

Two Types of Axonal Transport Fast and Slow • fast axonal transport – occurs at a rate of 20 – 400 mm/day – fast anterograde transport (up to 400 mm/day) • organelles, enzymes, synaptic vesicles and small molecules – fast retrograde transport • for recycled materials and pathogens - rabies, herpes simplex, tetanus, polio viruses – delay between infection and symptoms is time needed for transport up the axon • slow axonal transport or axoplasmic flow - 0. 5 to 10 mm/day – always anterograde – moves enzymes, cytoskeletal components, and new axoplasm down the axon during repair and regeneration of damaged axons – damaged nerve fibers regenerate at a speed governed by slow 12 -17 axonal transport

Neuroglial Cells • about a trillion (1012) neurons in the nervous system • neuroglia outnumber the neurons by as much as 50 to 1 • neuroglia or glial cells – support and protect the neurons – bind neurons together and form framework for nervous tissue – in fetus, guide migrating neurons to their destination – if mature neuron is not in synaptic contact with another neuron is covered by glial cells • prevents neurons from touching each other • gives precision to conduction pathways 12 -18

Six Types of Neuroglial Cells • four types occur only in CNS – oligodendrocytes • form myelin sheaths in CNS • each arm-like process wraps around a nerve fiber forming an insulating layer that speeds up signal conduction – ependymal cells • lines internal cavities of the brain • cuboidal epithelium with cilia on apical surface • secretes and circulates cerebrospinal fluid (CSF) – clear liquid that bathes the CNS – microglia • small, wandering macrophages formed white blood cell called monocytes • thought to perform a complete checkup on the brain tissue several times a day 12 -19 • wander in search of cellular debris to phagocytize

Six Types of Neuroglial Cells • four types occur only in CNS – astrocytes • most abundant glial cell in CNS • cover entire brain surface and most nonsynaptic regions of the neurons in the gray matter of the CNS • diverse functions – form a supportive framework of nervous tissue – have extensions (perivascular feet) that contact blood capillaries that stimulate them to form a tight seal called the blood-brain barrier – convert blood glucose to lactate and supply this to the neurons for nourishment – nerve growth factors secreted by astrocytes promote neuron growth and synapse formation – communicate electrically with neurons and may influence synaptic signaling – regulate chemical composition of tissue fluid by absorbing excess neurotransmitters and ions – astrocytosis or sclerosis – when neuron is damaged, astrocytes form hardened scar tissue and fill space formerly occupied by the neuron 12 -20

Six Types of Neuroglial Cells • two types occur only in PNS – Schwann cells • envelope nerve fibers in PNS • wind repeatedly around a nerve fiber • produces a myelin sheath similar to the ones produced by oligodendrocytes in CNS • assist in the regeneration of damaged fibers – satellite cells • surround the neurosomas in ganglia of the PNS • provide electrical insulation around the soma • regulate the chemical environment of the neurons 12 -21

Neuroglial Cells of CNS Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Capillary Neurons Astrocyte Oligodendrocyte Perivascular feet Myelinated axon Ependymal cell Myelin (cut) Cerebrospinal fluid Microglia Figure 12. 6 12 -22

Glial Cells and Brain Tumors • tumors - masses of rapidly dividing cells – mature neurons have little or no capacity for mitosis and seldom form tumors • brain tumors arise from: – meninges (protective membranes of CNS) – by metastasis from non-neuronal tumors in other organs – most come from glial cells that are mitotically active throughout life • gliomas grow rapidly and are highly malignant – blood-brain barrier decreases effectiveness of chemotherapy – treatment consists of radiation or surgery 12 -23

Myelin • myelin sheath – an insulating layer around a nerve fiber – formed by oligodendrocytes in CNS and Schwann cells in PNS – consists of the plasma membrane of glial cells • 20% protein and 80 % lipid • myelination – production of the myelin sheath – – begins the 14 th week of fetal development proceeds rapidly during infancy completed in late adolescence dietary fat is important to nervous system development 12 -24

Myelin • in PNS, Schwann cell spirals repeatedly around a single nerve fiber – lays down as many as a hundred layers of its own membrane – no cytoplasm between the membranes – neurilemma – thick outermost coil of myelin sheath • contains nucleus and most of its cytoplasm • external to neurilemma is basal lamina and a thin layer of fibrous connective tissue – endoneurium • in CNS – oligodendrocytes reaches out to myelinate several nerve fibers in its immediate vicinity – anchored to multiple nerve fibers – cannot migrate around any one of them like Schwann cells – must push newer layers of myelin under the older ones • so myelination spirals inward toward nerve fiber – nerve fibers in CNS have no neurilemma or endoneurium 12 -25

Myelin • many Schwann cells or oligodendrocytes are needed to cover one nerve fiber • myelin sheath is segmented – nodes of Ranvier – gap between segments – internodes – myelin covered segments from one gap to the next – initial segment – short section of nerve fiber between the axon hillock and the first glial cell – trigger zone – the axon hillock and the initial segment • play an important role in initiating a nerve signal 12 -26

Myelin Sheath in PNS Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Axoplasm Axolemma Schwann cell nucleus Neurilemma Figure 12. 4 c (c) Myelin sheath nodes of Ranvier and internodes 12 -27

