GENERAL FUNCTIONS:

detects environmental changes (inside and outside body) interprets changes responds in order to maintain normal or sufficient function (homeostasis)

SENSORY INPUT (sensory neurons) (gathers information from internal and external environment) INTEGRATION (interneurons) (interprets sensory input) MOTOR OUTPUT (motor neurons) (responds via effector organs)

ORGANIZATION:

2 Main Divisions:
1. Central Nervous System structures located in dorsal body cavity integration and command centre interprets sensory input a) Brain b) Spinal Cord

2. Peripheral Nervous System structures located outside CNS contains nerves (bundles of axons) which extend from brain and spinal cord; connects all parts of body (tissue beds) to CNS i) sensory (afferent) division conveys impulses to CNS from sensory receptors located in different organs and tissues ii) motor (efferent) division conveys impulses from CNS to effector organs motor responses and secretion by glands in response to sensory information a) Cranial Nerves carry impulses directly to and from brain b) Spinal Nerves carry impulses to and from spinal cord

motor division is further sub-divided into: a) somatic nervous system voluntary motor control b) autonomic nervous system involuntary motor control

1. Somatic Nervous System governs voluntary (conscious) actions involves the brain and cranial or spinal nerves effectors skeletal muscles 2. Autonomic Nervous System governs involuntary (unconscious) activity involves the brain/brain stem, cranial and spinal nerves effectors: glands, smooth muscle and cardiac muscle

Divisions of the Autonomic Nervous System SYMPATHETIC

Fight or Flight Responses Mobilizes body during increased activity

PARASYMPATHETIC
Rest and Digest Responses Conserves energy

these systems work in opposition to each other many involuntarily controlled organs/effectors are innervated by both sympathetic and parasympathetic nerve fibres (dual innervation but not all we will look at the more significant exceptions to this and what the wisdom is in this arrangement) with dual innervation, end effect at level of organ is the sum of opposing commands

NEURAL TISSUE

98% of neural tissue is found in brain and spinal cord; balance is found peripherally

1.

Neuron - main cell type of nervous system

Characteristics of Neurons:

irritable respond to stimuli conductive send impulses along axon via production of action potential and its propagation amitotic neurons located in CNS dont divide cant be replaced if destruction/death of cell occurs longevity designed to last entire life of organism (because of the above point) high metabolic rate require large oxygen and glucose supply cells die/cease to function adequately rapidly if supply is poor or absent

Basic Neuronal Structure a) soma (cell body) spherical nucleus contains all the same organelles as other cells, but lacks centrioles (no cellular division); soma is focal point for extension of processes (see below); produces proteins and membranes required for maintenance of neuron b) processes extend from soma; brain and spinal cord (CNS) contain cell bodies and their processes; peripheral nervous system (PNS) consists mainly of processes (dependent upon motor division in question)

2 types of processes: i) axon each neuron has 1 axon arises from axon hillock, then narrows to form the diameter of the process; some neurons lack axons or are very short, while others have significant length (long axons are known as nerve fibres) - at their distal ends, axons almost always branch into several terminal branches (often thousands); at the ends of these branches are synaptic knobs (AKA - axon terminals or boutons)

- axon is conducting region, with impulses usually being transmitted away from cell body - axon terminals are the secretory regions of the neuron site of release of neurotransmitters for excitation or inhibition of target tissue (effector cells ex. muscle tissue at neuromuscular junction; may also allow communication with other neurons)

ii) dendrite each neuron has several dendrites (hundreds); they are the main input regions (receive signals/impulses from other neurons) responsible for conduction of impulses toward cell body

Other Neuronal Structures c) myelin sheath long or large-diametered nerve fibres are covered by segmented sheath made of protein-lipid substance (layers of plasma membrane) - protects and insulates fibres and allows faster impulse transmission - fibres lacking myelin sheaths (unmyelinated) are slower conductors are usually thinner in diameter (dendrites lack myelin) - gaps left between segments of myelin are called Nodes of Ranvier

- small axons in the CNS are also unmyelinated - myelinated fibres form white matter in the CNS; unmyelinated fibres and cell bodies form the grey matter of the CNS

