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BIOL 125: HUMAN PHYSIOLOGYLECTURES 1-4: THE BRAIN AND THE NERVOUS SYSTEMPhysiology  Study of how the body works is largely concerned with homeostasis o Homeostasis is how body function is maintained at a reasonably constant level in different environments and circumstancesFunctions of the Nervous S...

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BIOL 125: HUMAN PHYSIOLOGY LECTURES 1-4: THE BRAIN AND THE NERVOUS SYSTEM Physiology  Study of how the body works is largely concerned with homeostasis o Homeostasis is how body function is maintained at a reasonably constant level in different environments and circumstances Functions of the Nervous System  Enables rapid and flexible response to changes in external and internal environment of the body o Sensory function  Senses external and internal changes o Integrative function  Analyses and stores this information to make decisions on appropriate voluntary and involuntary responses o Motor function  Initiates muscular activity or glandular secretion Central and Peripheral Nervous System  CNS (Brain and Spinal Cord) o Integrates sensory information o Generates thoughts and emotions o Stores memory o Makes decisions o Initiates motor activity  PNS (Cranial and Spinal Nerves) o Arise from brain and spinal cord o Carry nerve impulses to and from the CNS o Connects CNS to sensory receptors, muscles and glands Somatic and Autonomous Nervous System  Somatic Nervous System (SNS) o Controls skeletal muscle contraction which can be voluntary or involuntary  Autonomic Nervous System (ANS) o Provides automatic, subconscious control of smooth muscle, cardiac muscle, and glandular secretion A Simple Example – The Knee Jerk Reflex  Involves the somatic nervous system, under involuntary control  Integrative function is performed by CNS interneurons in the spinal cord, which inhibit contraction of the flexor muscles

Nervous System – Cells  Neurons are specialised for cell signalling and don’t divide (generally lack centrioles)  Glia (neuroglia) support and protect neurons, maintain homeostasis, and can divide, e.g. to form glial scars in brain damage o The brain contains ~ 1011 neurons and 1012 glial cells o Both contribute approximately equally to brain weight  Image to the right is of a pyramidal neuron

Apical dendrites

Synapses Cell body

Basal Components of a Nerve Cell  Cell body (soma or perikaryon) dendrites o Contains the normal cell organelles o Main site of protein synthesis and degradation o Has pronounced rough ER = ‘Nissl’ substance  Dendrites o Short, bristle-like, highly branched processes o Receive nerve input at synapses o Not myelinated (bottom left of image)  Neurite o An axon of a dendrite (undetermined)  Axon o Long, thin process o Propagates nerve impulses to another neuron, muscle fibre or gland o Often myelinated, by oligodendrocytes (CNS) or Schwann cells (PNS) o Terminates at axon terminals/ synapses

Axonal Transport  Intracellular organelles of neurons resemble those of other types of cell, but they have unique features o They can have very long axons, so nerve terminals are remote from the cell body, which is the main site of protein synthesis and degradation o Materials are transported from the cell body to (orthograde or anterograde transport) and from (retrograde transport) the axon terminals o Have a well-defined cytoskeleton with a special type of intermediate filament (neurofilament) Components of Neuronal Cytoskeleton  Actin microfilaments for a meshwork under the cell surface  Microtubules and neurofilaments o Cross-linked to themselves and to each other by microtubule-associated proteins (MAPs)  involved in motility, structural support and axonal transport  Tau is a MAP that accumulates inside nerve cells in Alzheimer’s disease, to form neurofibrillary tangles Materials Carried by Axonal Transport

Axonal Transport in Action  Vesicles labelled with fluorescent dye trafficking along the axon of a chick dorsal root ganglion Structural Classification of Neurons  Bipolar Neurons o One main dendrite and one axon o Retina of the eye, inner ear, olfactory area of the brain  Unipolar Neurons o Just one process from the cell body, part way down the axon o Always sensory neurons (pain, temperature, touch, pressure)  Multipolar Neurons o Many dendrites and one axon

o Most neurons in the CNS are multipolar neurons Glial Cells in the CNS  Astrocytes (Star Shaped) o Surround neurons and bloody vessels o Aid neuronal cell migration and axon growth o Contribute to blood-brain barrier o Regulate ionic environment of nerve cells o Take up neurotransmitters o Make growth factors o Activated in disease o Can form glial scars o Note that the ‘end feet’ of astrocytes about on to capillary blood vessels and contribute to the blood-brain barrier (BBB)  This helps to maintain the unique internal environment of the brain by preventing easy passage of materials from blood into brain  Oligodendrocytes o Source of CNS myelin o Single cell can myelinate >50 axons with each myelin segment for a single oligodendrocyte  Microglial Cells o Scavenger cells (macrophages) which can remove debris from dying neurons o May enter from blood  Ependymal Cells o Line fluid filled ventricles o Produce and circulate cerebrospinal fluid Glial Cells in the PNS  Schwann Cells (neurolemmocytes) o Source of PNS myelin, each cell produces part of the myelin, around only a single axon  Satellite Cells o Flattened cells around cell bodies of neurons in PNS ganglia Myelin Sheath in CNS vs PNS