Myelination in CNS Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Oligodendrocyte Myelin Nerve fiber Figure 12. 7 b (b) 12 -28

Myelination in PNS Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Schwann cell Axon Basal lamina Endoneurium Nucleus (a) Neurilemma Myelin sheath Figure 12. 7 a 12 -29

Diseases of Myelin Sheath • degenerative disorders of the myelin sheath – multiple sclerosis • oligodendrocytes and myelin sheaths in the CNS deteriorate • myelin replaced by hardened scar tissue • nerve conduction disrupted (double vision, tremors, numbness, speech defects) • onset between 20 and 40 and fatal from 25 to 30 years after diagnosis • cause may be autoimmune triggered by virus – Tay-Sachs disease - a hereditary disorder of infants of Eastern European Jewish ancestry • abnormal accumulation of glycolipid called GM 2 in the myelin sheath – – normally decomposed by lysosomal enzyme missing in individuals homozygous for Tay-Sachs allele accumulation of ganglioside (GM 2) disrupts conduction of nerve signals blindness, loss of coordination, and dementia • fatal before age 4 12 -30

Unmyelinated Axons of PNS Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Neurilemma Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Myelin sheath Unmyelinated nerve fibers Myelinated axon Schwann cell cytoplasm Basal lamina Neurilemma Unmyelinated axon (c) 3µm © The Mc. Graw-Hill Companies, Inc. /Dr. Dennis Emery, Dept. of Zoology and Genetics, Iowa State University, photographer Figure 12. 7 c Schwann cell Figure 12. 8 Basal lamina • Schwann cells hold 1 – 12 small nerve fibers in grooves on its surface • membrane folds once around each fiber overlapping itself along the edges 12 -31 • mesaxon – neurilemma wrapping of unmyelinated nerve fibers

Conduction Speed of Nerve Fibers • speed at which a nerve signal travels along a nerve fiber depends on two factors – diameter of fiber – presence or absence of myelin • signal conduction occurs along the surface of a fiber – larger fibers have more surface area and conduct signals more rapidly – myelin further speeds signal conduction • conduction speed – – small, unmyelinated fibers - 0. 5 - 2. 0 m/sec small, myelinated fibers 3 - 15. 0 m/sec large, myelinated fibers - up to 120 m/sec slow signals supply the stomach and dilate pupil where speed is less of an issue – fast signals supply skeletal muscles and transport sensory 12 -32 signals for vision and balance

Regeneration of Peripheral Nerves • regeneration of a damaged peripheral nerve fiber can occur if: – its soma is intact – at least some neurilemma remains • fiber distal to the injury cannot survive and degenerates – macrophages clean up tissue debris at the point of injury and beyond • soma swells, ER breaks up, and nucleus moves off center – due to loss of nerve growth factor from neuron’s target cell • axon stump sprouts multiple growth processes – severed distal end continues to degenerate • regeneration tube – formed by Schwann cells, basal lamina, and the neurilemma near the injury – regeneration tube guides the growing sprout back to the original target cells and reestablishes synaptic contact • nucleus returns to normal shape 12 -33 • regeneration of damaged nerve fibers in the CNS cannot occur at all

Regeneration of Nerve Fiber Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Neuromuscular junction Myelin sheath Endoneurium Muscle fiber 1 Normal nerve fiber Local trauma Degenerating terminal Macrophages 2 Injured fiber Degenerating Schwann cells Degenerating axon 3 Degeneration of severed fiber Growth processes 4 Early regeneration Schwann cells denervation atrophy of muscle due to loss of nerve contact by damaged nerve Regeneration tube Atrophy of muscle fibers Retraction of growth processes Growth processes 5 Late regeneration 6 Regenerated fiber Regrowth of muscle fibers Figure 12. 9 12 -34

Electrophysiology of Neurons • Galen thought that the brain pumped a vapor called psychic pneuma through hollow nerves and squirted in to the muscles to make them contract • Rene’ Descartes in the 17 th century supported this theory • Luigi Galvani discovered the role of electricity in muscle contraction in the 18 th century • Camillo Golgi developed important method for staining neurons with silver in the 19 th century • Santiago Ramon y Cajal set forth the neuron doctrine – nervous pathway is not a continuous ‘wire’ or tube, but a series of cells separated by gaps called synapses. • neuron doctrine brought up two key questions: – how does a neuron generate a electrical signal? – how does it transmit a meaningful message to the next cell? 12 -35

Nerve Growth Factor • nerve growth factor (NGF) – a protein secreted by a gland, muscle, and glial cells and picked up by the axon terminals of the neurons. – prevents apoptosis (programmed cell death) in growing neurons – enables growing neurons to make contact with their target cells • isolated by Rita Levi-Montalcini in 1950 s • won Nobel prize in 1986 with Stanley Cohen • use of growth factors is now a vibrant field of research 12 -36