Classification of Neurons by Function

a) Sensory (Afferent) Neurons - impulses travel from receptors (dendrites) at level of organs toward the CNS - processes are generally quite long; distal branch acts as receptor region - cell body is usually located outside the CNS in sensory ganglia (cluster of cell bodies, often located close to spinal cord)

c) Interneurons - communication (links) between sensory and motor neurons within the CNS integration/interpretation occurs here based on impulse received from sensory neuron, then synapse occurs between interneuron and motor neuron b) Motor (Efferent) Neurons - impulses travel from CNS to effectors (ex. muscles and glands) in the peripheral regions; cell bodies are located in CNS

***Of greater interest for us regarding this basic pathway: monitoring of the internal (physiological) environment, with subsequent involuntary responses via smooth and cardiac muscle effectors (autonomic nervous system).

2. Neuroglial Cells (other supporting cells of the nervous system) - characteristics: a) no irritability do not respond to stimuli b) no conductivity c) no release of neurotransmitters d) mitotic are capable of division

- some types of neuroglial cells of interest for us: a) astrocytes located in CNS - star-shaped and cling to neurons and capillaries of CNS - allow transfer of nutrients, dissolved gases and ions between neurons and blood - control blood flow through capillaries - absorb and recycle some neurotransmitters - extensions of astrocytes, in part, contribute to structure of blood-brain barrier (assist in making capillaries less permeable in CNS); well look at this more closely later - provide structural framework for neurons in brain

b) ependymal cells - located in CNS - cuboidal or columnar with processes which contact other glial cells - may have cilia or microvilli; some produce cerebrospinal fluid (CSF); line central cavity (ventricle) of brain and spinal cord well look at this more closely later - form barrier between CSF and fluid surrounding nerve cells

NERVES

located in the PNS; contain nerve fibres (axons) and blood vessels wrapped in connective tissue a) sensory nerves sensory receptors of many neurons, wrapped in connective tissue; cell bodies are located in ganglion (cluster of cell bodies) outside of CNS b) motor nerves axons of many neurons, wrapped in connective tissue; cell bodies are not contained in the nerve, but in the spinal cord (CNS) c) mixed nerve both sensory receptors and axons of many different neurons, wrapped in connective tissue

TRACTS

bundles of axons (nerve fibres) located inside the CNS; similar to nerves, but without the connective tissue wrapping a) Ascending Tracts carry sensory impulses from spinal cord to brain b) Descending Tracts transmit motor impulses from the brain to the spinal cord FACTORS AFFECTING SPEED OF NERVE IMPULSES 1. myelin sheath increased speed if myelinated 2. size of fibres large diameter fibres conduct impulses faster

SYNAPSE

synapse = area where 2 neurons meet (axon of one neuron communicates with a dendrite of a second) pre-synaptic neuron is neuron conducting the impulse toward the synapse; post-synaptic neuron carries signal away from synapse post-synaptic cells may be neurons or effector cells (ex. muscle cell or glandular cell) area where neuron meets effector (muscle or gland) is neuroeffector junction (ex. neuromuscular junction)

SYNAPSES and IMPULSE CONDUCTION

- chemical synapses use release and reception of neurotransmitters for communication

consist of 2 parts: i) pre-synaptic axon terminal which contains neurotransmitter substance (in synaptic vesicles) ii) post-synaptic receptor region on dendrite of post-synaptic neuron (or at effector cell membrane)

What Occurs at the Chemical Synapse?

pre and post-synaptic membranes are separated by the synaptic cleft fluid filled space across which chemical signal must travel signal starts as electrical signal at pre-synaptic membrane (nerve impulse) impulse stimulates calcium (Ca2+) channels on the synaptic bulb to open calcium enters the pre-synaptic membrane stimulates neurotransmitter to be released into synaptic cleft neurotransmitter crosses the cleft neurotransmitter binds to receptor on post-synaptic membrane and chemical signal is converted back into electrical signal at post-synaptic membrane post-synaptic membrane depolarizes, initiating an action potential (nerve impulse)

nism of nsmission

PM

ppt 3 -neural synapse h drive winter 2006

16

TYPES OF SYNAPSES BY STIMULATED ACTIVITY

neurotransmitters can activate or inhibit cell activities 1. Excitatory Synapses

neurotransmitter-receptor combination causes sodium channels to open, allowing diffusion of massive amounts of sodium ions inside the cell DEPOLARIZATION of membrane; cell polarity changes from being negative to being positive inside the cell membrane (does this sound familiar? I think you can expect to see some impulse activation here!)