The Human Brain – External Features

The Four Major Parts of the Brain  Brain Stem o Continuous with spinal cord o Respiratory and cardiovascular control, swallowing, vomiting  Cerebellum o Behind brain stem o Co-ordinates movement, balance, posture and maintains muscle tone  Diencephalon o Principally the thalamus and hypothalamus, above brain stem o Pain, touch, hot/ cold sensations, sound, taste, smell, thirst, sleep patterns Cerebellum  Outside is grey matter (cortex), inside is white matter  Divided into 2 hemispheres, connected by the corpus callosum  Cortex is highly convoluted with sulci and gyri  Each hemisphere is divided into frontal, parietal, occipital and temporal lobes  Cerebral cortex contains: o Somatosensory areas (anterior parietal) o Motor areas (posterior frontal) o Association cortex (others)

Signalling in Nerve Cells  Neurons receive information at dendrites (up to 100,000 synaptic inputs/ neuron) and integrate in cell body  Information is transmitted along the axon in the form of electrochemical signals or nerve impulses (action potentials)  Action potentials are due to the flow of ions (Na+ and K+) through specific protein channels in the membrane  The lipid bilayer of the membrane is impermeable to these charged ions  You can scan EM pictures with synaptic boutons Transport of Ions Across Cell Membranes  Some ion channels are always open whereas others are regulated or gated  Both types are important in nerve cell physiology Gated Ion Channels  Closed unless activated  Specific for certain ion/s  Can be mechanically gated, ligand-gated, or voltagegated  Voltage-gated are involved in the generation and propagation of nerve impulses  Ligand gated are involved in neurotransmission at the synapse  Mechanically gated (or tension-gated) are involved in the perception of hearing, tough and proprioception  A ligand is a messenger molecule (e.g. a hormone or neurotransmitter)

What Forces Move Ions Across Membranes?

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Chemical driving force (top row) o Due to diffusion from a region of high concentration to a region of low concentration Electrical driving force (bottom row) o Interior of cell is negatively charged so positive cations will be retained, and negative anions will be expelled o The electrochemical driving force is a combination of the chemical and electrical forces acting on any particular ion o It gives the nett force that acts to drive an ion into or out of the cell, through an open membrane channel

Resting Membrane Potential  Inside the axon has a resting membrane potential of around -70mV with respect to the outside  These studies were initially carried out with squid giant axon which can be up to 1mm in diameter  The resting membrane potential (resting Vm) of a nerve cell is the difference in voltage across the plasma membrane when the cell is at rest (i.e. when it is not receiving or sending any signals  The resting membrane potential depends on concentration gradients for multiple ions across the membrane, and on the relative permeability of the membrane to those ions  Most important ions are Na+ and K+ Intracellular and Extracellular Ion Concentrations  ICF = intracellular fluid  ECF = extracellular fluid  There are concentration differences for K+ and Na+ Which Direction will Na+ and K+ Ions Move In?

Equilibrium Potential  The equilibrium potential (E) is the membrane potential required to exactly counteract the chemical forces acting to move one particular ion across the membrane

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The equilibrium potential can be calculated from the Nernst equation as followed: Co 61 o E= log Ci z o E = equilibrium potential (mV) o Z = charge (valence) of the ion o C0 = outside concentration of the ion o Ci = inside concentration of the ion ENa is +60mV (greater than resting Vm) so sodium ions will try and enter the cell o Both chemical and electrical forces act in the same direction EK is -94mV (less than resting Vm) so potassium ions will try to move out of the cell o Chemical and electrical forces act in opposite directions, but chemical force is greater

Forces at Equilibrium Potential  Note that at -70mV the electrical force will be weaker, and will be overcome by the chemical force Stimulation of Nerve Cells  Incoming signals (from sensory stimulus or other neurons) can depolarise the cell membrane, causing the membrane potential to rise from its resting potential -70mV (e.g. open Na+ channels)  If the membrane potential is depolarised beyond a certain critical level (threshold potential = -55mV) then an action potential (nerve impulse) is triggered in the axon  Other incoming signals can reverse and hyperpolarise the membrane (i.e. cause the membrane potential to decrease), so making an action potential less likely Axon Hillock and Trigger Zone  An action potential is initiated at the ‘trigger zone’ of the axon hillock  Flat line – resting potential Stimulation of an Action Potential  Left = weak stimulus  Right = strong stimulus