Electrical Potentials and Currents • electrophysiology – cellular mechanisms for producing electrical potentials and currents – basis for neural communication and muscle contraction • electrical potential – a difference in the concentration of charged particles between one point and another • electrical current – a flow of charged particles from one point to another – in the body, currents are movement of ions, such as Na+ or K+ through gated channels in the plasma membrane – gated channels are opened or closed by various stimuli – enables cell to turn electrical currents on and off • living cells are polarized • resting membrane potential (RMP) – charge difference across the plasma membrane – -70 m. V in a resting, unstimulated neuron – negative value means there are more negatively charged particles on the inside of the membrane than on the outside 12 -37

Resting Membrane Potential • RMP exists because of unequal electrolyte distribution between extracellular fluid (ECF) and intracellular fluid (ICF) • RMP results from the combined effect of three factors: – ions diffuse down their concentration gradient through the membrane – plasma membrane is selectively permeable and allows some ions to pass easier than others – electrical attraction of cations and anions to each other 12 -38

Creation of Resting Membrane Potential • potassium ions (K+) have the greatest influence on RMP – plasma membrane is more permeable to K+ than any other ion – leaks out until electrical charge of cytoplasmic anions attracts it back in and equilibrium is reached and net diffusion of K+ stops – K+ is about 40 times as concentrated in the ICF as in the ECF • cytoplasmic anions can not escape due to size or charge (phosphates, sulfates, small organic acids, proteins, ATP, and RNA) • membrane much less permeable to high concentration of sodium (Na+) found outside the cell – some leaks and diffuses into the cell down its concentration gradient – Na+ is about 12 times as concentrated in the ECF as in the ICF – resting membrane is much less permeable to Na+ than K+ • Na+/K+ pumps out 3 Na+ for every 2 K+ it brings in – works continuously to compensate for Na+ and K+ leakage, and requires great deal of ATP • 70% of the energy requirement of the nervous system – necessitates glucose and oxygen be supplied to nerve tissue (energy needed to create the resting potential) – pump contributes about -3 m. V to the cell’s resting membrane potential of -70 m. V 12 -39

Ionic Basis of Resting Membrane Potential Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. ECF Na+ 145 m. Eq/L K+ Na+ channel K+ channel 4 m. Eq/L Figure 12. 11 Na+ 12 m. Eq/L ICF K+ 150 m. Eq/L Large anions that cannot escape cell • Na+ concentrated outside of cell (ECF) • K+ concentrated inside cell (ICF) 12 -40

Local Potentials • local potentials - disturbances in membrane potential when a neuron is stimulated • neuron response begins at the dendrite, spreads through the soma, travels down the axon, and ends at the synaptic knobs • when neuron is stimulated by chemicals, light, heat or mechanical disturbance – – opens the Na+ gates and allows Na+ to rush in to the cell Na+ inflow neutralizes some of the internal negative charge voltage measured across the membrane drifts toward zero depolarization - case in which membrane voltage shifts to a less negative value – Na+ diffuses for short distance on the inside of the plasma membrane producing a current that travels towards the cell’s trigger zone – this shortrange change in voltage is called a local potential 12 -41

Characteristics of Local Potentials • differences of local potentials from action potentials – are graded - vary in magnitude with stimulus strength • stronger stimuli open more Na+ gates – are decremental - get weaker the farther they spread from the point of stimulation • voltage shift caused by Na+ inflow diminishes rapidly with distance – are reversible - when stimulation ceases, K+ diffusion out of cell returns the cell to its normal resting potential – can be either excitatory or inhibitory - some neurotransmitters (glycine) make the membrane potential more negative – hyperpolarize it – becomes less sensitive and less likely to produce an action 12 -42 potential

Excitation of a Neuron by a Chemical Stimulus Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Dendrites Soma Trigger zone Axon Current ECF Ligand Receptor Plasma membrane of dendrite Na+ ICF Figure 12. 12 12 -43

Action Potentials • action potential – more dramatic change produced by voltageregulated ion gates in the plasma membrane – only occur where there is a high enough density of voltage-regulated gates – soma (50 -75 gates per m 2 ) - cannot generate an action potential – trigger zone (350 – 500 gates per m 2 ) – where action potential is generated • if excitatory local potential spreads all the way to the trigger zone, and is still strong enough when it arrives, it can open these gates and generate an action potential • action potential is a rapid up-and-down shift in the membrane voltage – sodium ions arrive at the axon hillock – depolarize the membrane at that point – threshold – critical voltage to which local potentials must rise to open the voltage-regulated gates • -55 m. V 12 -44

Action Potentials – when threshold is reached, neuron ‘fires’ and produces an action potential – more and more Na+ channels open in in the trigger zone in a positive feedback cycle creating a rapid rise in membrane voltage – spike – when rising membrane potential passes 0 m. V, Na+ gates are inactivated • • begin closing when all closed, the voltage peaks at +35 m. V membrane now positive on the inside and negative on the outside polarity reversed from RMP - depolarization – by the time the voltage peaks, the slow K+ gates are fully open • K+ repelled by the positive intracellular fluid now exit the cell • their outflow repolarizes the membrane – shifts the voltage back to negative numbers returning toward RMP – K+ gates stay open longer than the Na+ gates • slightly more K+ leaves the cell than Na+ entering • drops the membrane voltage 1 or 2 m. V more negative than the original RMP – negative overshoot – hyperpolarization or afterpotential – Na+ and K+ switch places across the membrane during an action potential 12 -45