2. Inhibitory Synapses

neurotransmitter-receptor combination causes potassium and chloride channels to open, causing potassium ions to leave the cell and chloride ions (which are negatively charged) to enter the cell HYPERPOLARIZATION of membrane cell polarity changes, becoming more negative inside the cell membrane (therefore, is it going to be more difficult to cause an impulse if the inside of the cell is more negative? I bet it will be!)

NERVE IMPULSE EXCITATION

purpose of impulse is to carry message from sense organ to brain or from brain to effector; impulse is an electrical disturbance traveling down the length of a neuron; the movement of sodium and potassium ions in and out of a neuron creates the disturbance

1. Neurons at REST are POLARIZED

sodium ions are found on outside of neuron, potassium ions on inside; therefore, inside of membrane is negatively charged relative to the outside because membrane is more permeable to potassium with constant leakage out of the membrane; the gradient for sodium to enter cell is greater due to its concentrations on both sides of the membrane, but membrane is relatively impermeable to sodium; normal resting potential for nerve cells is approx. -70 mV

2. DEPOLARIZATION of Neuron

when stimulus is applied (neurotransmitter), sodium channels open, and sodium enters the membrane electrical potential is reversed; inside of membrane becomes positive relative to outside threshold for potential to cause impulse is approx. -55 to -50 mV (potential often over shoots to +30 mV, causing an initial spike in electrical activity) in myelinated axons, the voltage-regulated sodium channels are concentrated at the Nodes of Ranvier

3. Nerve IMPULSE is Carried

relatively negative charge outside of membrane stimulates next point on membrane to depolarize and so on down the length of membrane

4. REPOLARIZATION of Neuron

reversal of charge lasts fractions of a second; sodium channels close, stopping the flow of sodium ions and potassium channels open, allowing potassium ions to leave the inside of the membrane returns charge on outside to being more positive than inside again

5. Neuron at Rest or POLARIZED

active transport mechanisms (Na+/K+-ATPase pumps) return membrane potential to resting potential (remember, 2 potassium ions in, 3 sodium ions out)

6. REFRACTORY Period

until resting potential is restored by active transport, stimulation with the creation of an impulse cannot occur

Neurotransmitters Messenger Molecules

chemical messenger molecules of nervous system synthesized in cytoplasm of axon terminal; neurons are limited in terms of types of transmitters they synthesize by enzyme systems located in a specific neuron once synthesized, neurotransmitters are stored in synaptic vesicles (each terminal may contain thousands of vesicles; each vesicle may contain up to 100,000 transmitter molecules) nerve impulse causes vesicles to be moved into the cell membrane with release of transmitters into the synaptic cleft

action of transmitters is exerted on specific proteins existing on the post-synaptic membrane RECEPTORS precisely match size and shape of specific transmitter (lock and key theory) the interaction of the transmitter with the receptor results in a specific physiological response; the response may be excitatory or inhibitory in nature if excitatory neurotransmitter is released at effector cell (example: skeletal muscle cell), muscle contraction occurs if inhibitory neurotransmitter is released at effector cell (example: smooth muscle cell), muscle contraction is inhibited receptors are named according to the type of neurotransmitter with which they bind (ex. cholinergic receptors bind with acetylcholine)