Action Potentials Move Along Axons

Other Properties of Action Potentials  Each stimulus produces full action potential or none at all (all or none)  Impulses jump from the node of Ranvier to node in myelinated axons (saltatory conduction) at speeds of up to 150 m/sec  Intensity of signal is conveyed by frequency of nerve impulses  There is a short refractory period during which another action potential cannot be stimulated (explains unidirectional movement) Synapses  Can be electrical but usually chemical  Transmitters stored in synaptic vesicles  Amount in one vesicle is called a quantum  Arrival of action potential causes influx of Ca2+ then fusion of vesicles with presynaptic membrane and release of transmitter into synaptic cleft  Transmitter binds to receptor on postsynaptic membrane  Effect of transmitter can be excitatory or inhibitory  Must be mechanism to terminate transmitter’s activity o Catabolism (Degradation) o Uptake of transmitter into axon terminal or glial cells  Gap junctions in an electrical synapse directly connect the cytoplasm of two nerve cells

Chemical Synapse

Physiology of A Chemical Synapse

Integration of Multiple Synaptic Inputs

Criteria for Transmitter Substance

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Synthesised in the neuron Present at presynaptic terminals, packaged within synaptic vesicles Endogenous substance (drug) at reasonable concentration mimics exactly the action of endogenously released transmitter Specific mechanism exists for removing transmitter from synaptic cleft

The Major Known Neurotransmitters

and epinephri ne

-NHCH3

Acetylcholine  Found in the brain (involved in learning and memory), at the neuromuscular junction and in autonomic ganglia  Brain Ach is deficient in Alzheimer’s Disease  Synthesised by choline acetyl transferase  Receptors can be nicotinic (neuromuscular junction, brain, autonomic nerves) or muscarinic (smooth muscle, exocrine glands, brain)  Action is stopped by acetylcholinesterase attached to the extracellular side of synaptic membranes (neuronal and glial) Agonists and Antagonists  Agonists bind to the receptor and stimulate it (mimics transmitter)  Antagonists bind to the receptor but don’t stimulate it (blocks transmitter)

Neuromuscular Junction

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This junction between the axon terminal of a motor neuron and striated muscle fibres is responsible for imitation of muscle contraction In vertebrate’s numerous nicotinic acetylcholine receptors are found at the NMJ

Cholinergic Synapse

Alzheimer’s Disease  First described in 1907 by Alois Alzheimer  Characterised by progressive loss of short-term memory until the patient is completely demented  Neuropathological changed include loss of brain weight, enlargement of ventricles, numerous senile plagues (red dots) and neurofibrillary tangles (NFTs) in the brain (black dots)  NFTs are found inside nerve cells – Tau (a microtubule-associated axonal protein) accumulates in cell bodies and dendrites  Also degeneration of cholinergic nerve cells and loss of cholinergic marker enzymes Catecholamines  Synthesised from tyrosine (Tyr)  Includes noradrenaline, adrenaline and dopamine  Brain lacks phenylalanine hydroxylase (converts Phe to Tyr) so Tyr is transported into brain from blood  Dopamine is associated with motor function and is lost in Parkinson’s disease  Catabolism involves enzymes monoamine oxidase (MAO) and catechol 0methyltransferase (COMT)

Catecholamine Synthesis  Very simple 2 step process

Noradrenaline

Adrenaline

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e o First step using an enzyme (Tyrosine B-hydroxylase) adds an OH group to the benzene o Gives us L-DOPA, ring with 2 hydroxyl groups is a catecholamine (ring structure with 2 hydroxyls) o Removes COOH (Carboxyl group) o Gives you the neurotransmitter dopamine (involved in regulation of movement) o Dopamine pathway is lost in Parkinson’s disease Right Image: Conversion of Dopamine to Noradrenaline and Adrenaline o OH added to create norepinephrine/ noradrenaline o Extra methyl added to noradrenaline to create adrenaline/epinephrine  Can act as a neurotransmitter or a hormone

Parkinson’s Disease  First described in 1817 by James Parkinson  Mean age of onset is around 60 years  It affects 1-2% of those over the age of 65  Characterised by three main symptoms: o Muscle rigidity o Tremor o Bradykinesia (slowness of movement)  Multifactorial disease o Age o Environmental factors o Genetics Parkinson’s Disease and Dopamine  Parkinson’s disease is due to the degeneration of pigmented cells of the substantia nigra pars compacta in the basal ganglia  Results in >50% depletion of the transmitter dopamine L-DOPA Treats Parkinson’s Disease  Symptoms alleviated by L-DOPA which is transported into brain and converted into dopamine  Simultaneous administration of a dopa decarboxylase inhibitor which cannot penetrate into the brain preventing the metabolism to dopamine in the periphery  Inhibitors of MAO and COMT can be given to inhibit dopamine degradation Serotonin (5HT = 5-hydroxytryptamine)  Synthesised from tryptophan by tryptophan hydroxylase and 5-hydroxytryptophan (5-HTP) decarboxylase