Action Potentials • only a thin layer of the cytoplasm next to the cell membrane is affected Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. 4 +35 • in reality, very few ions are involved – follows an all-or-none law • if threshold is reached, neuron fires at its maximum voltage • if threshold is not reached it does not fire – nondecremental - do not get weaker with distance – irreversible - once started goes to completion and can not be stopped 5 0 Depolarization m. V • action potential is often called a spike – happens so fast • characteristics of action potential versus a local potential 3 Repolarization Action potential Threshold 2 – 55 Local potential 1 7 – 70 Resting membrane potential 6 Hyperpolarization Time (a) Figure 12. 13 a 12 -46

Action Potential vs. Local Potential Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. 4 +35 3 +35 Spike 5 0 Repolarization 0 Action potential m. V Depolarization Threshold 2 – 55 Local potential 1 7 Hyperpolarization – 70 Resting membrane potential 6 Hyperpolarization – 70 0 Time (a) (b) 10 20 30 40 50 msec Figure 12. 13 a-b 12 -47

Sodium and Potassium Gates Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. K+ Na+ K+ gate 1 Na+ and K+ gates closed 35 0 – 70 Resting membrane potential m. V Na+ gate 2 Na+ gates open, Na + enters cell, K + gates beginning to open 35 0 – 70 Depolarization begins 35 0 – 70 Depolarization ends, repolarization begins 4 Na+ gates closed, K+ gates closing m. V 3 Na+ gates closed, K + gates fully open, K+ leaves cell m. V Figure 12. 14 – 70 Repolarization complete 12 -48

The Refractory Period • • during an action potential and for a few milliseconds after, it is difficult or impossible to stimulate that region of a neuron to fire again. refractory period – the period of resistance to stimulation two phases of the refractory period – absolute refractory period • no stimulus of any strength will trigger AP • as long as Na+ gates are open • from action potential to RMP – relative refractory period • only especially strong stimulus will trigger new AP – K+ gates are still open and any affect of incoming Na+ is opposed by the outgoing K+ refractory period is occurring only at a small patch of the neuron’s membrane at one time other parts of the neuron can be stimulated while the small part is in refractory period Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Absolute refractory period Relative refractory period +35 0 m. V • Threshold – 55 Resting membrane potential – 70 Time Figure 12. 15 12 -49

Signal Conduction in Unmyelinated Fibers • for communication to occur, the nerve signal must travel to the end of the axon • unmyelinated fiber has voltage-regulated ion gates along its entire length • action potential from the trigger zone causes Na+ to enter the axon and diffuse into adjacent regions beneath the membrane • the depolarization excites voltage-regulated gates immediately distal to the action potential. • Na+ and K+ gates open and close producing a new action potential • by repetition the membrane distal to that is excited • chain reaction continues to the end of the axon 12 -50

Nerve Signal Conduction Unmyelinated Fibers Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Dendrites Cell body Axon Signal Action potential in progress Refractory membrane Excitable membrane ++++–––++++++ ––––+++–––––– +++–––––– ++++–––++++++–––++++++ –––––––––+++–––––– +++++–––+++++++–––++ –––––––––––––+++–– +++++++–––++ Figure 12. 16 12 -51

Saltatory Conduction Myelinated Fibers • voltage-gated channels needed for APs – fewer than 25 per m 2 in myelin-covered regions (internodes) – up to 12, 000 per m 2 in nodes of Ranvier • fast Na+ diffusion occurs between nodes – signal weakens under myelin sheath, but still strong enough to stimulate an action potential at next node • saltatory conduction – the nerve signal seems to jump from node to node Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Figure 12. 17 a (a) Na+ inflow at node generates action potential (slow but nondecremental) Na+ diffuses along inside of axolemma to next node (fast but decremental) Excitation of voltageregulated gates will generate next action potential here 12 -52

Saltatory Conduction Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. + – – + – + + – + – – + + – – + + – – + + – – + + – – + + – – + – + – – + + – – + (b) Action potential in progress Refractory membrane Excitable membrane Figure 12. 17 b • much faster than conduction in unmyelinated fibers 12 -53

Synapses • a nerve signal can go no further when it reaches the end of the axon – triggers the release of a neurotransmitter – stimulates a new wave of electrical activity in the next cell across the synapse • synapse between two neurons – 1 st neuron in the signal path is the presynaptic neuron • releases neurotransmitter – 2 nd neuron is postsynaptic neuron • responds to neurotransmitter • presynaptic neuron may synapse with a dendrite, soma, or axon of postsynaptic neuron to form axodendritic, axosomatic or axoaxonic synapses • neuron can have an enormous number of synapses – spinal motor neuron covered by about 10, 000 synaptic knobs from other neurons • 8000 ending on its dendrites • 2000 ending on its soma • in cerebellum of brain, one neuron can have as many as 100, 000 synapses 12 -54

Synaptic Relationships Between Neurons Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Soma Synapse Axon Presynaptic neuron Direction of signal transmission Postsynaptic neuron (a) Axodendritic synapse Axosomatic synapse (b) Figure 12. 18 Axoaxonic synapse 12 -55