Basic Receptor Theory Direct vs. Indirect Receptor and Neurotransmitter Mechanisms A. Direct Mechanism binding of neurotransmitter to cell membrane receptors, causing opening of membrane ion channels (ex. seen with ACh on skeletal muscle cell membrane) B. Indirect Mechanism - proteins on inner surface of plasma membrane of effector cells are activated by binding of neurotransmitter to transmembrane receptors - the inner surface proteins (G-proteins) are then activated to: a) open or close membrane ion channels or b) produce second messenger molecules which stimulate a series of enzymatic activities inside effector cells; these series of activities then modify activities of other proteins (ex. channel proteins)

examples of second messengers used via indirect neurotransmitter and receptor mechanisms include: cyclic AMP, cyclic GMP, Ca2+ and diacylglycerol most amino acid based neurotransmitters, when they bind with membrane receptors on effector cells, exert their effects via second messenger systems these types of neurotransmitter/receptor interactions tend to result in slower, longer-lasting and broader physiological effects (ex. smooth and cardiac muscle contraction stimulation or inhibition) a well known and wide spread example of a second messenger system is the cyclic-AMP (c-AMP) mechanism

Cyclic-AMP Second Messenger Mechanism: First Messenger Neurotransmitter binds with Target Cell Membrane Receptor Receptor Configuration is modified and binds alternatively with G Protein (plasma membrane protein) which moves freely through plasma membrane until it binds with Adenyl Cyclase (effector enzyme) which catalyzes ATP (adenosine triphosphate) Cyclic-AMP (cyclic-adenosine monophosphate = ring shaped molecule) C- AMP = second messenger Activates further enzymatic cascades (by activating protein kinases), causing specific cellular response, depending upon tissue target and enzymes present at the effector site

- stimulated enzymatic cascades from above mechanism may result in:

a) altering cell membrane permeability (ex. opens or closes cell membrane channels) to promote or prevent entry of substances into effector cells (ex. increased or decreased Ca2+ entry into vascular or bronchiolar smooth and cardiac muscle cells) b) stimulation of smooth and cardiac muscle cell contraction - ex. as more calcium ion enters vascular smooth, bronchiolar smooth or cardiac muscle cells, muscle contraction occurs more readily or to a greater degree c) inhibition of smooth and cardiac muscle cell contraction - ex. as less calcium ion enters vascular smooth, bronchiolar smooth or cardiac muscle cells, muscle contraction is inhibited

neurotransmitters must be quickly removed after exerting their effects on the post-synaptic membrane or effector cell membrane in one of 3 ways: a) broken down by specific enzymes (ex. remember acetylcholine is broken down by acetylcholinesterase at neuromuscular junction) b) taken back up (reabsorbed) into the presynaptic neuron or axon terminal

c) diffuses/migrates away from synaptic cleft concentration of neurotransmitter becomes too low to exert further effects on post-synaptic receptor sites

Major Classifications of Neurotransmitters and Their Receptors

1. Acetylcholine (ACh) and Cholinergic Receptors

a) ACh released by all neurons that stimulate skeletal muscles voluntary control (somatic) - released at neuromuscular junction - specific type of ACh receptor on skeletal muscle cell membrane is called NICOTINIC receptor - neurotransmitter/receptor combination results in excitatory response skeletal muscle contraction

b) ACh released by motor neurons of the AUTONOMIC NERVOUS SYSTEM (ANS) - released specifically by all preganglionic axons (ganglion = cluster of cell bodies; so, released at region where 2 or more neurons meet preganglionic neuron and post-ganglionic neuron; or where pre-ganglionic neuron meets a gland) - receptors for ACh are located at all ANS ganglia (sympathetic motor pathways and parasympathetic pathways) and on adrenal medulla (gland on kidney) - these receptors are also specifically NICOTINIC receptors - this neurotransmitter/receptor combination is always excitatory results is impulse conduction to post-ganglionic neuron or release of hormone from a gland (adrenal gland)

c) ACh released by all post-ganglionic parasympathetic neurons - receptors are located on all parasympathetic target cells (involuntarily controlled tissues); ex. cardiac muscle, pupillary muscle, bronchial smooth muscle, gastrointestinal tract - this specific type of receptor is called a MUSCARINIC RECEPTOR - may be inhibitory (inhibits smooth/cardiac muscle contraction) or excitatory (stimulates smooth/cardiac muscle contraction) - whether inhibition or excitation occurs is dependent upon enzyme systems located in specific cell type (tend to be indirect receptor mechanisms) - ex. release of ACh at bronchial smooth muscle causes excitation (bronchial smooth muscle contraction)