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Located mainly in the GI tract and CNS 14 different receptors which are all G-protein-coupled, except for 5-HT3 which is a ligand-gated ion channel Some are excitatory, others inhibitory Hallucinogenic drugs (LSD) act as 5-HT agonists at 5-HT2A/2C receptors Action terminated mainly by reuptake from the synapse via the 5-HT reuptake transported on the presynaptic neuron Can also be inactivated by MAO

Amino Acid Neurotransmitters  Amino acids are present at a higher concentration in the CNS (30 mM) than in any other body tissue  All are non-essential amino acids (made in situ from glycolytic and citric acid cycle intermediates)  Dicarboxylic amino acids (glutamate, aspartate) are excitatory whereas glycine and GABA are inhibitory  Glutamate and GABA are major transmitters in the brain

Peptide Neurotransmitters  There are many types of small peptides (~100 known examples)  The most common type of neurotransmitter is in the hypothalamus  Synthesised as large precursor proteins and transported to synaptic release site – activated by proteolytic cleavage  Slow postsynaptic effects  Actions terminated by extracellular proteases  Often co-released with other classical transmitters  Includes opioids – endorphins, enkephalins and dynorphins  Other examples are substance P, neurotensin, vasoactive intestinal peptide (VIP), etc Other Neurotransmitters  Purines (ATP, GTP and others)  Histamine  Gases – nitric oxide (NO) o Discovery of NO as a neurotransmitter has radically altered our thinking about synaptic transmission o Being a gas, NO is not stored in synaptic vesicles, but is made as required by an enzyme (NOS), from arginine o NO simply diffuses from nerve terminals into adjacent cells and forms of covalent linkages to a multiplicity of targets, which may be enzymes or other targets o Inactivation presumably involves diffusion away

Two Main Types of Neurotransmitter Receptor  Transmitter acts directly on a ligand-gated ion channel to open the channel o Also called an ionotropic receptor o Always stimulatory o Fast – few milliseconds  Transmitter acts indirectly on a G protein-coupled receptor o Also called a metanotrophic receptor o Can trigger opening or closing of a separate ion channel o Can also lead to many other effects on the cell o Slow – up to hours Nicotinic and Muscarinic Receptors

G-Protein Acts Directly On an Ion Channel

Sequence of Events 1. Transmitter binds to receptor

2. 3. 4. 5. 6.

GTP exchanges for GDP on the G protein alpha subunit G protein dissociates from receptor – then ligand as well The 3 subunits (Alpha, beta and Y) of the G protein also dissociate The alpha subunit activates the ion channel The alpha subunit is inactivated by the hydrolysis of GTP to form GDP (GTPase activity is intrinsic to this subunit) 7. The alpha subunit recombines with beta and Y subunits and attaches to the receptor, which can then bind another agonist

G-Proteins and Second Messengers  Some G proteins stimulate (Gs) or inhibit (Gi) enzyme targets instead of acting on ion channels  The most common of these targets are the enzymes o Adenylate cyclase o Guanylate cyclase o Phospholipase C  These enzymes make the corresponding second messengers which can then cause a slow response in the cell o Cyclic AMP or cAMP o Cyclic CMP or cGMP o Inositol triphosphate and diacylglycerol Structure of Ligand-Gated Receptors  Composed of 4 or 5 subunits arranged around a central pore in the membrane  Examples: nicotinic acetylcholine, GABAA, glycine, 5-HT3 receptors o Nicotinic receptor has 5 subunits selected from a possible 17, so there are many combinations (differs in skeletal muscle, autonomic ganglia, brain) o The alpha-subunit binds to acetylcholine, resulting in a conformational change which opens the central ion channel o Nicotinic receptor from electric organ of Torpedo californica Structure of G-Protein Coupled Receptors

Some Well Known Drug Targets

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Tryclic antidepressants (depression) block noradrenaline and serotonin-reuptake SSRIs (depression, obsessive compulsive disorder) also block serotonin re-uptake Valium and other benzodiazepines (anxiety) activate GABA receptors MAO inhibitors (depression, Parkinson’s disease) block breakdown of biogenic amines L-DOPA (Parkinson’s disease) is a dopamine precursor Acetylcholinesterase inhibitors (Alzheimer’s disease) block breakdown of acetylcholine LECTURES 5-8: THE HEART AND CARDI...