Discovery of Neurotransmitters • synaptic cleft -gap between neurons was discovered by Ramón y Cajal through histological observations • Otto Loewi, in 1921, demonstrated that neurons communicate by releasing chemicals – chemical synapses – – he flooded exposed hearts of two frogs with saline stimulated vagus nerve of the first frog and the heart slowed removed saline from that frog and found it slowed heart of second frog named it Vagusstoffe (“vagus substance”) • later renamed acetylcholine, the first known neurotransmitter • electrical synapses do exist – some neurons, neuroglia, and cardiac and single-unit smooth muscle – gap junctions join adjacent cells • ions diffuse through the gap junctions from one cell to the next – advantage of quick transmission • no delay for release and binding of neurotransmitter • cardiac and smooth muscle and some neurons – disadvantage is they cannot integrate information and make decisions • ability reserved for chemical synapses in which neurons communicate by releasing neurotransmitters 12 -56

Synaptic Knobs Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Axon of presynaptic neuron Synaptic knob Soma of postsynaptic neuron © Omikron/Science Source/Photo Researchers, Inc Figure 12. 19 12 -57

Structure of a Chemical Synapse • synaptic knob of presynaptic neuron contains synaptic vesicles containing neurotransmitter – many docked on release sites on plasma membrane • ready to release neurotransmitter on demand – a reserve pool of synaptic vesicles located further away from membrane • postsynaptic neuron membrane contains proteins that function as receptors and ligand-regulated ion gates 12 -58

Structure of a Chemical Synapse Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Microtubules of cytoskeleton Axon of presynaptic neuron Mitochondria Postsynaptic neuron Synaptic knob Synaptic vesicles containing neurotransmitter Synaptic cleft Neurotransmitter receptor Postsynaptic neuron Neurotransmitter release Figure 12. 20 • presynaptic neurons have synaptic vesicles with neurotransmitter and postsynaptic have receptors and ligand-regulated ion channels 12 -59

Neurotransmitters and Related Messengers • more than 100 neurotransmitters have been identified • fall into four major categories according to chemical composition – acetylcholine • in a class by itself • formed from acetic acid and choline – amino acid neurotransmitters • include glycine, glutamate, aspartate, and -aminobutyric acid (GABA) – monoamines • synthesized from amino acids by removal of the –COOH group • retaining the –NH 2 (amino) group • major monoamines are: – epinephrine, norepinephrine, dopamine (catecholamines) – histamine and serotonin – neuropeptides 12 -60

Categories of Neurotransmitters Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Acetylcholine CH 3 O + H 3 C N CH 2 O C CH 3 Catecholamines HO OH CH CH 2 NH CH 2 Amino acids HO HO C CH 2 NH 2 O HO GABA C CH 2 Glycine O O C CH CH 2 C HO OH NH 2 O C CH CH 2 HO NH 2 C CH 2 NH 2 Dopamine HO O OH Glutamic acid CH 2 NH 2 N N N Pro Arg Pro Lys Norepinephrine HO Aspartic acid Tyr Enkephalin OH CH CH 2 NH 2 HO HO NH 2 Met Phe Gly Epinephrine HO O Neuropeptides Monoamines Serotonin CH 2 NH 2 Histamine Glu Phe Gly Leu Met Substance P Asp Tyr Met Gly Trp Met Asp Met Phe Ser Thr Gly Glu Gly Lys SO 4 Phe Cholecystokinin Tyr ß-endorphin Ser Glu Thr Pro Leu Val Thr Leu Phe Asn Lys Ala IIe Lys Asn Ala Tyr Lys Gly Glu Figure 12. 21 12 -61

Neuropeptides • chains of 2 to 40 amino acids – beta-endorphin and substance P • act at lower concentrations than other neurotransmitters Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Neuropeptides Met Phe Gly Tyr Enkephalin Pro Arg Pro Lys • longer lasting effects • stored in axon terminal as larger secretory granules (called dense-core vesicles) • some function as hormones or neuromodulators • some also released from digestive tract – gut-brain peptides cause food cravings Glu Phe Gly Leu Met Substance P Asp Tyr Met Gly Trp Met Asp Met Phe Ser Thr Gly Glu Gly Lys SO 4 Phe Cholecystokinin Tyr ß-endorphin Ser Glu Thr Pro Leu Val Thr Leu Phe Asn Lys Ala IIe Lys Asn Ala Tyr Lys Gly Glu Figure 12. 21 12 -62

Function of Neurotransmitters at Synapse • they are synthesized by the presynaptic neuron • they are released in response to stimulation • they bind to specific receptors on the postsynaptic cell • they alter the physiology of that cell 12 -63

Effects of Neurotransmitters • a given neurotransmitter does not have the same effect everywhere in the body • multiple receptor types exist for a particular neurotransmitter – 14 receptor types for serotonin • receptor governs the effect the neurotransmitter has on the target cell 12 -64