Acetylcholine Cholinergic Receptor Type Nicotinic

Site of Release

Target Organ

Effect

Neuromuscular junction By Pre-Ganglionic Neuron at All ANS ganglia (PNS) By Pre-Ganglionic Neuron at Adrenal Medulla

Skeletal muscle Ganglia

Excitatory (voluntary) Excitatory (involuntary)

Hormone producing cells

Excitatory (epinephrine and NE release)

Muscarinic

By Post-Ganglionic Parasympathetic Motor Neuron at target organ

Heart

Inhibitory (decreased rate of contraction)

By Post-Ganglionic Parasympathetic Motor Neuron at target organ

Bronchioles

Excitatory (bronchial smooth muscle contraction); increased airways secretion production

2. Biogenic Amines and Adrenergic Receptors a) Catecholamines and Adrenergic Receptors in the PNS, norepinephrine is the main neurotransmitter released by post-ganglionic neurons (so, released at involuntarily controlled target tissues) in the sympathetic nervous system - epinephrine (really a hormone) is released by the adrenal medulla (gland on kidney site of large ganglion) in response to sympathetic nervous system stimulation norepinephrine is also a hormone secreted here (in smaller amounts than epinephrine - very similar in chemical structure to epinephrine)

- hormones exert their effects via circulation (released into blood) at distal target organs - both epinephrine or norepinephrine may be excitatory or inhibitory, depending upon the target organ and the receptor sub-types that they bind with at the target organ; dopamine is also released by some sympathetic post-ganglionic neurons (also very similar structurally to NE missing the hydroxyl group) - the receptors on target organs for these transmitters and/or hormones are known as adrenergic receptors

ADRENERGIC RECEPTOR SUB-TYPES:

a) alpha adrenergic receptors ()

- alpha-1 (1) adrenergic receptors found on smooth muscle cell membranes - binding with norepinephrine or epinephrine is excitatory, causing smooth muscle contraction in peripheral arterioles (excitatory); RESULT= vasoconstriction - alpha-2 (2) adrenergic receptors found on membranes of sympathetic motor axon terminals stimulation of these receptors inhibits norepinephrine release, causing less smooth muscle contraction in peripheral arterioles (inhibitory) ; RESULT= relative vasodilation

b) beta adrenergic receptors () - beta-1 (1) receptors cardiac muscle binding with norepinephrine or epinephrine is excitatory, increasing heart rate (chronotropy) and strength of contraction (inotropy) - beta-2 (2) receptors bronchial smooth muscle binding with epinephrine (released by adrenal medulla) causes bronchodilation (inhibitory action on bronchial smooth muscle less contraction); binding with epinephrine at arterioles serving skeletal muscle and heart (coronary arterioles) causes less smooth muscle contraction and relative dilation of these blood vessels; (inhibitory) - beta-3 (3) receptors on tissue cells like fat tissue and liver; epinephrine stimulates increased glucose release by the liver and fatty acid mobilization from adipose tissue cell into blood (metabolic fuels are made more readily available)

Receptor Site Cardiovascular System heart rate (chronotropic effect rate of contraction) cardiac muscle contractility (inotropic strength of contractility) vascular smooth muscle

Sympathetic (adrenergic)

Parasympathetic (muscarinic)

1: increases Via NE and E 1: increases Via NE and E 1 = contracts (decreases peripheral blood supply skin, GI tract, kidney, non-vital organs via NE and E ) 2 = relaxes (increases coronary and skeletal muscle blood supply via E)

Decreases Via ACh Decreases Via ACh no effect (no parasympathetic innervation to blood vessels)

NE = norepinephrine; E = epinephrine; ACh = acetylcholine

Receptor Site

Sympathetic (adrenergic)

Parasympathetic (muscarinic)

Respiratory System

smooth muscle in bronchioles

2: relaxes (bronchodilation) Via E (no direct sympathetic innervation to bronchial smooth muscle)

Contracts (bronchoconstriction) Via ACh

Other

pupil of eye

1: relaxes (dilates pupils) Via NE and E

Contracts (constricts pupils) Via ACh

Secretions (saliva)

: decreased secretions (via NE and E)

Nicotinic* - stimulates increased secretion of epinephrine and norepinephrine see all above effects

Stimulates watery secretions Via ACh

adrenal medulla

NE = norepinephrine; E = epinephrine; ACh = acetylcholine

Target Site Liver

Sympathetic (adrenergic) 3: increased release of stored glucose into circulation Via E 3: increased lipolysis (increased release of fatty acids into circulation for metabolism by cells more ATP production) Via E increased metabolic rate: Via E (see above effects ie: blood flow to vital regions and fuel release into circulation, etc.)