Synaptic Transmission • neurotransmitters are diverse in their action – some excitatory – some inhibitory – some the effect depends on what kind of receptor the postsynaptic cell has – some open ligand-regulated ion gates – some act through second-messenger systems • three kinds of synapses with different modes of action – excitatory cholinergic synapse – inhibitory GABA-ergic synapse – excitatory adrenergic synapse • synaptic delay – time from the arrival of a signal at the axon terminal of a presynaptic cell to the beginning of an action potential in the postsynaptic cell – 0. 5 msec for all the complex sequence of events to occur 12 -65

Excitatory Cholinergic Synapse • cholinergic synapse – employs acetylcholine (ACh) as its neurotransmitter – ACh excites some postsynaptic cells • skeletal muscle – inhibits others • describing excitatory action – nerve signal approaching the synapse, opens the voltage-regulated calcium gates in synaptic knob – Ca 2+ enters the knob – triggers exocytosis of synaptic vesicles releasing ACh – empty vesicles drop back into the cytoplasm to be refilled with ACh – reserve pool of synaptic vesicles move to the active sites and release their ACh – ACh diffuses across the synaptic cleft – binds to ligand-regulated gates on the postsynaptic neuron – gates open – allowing Na+ to enter cell and K+ to leave • pass in opposite directions through same gate – as Na+ enters the cell it spreads out along the inside of the plasma membrane and depolarizes it producing a local potential called the postsynaptic potential – if it is strong enough and persistent enough – it opens voltage-regulated ion gates in the trigger zone 12 -66 – causing the postsynaptic neuron to fire

Excitatory Cholinergic Synapse Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Presynaptic neuron 3 Ca 2+ 1 2 ACh Na+ – – – + + + 4 K+ – – + + 5 Figure 12. 22 Postsynaptic neuron 12 -67

Inhibitory GABA-ergic Synapse • GABA-ergic synapse employs -aminobutyric acid as its neurotransmitter • nerve signal triggers release of GABA into synaptic cleft • GABA receptors are chloride channels • Cl- enters cell and makes the inside more negative than the resting membrane potential • postsynaptic neuron is inhibited, and less likely to fire 12 -68

Excitatory Adrenergic Synapse • adrenergic synapse employs the neurotransmitter norepinephrine (NE) also called noradrenaline • NE and other monoamines, and neuropeptides acts through second messenger systems such as cyclic AMP (c. AMP) • receptor is not an ion gate, but a transmembrane protein associated with a G protein – unstimulated NE receptor is bound to a G protein – binding of NE to the receptor causes the G protein to dissociate from it – G protein binds to adenylate cyclase • activates this enzyme – induces the conversion of ATP to cyclic AMP – cyclic AMP can induce several alternative effects in the cell • causes the production of an internal chemical that binds to a ligand-regulated ion gate from inside of the membrane, opening the gate and depolarizing the cell • can activate preexisting cytoplasmic enzymes that lead do diverse metabolic changes • can induce genetic transcription, so that the cell produces new cytoplasmic enzymes that can lead to diverse metabolic effects • slower to respond than cholinergic and GABA-ergic synapses • has advantage of enzyme amplification – single molecule of NE can produce vast numbers of product molecules in the cell 12 -69

Excitatory Adrenergic Synapse Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Presynaptic neuron Postsynaptic neuron Neurotransmitter receptor Norepinephrine Adenylate cyclase G protein – – – + + + 1 2 3 ATP c. AMP Ligand 5 regulated gates opened 4 Enzyme activation 6 Metabolic changes Multiple possible effects Na+ Postsynaptic potential Figure 12. 23 7 Genetic transcription 12 -70 Enzyme synthesis

Cessation of the Signal • mechanisms to turn off stimulation to keep postsynaptic neuron from firing indefinitely – neurotransmitter molecule binds to its receptor for only 1 msec or so • then dissociates from it – if presynaptic cell continues to release neurotransmitter • one molecule is quickly replaced by another and the neuron is restimulated • stop adding neurotransmitter and get rid of that which is already there – stop signals in the presynaptic nerve fiber – getting rid of neurotransmitter by: • diffusion – neurotransmitter escapes the synapse into the nearby ECF – astrocytes in CNS absorb it and return it to neurons • reuptake – synaptic knob reabsorbs amino acids and monoamines by endocytosis – break neurotransmitters down with monoamine oxidase (MAO) enzyme – some antidepressant drugs work by inhibiting MAO • degradation in the synaptic cleft – enzyme acetylcholinesterase (ACh. E) in synaptic cleft degrades ACh into acetate and choline 12 -71 – choline reabsorbed by synaptic knob

Neuromodulators • neuromodulators – hormones, neuropeptides, and other messengers that modify synaptic transmission – may stimulate a neuron to install more receptors in the postsynaptic membrane adjusting its sensitivity to the neurotransmitter – may alter the rate of neurotransmitter synthesis, release, reuptake, or breakdown • enkephalins – a neuromodulator family – small peptides that inhibit spinal interneurons from transmitting pain signals to the brain • nitric oxide (NO) – simpler neuromodulator – a lightweight gas release by the postsynaptic neurons in some areas of the brain concerned with learning and memory – diffuses into the presynaptic neuron – stimulates it to release more neurotransmitter – one neuron’s way of telling the other to ‘give me more’ – some chemical communication that goes backward across 12 -72 the synapse

Neural Integration • synaptic delay slows the transmission of nerve signals • more synapses in a neural pathway, the longer it takes for information to get from its origin to its destination – synapses are not due to limitation of nerve fiber length – gap junctions allow some cells to communicate more rapidly than chemical synapses • then why do we have synapses? – to process information, store it, and make decisions – chemical synapses are the decision making devises of the nervous system – the more synapses a neuron has, the greater its informationprocessing capabilities. – pyramidal cells in cerebral cortex have about 40, 000 synaptic contacts with other neurons – cerebral cortex (main information-processing tissue of your brain) has an estimated 100 trillion (1014) synapses • neural integration – the ability of your neurons to process 12 -73 information, store and recall it, and make decisions

Postsynaptic Potentials - EPSP • neural integration is based on the postsynaptic potentials produced by neurotransmitters • typical neuron has a resting membrane potential of -70 m. V and threshold of about -55 m. V • excitatory postsynaptic potentials (EPSP) – any voltage change in the direction of threshold that makes a neuron more likely to fire • usually results from Na+ flowing into the cell cancelling some of the negative charge on the inside of the membrane – glutamate and aspartate are excitatory brain neurotransmitters that produce EPSPs 12 -74

Postsynaptic Potentials - IPSP • inhibitory postsynaptic potentials (IPSP) – any voltage change away from threshold that makes a neuron less likely to fire • neurotransmitter hyperpolarizes the postsynaptic cell and makes it more negative than the RMP making it less likely to fire • produced by neurotransmitters that open ligand-regulated chloride gates – causing inflow of Cl- making the cytosol more negative – glycine and GABA produce IPSPs and are inhibitory – acetylcholine (ACh) and norepinephrine are excitatory to some cells and inhibitory to others • depending on the type of receptors on the target cell • ACh excites skeletal muscle, but inhibits cardiac muscle due to the different type of receptors 12 -75

Postsynaptic Potentials Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. 0 m. V – 20 – 40 Threshold Repolarization – 80 (a) Resting membrane potential EPSP – 60 Depolarization Stimulus Time 0 m. V – 20 – 40 Threshold – 60 IPSP Resting membrane potential – 80 Hyperpolarization (b) Stimulus Time Figure 12. 24 12 -76

Summation, Facilitation, and Inhibition • one neuron can receive input from thousands of other neurons • some incoming nerve fibers may produce EPSPs while others produce IPSPs • neuron’s response depends on whether the net input is excitatory or inhibitory • summation – the process of adding up postsynaptic potentials and responding to their net effect – occurs in the trigger zone • the balance between EPSPs and IPSPs enables the nervous system to make decisions • temporal summation – occurs when a single synapse generates EPSPs so quickly that each is generated before the previous one fades – allows EPSPs to add up over time to a threshold voltage that triggers an action potential • spatial summation – occurs when EPSPs from several different synapses add up to threshold at an axon hillock. – several synapses admit enough Na+ to reach threshold – presynaptic neurons cooperate to induce the postsynaptic neuron to fire 12 -77

Temporal and Spatial Summation Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. 1 Intense stimulation by one presynaptic neuron 2 EPSPs spread from one synapse to trigger zone 3 Postsynaptic neuron fires (a) Temporal summation 3 Postsynaptic neuron fires 2 EPSPs spread from several synapses 1 Simultaneous stimulation to trigger zone by several presynaptic neurons (b) Spatial summation Figure 12. 25 12 -78

Summation of EPSPs Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. +40 +20 0 m. V Action potential – 20 Threshold – 40 – 60 – 80 EPSPs Resting membrane potential Stimuli Figure 12. 26 Time • does this represent spatial or temporal summation? 12 -79

Summation, Facilitation, and Inhibition • neurons routinely work in groups to modify each other’s action • facilitation – a process in which one neuron enhances the effect of another one – combined effort of several neurons facilitates firing of postsynaptic neuron • presynaptic inhibition – process in which one presynaptic neuron suppresses another one – the opposite of facilitation – reduces or halts unwanted synaptic transmission – neuron I releases inhibitory GABA • prevents voltage-gated calcium channels from opening in synaptic knob and presynaptic neuron releases less or no neurotransmitter Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Signal in presynaptic neuron Signal in inhibitory neuron No activity in inhibitory neuron I I Neurotransmitter No neurotransmitter release here Neurotransmitter Excitation of postsynaptic neuron (a) Inhibition of presynaptic neuron S EPSP No neurotransmitter release here R No response in postsynaptic neuron (b) Figure 12. 27 IPSP S R 12 -80

Neural Coding • neural coding – the way in which the nervous system converts information to a meaningful pattern of action potentials • qualitative information depends upon which neurons fire – labeled line code – each nerve fiber to the brain leads from a receptor that specifically recognizes a particular stimulus type • quantitative information – information about the intensity of a stimulus is encoded in two ways: – one depends on the fact that different neurons have different thresholds of excitation • stronger stimuli causes a more rapid firing rate • excitement of sensitive, low threshold fibers gives way to excitement of less sensitive, high-threshold fibers as intensity of stimuli increases – other way depends on the fact that the more strongly a neuron is stimulated, the more frequently it fires • CNS can judge stimulus strength from the firing frequency of afferent neurons 12 -81