Parasympathetic (muscarinic) No effect (no parasympathetic innervation)

Fat (Adipose) Tissue

No effect (no parasympathetic innervation)

Cellular Metabolism

NE = norepinephrine; E = epinephrine; ACh = acetylcholine

CNS

PNS

EFFECTORS

Somatic

Cell Body Ganglion (ACh - Nicotinic) Adrenal Medulla (ACh - Nicotinic) Ganglion (ACh/Nicotinic)

Skeletal Muscle (Ach - Nicotinic) Smooth/Cardiac Muscle and Glands (Norepinephrine - Adrenergic) Smooth/Cardiac Muscle and Glands (Epi/Norepi Adrenergic) Smooth/Cardiac Muscle and Glands (ACh Muscarinic)

Sympathetic Cell Body

Cell Body

ParaCell Body Sympathetic

Pre-ganglionic Axon Post-ganglionic Axon Release of Hormones Directly into Circulation (Epinephrine and Norepinephrine)

B/ Indolamines
a) serotonin (feel good neurotransmitter released in response to pain) b) histamine is released in the CNS (hypothalamus, but its affects are poorly understood) and by mast cells during inflammatory process (really a mediator in this case, not a neurotransmitter) and acts as a powerful vasodilator (decreases smooth muscle contraction inhibitory in the case of blood vessels) - basophils and mast cells (found in tissues contain mediators for inflammation a lot found in lung tissue) can release histamine during antigenantibody (allergic) reactions and in response to drugs and toxic products; histamine release causes bronchiolar smooth muscle contraction - H1 and H2 receptors for histamine are found widely throughout the body at target effector organs

Effects of Histamine Receptor Heart H1 Slowing of conduction H2 - positive inotropic effect (increased strength of contractility) - positive chronotropic effect (increased rate of contraction) Dilation

Blood Vessels (smooth muscle) Bronchial (smooth muscle)

Dilation Contraction

3. Amino Acid Neurotransmitters

found only in CNS

GABA (gamma-aminobutyric acid)

- inhibitory neurotransmitter that is very widely distributed in the neurons of the brain (close to 40% of the synapses in the human brain work with GABA and therefore have GABA receptors) - GABA receptors are channel receptors - when GABA binds to them, they change shape slightly to allow ions to pass through their central channel

- allows mainly negatively charged chloride ions to enter the neuron, causing hyperpolarization of the membrane, thus reducing its excitability - sedative drugs and agents used for the induction of general anesthesia (hypnotics) enhance the natural effect of GABA; in other words, they help GABA to reduce neural activity even further - classes of medications which enhance GABA binding to receptors or mimic the effects of GABA include benzodiazepines (examples of common agents include: midazolam AKA Versed and lorazepam AKA Ativan) and hypnotic agents (examples of common agents include: propofol, ketamine, etomidate and barbiturates thiopental is a common barbiturate)

4. Peptides A. endorphins and enkephalins (inhibitory) - found in CNS (brain and spinal cord) - bind with opiate receptors: (mu), (delta), (kappa) and (sigma) and hyperpolarize neuronal cell membranes to inhibit pain reception - endorphins and enkephalins are known as natural opiates (endogenous controllers of pain) - narcotic analgesics bind to opiate receptors in the brain and spinal cord to mimic endorphin/enkephalin activity (specific drugs: codeine, morphine, Demerol, Dilaudid, fentanyl, oxycodone)

B. Substance P - found in PNS - allows pain transmission (excitatory) ***See Tables in Marieb, Chapter 11 Neurotransmitters