Neural Coding Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Action potentials 2 g 5 g 10 g 20 g Time Figure 12. 28 12 -82

Neural Pools and Circuits • neural pools – neurons function in large groups, each of which consists of millions of interneurons concerned with a particular body function – control rhythm of breathing – moving limbs rhythmically when walking • information arrives at a neural pool through one or more input neurons – branch repeatedly and synapse with numerous interneurons in the pool – some input neurons form multiple synapses with a single postsynaptic cell • can produce EPSPs in all points of contact with that cell • through spatial summation, make it fire more easily than if they synapsed with it at only one point – within the discharge zone of an input neuron • that neuron acting alone can make the postsynaptic cells fire – in a broader facilitated zone, it synapses with still other neurons in the pool • fewer synapses on each of them • can only stimulate those neurons to fire only with the assistance of other input neurons Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Input neuron Facilitated zone Discharge zone Figure 12. 29 Facilitated zone 12 -83

Kinds of Neural Circuits • diverging circuit – one nerve fiber branches and synapses with several postsynaptic cells – one neuron may produce output through hundreds of neurons • converging circuit – input from many different nerve fibers can be funneled to one neuron or neural pool – opposite of diverging circuit • reverberating circuits – neurons stimulate each other in linear sequence but one cell restimulates the first cell to start the process all over – diaphragm and intercostal muscles • parallel after-discharge circuits – input neuron diverges to stimulate several chains of neurons • each chain has a different number of synapses • eventually they all reconverge on a single output neuron • after-discharge – continued firing after the stimulus stops 12 -84

Neural Circuits Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Diverging Converging Input Output Input Reverberating Parallel after-discharge Figure 12. 30 Input Output 12 -85

Memory and Synaptic Plasticity • physical basis of memory is a pathway through the brain called a memory trace or engram – along this pathway, new synapses were created or existing synapses modified to make transmission easier – synaptic plasticity – the ability of synapses to change – synaptic potentiation - the process of making transmission easier • kinds of memory – immediate, short- and long-term memory – correlate with different modes of synaptic potentiation 12 -86

Immediate Memory • immediate memory – the ability to hold something in your thoughts for just a few seconds – essential for reading ability • feel for the flow of events (sense of the present) • our memory of what just happened “echoes” in our minds for a few seconds – reverberating circuits 12 -87

Short-Term or Working Memory • short-term memory (STM) - lasts from a few seconds to several hours – quickly forgotten if distracted – calling a phone number we just looked up – reverberating circuits • facilitation causes memory to last longer – tetanic stimulation – rapid arrival of repetitive signals at a synapse • causes Ca 2+ accumulation and postsynaptic cell more likely to fire – post-tetanic potentiation - to jog a memory • Ca 2+ level in synaptic knob stays elevated • little stimulation needed to recover memory 12 -88

Long-Term Memory • types of long-term memory – declarative - retention of events that you can put into words – procedural - retention of motor skills • physical remodeling of synapses – new branching of axons or dendrites • molecular changes - long-term potentiation – changes in receptors and other features increases transmission across “experienced” synapses – effect is longer-lasting 12 -89

Molecular Changes and -Term Memory Long • molecular changes are called long-term potentiation • method described – receptors on synaptic knobs are usually blocked by Mg+2 ions – when bind glutamate and receive tetanic stimuli, they repel Mg+2 and admit Ca+2 into the dendrite – Ca+2 acts as second messenger • more synaptic knob receptors are produced • synthesizes proteins involved n synapse remodeling • releases nitric oxide that triggers more neurotransmitter release at presynaptic neuron 12 -90

Alzheimer Disease • 100, 000 deaths/year – 11% of population over 65; 47% by age 85 • memory loss for recent events, moody, combative, lose ability to talk, walk, and eat • show deficiencies of acetylcholine (ACh) and nerve growth factor (NGF) • diagnosis confirmed at autopsy – atrophy of gyri (folds) in cerebral cortex – neurofibrillary tangles and senile plaques – formation of beta-amyloid protein from breakdown product of plasma membranes • genetics implicated • treatment - halt beta-amyloid production – research halted due to serious side effects – Give NGF or cholinesterase inhibitors 12 -91

Alzheimer Disease Effects Copyright © The Mc. Graw-Hill Companies, Inc. Permission required for reproduction or display. Neurons with neurofibrillary tangles Shrunken gyri Wide sulci Senile plaque (b) (a) Custom Medical Stock Photo, Inc. Figure 12. 31 a © Simon Fraser/Photo Researchers, Inc. Figure 12. 31 b 12 -92

Parkinson Disease • progressive loss of motor function beginning in 50’s or 60’s no recovery – degeneration of dopamine-releasing neurons • dopamine normally prevents excessive activity in motor centers (basal nuclei) • involuntary muscle contractions – pill-rolling motion, facial rigidity, slurred speech, – illegible handwriting, slow gait • treatment - drugs and physical therapy – dopamine precursor (L-dopa) crosses brain barrier – bad side effects on heart & liver – MAO inhibitor slows neural degeneration – surgical technique to relieve tremors 12 -93