Neuronal Processing Faisal I Mohammed MD Ph D

Neuronal Processing Faisal I. Mohammed, MD, Ph. D University of Jordan 1

Relaying Signals through Neuronal Pools University of Jordan 2

Neuronal Pools Ø Ø groups of neurons with special characteristics of organization comprise many different types of neuronal circuits Ø Ø Ø converging diverging reverberating University of Jordan 3

Neuronal Pools: Localization of sensory Information modification University of Jordan 4

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Neuronal Pools: Modification of Localization: Sharpening of signals Lateral inhibition University of Jordan 6

Lateral Inhibition o Sharpening of sensation. n When a blunt object touches the skin, sensory neurons in the center areas are stimulated more than neighboring fields. n Stimulation will gradually diminish from the point of greatest contact, without a clear, sharp boundary. o Will be perceived as a single touch with well defined borders. n Occurs within CNS. University of Jordan 7

Lateral Inhibition in the sensory System as a way of sharpening of the stimulus

Reverberating Circuits: prolongation of Time of the signals University of Jordan 9

The Organization of Neuronal Pools Copyright © 2004 Pearson Education, Inc. , publishing as Benjamin Cummings

Neural Circuits 12

Other mechanisms for prolongation of time o o Synaptic afterdischarge: since the time of EPSP (15 -20 msec) is longer than the time of AP(0. 1 – 10 msec) then more No. of AP per one EPSP Parallel circuits University of Jordan 13

Stabilization of neuronal discharge o o Synaptic fatigue: short term and acute adjustment of sensitivity Neuronal inhibitory circuits: n n o Gross inhibition –Basal ganglia inhibits muscle tone Feed back inhibition-Cortico-fugal fibers from cerebral cortex descending fibers to control the intensity and sharpness Downregulation and upregulation- Long term stabilization through modification of the receptor availability (internalization or externalization) University of Jordan 14

Neuron types and Neurotransmitters Faisal I. Mohammed. Ph. D, MD University of Jordan 15

Transmission of Receptor Information to the Brain Ø the larger the nerve fiber diameter the faster the rate of transmission of the signal Ø velocity of transmission can be as fast as 120 m/sec or as slow as 0. 5 m/sec Ø nerve fiber classification Øtype A - myelinated fibers of varying sizes, generally fast transmission speed Øsubdivided into , , d, g Øtype C - unmyelinated fibers, small with slow transmission speed University of Jordan 16

Types of Nerve Fiber -Myelinated fibers – Type A (types I, II and III) -A α -Aβ -Aγ -Aδ -Umyelinated Fibers. Type C (type IV) University of Jordan 17

Neuron Classification University of Jordan 18

Structural Classification of Neurons University of Jordan 19

Neurotransmitters v Chemical substances that function as synaptic transmitters 1. Small molecules which act as rapidly acting transmitters vacetylcholine, norepinephrine, dopamine, serotonin, GABA, glycine, glutamate, NO 2. Neuropeptides vmore potent than small molecule transmitters, cause more prolonged actions vendorphins, enkephalins, VIP, ect. vhypothalamic releasing hormones v. TRH, LHRH, ect. vpituitary peptides v. ACTH, prolactin, vasopressin, ect. University of Jordan 20

Neurotransmitters University of Jordan 21

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Comparison between Small Molecules and Neuropeptides Neurotramsmitters (NT) v Small molecules NT are rapidly acting as compared to slowly acting neuropepides v Neuron has only one NT but may have one or more NP v Small molecules NT are have short lived action compared to prolonged time of action for neuropeptides v Small molecules NT are excreted in larger amounts compared to smaller quantities of neuropeptide v Small molecules NT vesicles are recycled but neuropeptide ones are not v Neuropeptides are co-secreted with small molecules NT v Neuropeptides are synthesized at the soma while small molecules could be formed at the presynaptic terminals University of Jordan 23

Removal of Neurotransmitter v. Diffusion vmove down concentration gradient v. Enzymatic degradation v. Acetylcholinesterase for (Ach), peptidases for neuropeptides v. Uptake by neurons or glia cells vneurotransmitter transporters v. Prozac = serotonin reuptake inhibitor University of Jordan 24

§ Transmitter Inactivation: reuptake and enzymatic breakdown s tr er po y b e tak Reuptake by transporters (glial cells) ns a tr up e R Enzymatic breakdown Neurotransmitter can be recycled in presynaptic terminal or can be broken down by enzymes within the cell University of Jordan 25

II Neurotransmitters and receptors University of Jordan 26

Basic Concepts of NT and receptor Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells. Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells University of Jordan 27

• Vast array of molecules serve as neurotransmitters • The properties of the transmitter do not determine its effects on the postsynaptic cells • The properties of the receptor determine whether a transmitter is excitatory or inhibitory University of Jordan 28

A neurotransmitter must (classical definition) • • • Be synthesized and released from neurons Be found at the presynaptic terminal Have same effect on target cell when applied externally Be blocked by same drugs that block synaptic transmission Be removed in a specific way University of Jordan 29

Agonist A substance that mimics a specific neurotransmitter, is able to attach to that neurotransmitter's receptor and thereby produces the same action that the neurotransmitter usually produces. Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted. University of Jordan 30

Antagonist Drugs that bind to but do not activate neuroreceptors, thereby blocking the actions of neurotransmitters or the neuroreceptor agonists. University of Jordan 31

• Same NT can bind to different -R • different part of NT ~ NT Receptor A Receptor B University of Jordan 32

Specificity of drugs Drug A Receptor A Drug B NT Receptor B University of Jordan 33

Five key steps in neurotransmission • Synthesis • Storage • Release • Receptor Binding • Inactivation University of Jordan 34

Synaptic vesicles • Concentrate and protect transmitter • Can be docked at active zone • Differ for classical transmitters (small, clear -core) vs. neuropeptides (large, dense-core) University of Jordan 35

Neurotransmitter Co-existence (Dale principle) Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter. They are contained in different synaptic vesicles that can be distinguished using the electron microscope. The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions. University of Jordan 36

University of Jordan Purves, 200137

Receptors determine whether: • Synapse is excitatory or inhibitory – NE is excitatory at some synapses, inhibitory at others • Transmitter binding activates ion channel directly or indirectly. – Directly • ionotropic receptors • fast – Indirectly • metabotropic receptors • G-protein coupled • slow University of Jordan 38

Receptor Activation • Ionotropic channel – directly controls channel – fast • Metabotropic channel – second messenger systems – receptor indirectly controls channel ~ University of Jordan 39

(1) Ionotropic Channels Channel NT neurotransmitter University of Jordan 40

Ionotropic Channels NT Pore University of Jordan 41

Ionotropic Channels NT University of Jordan 42

Ionotropic Channels NT University of Jordan 43

Metabotropic Channels • Receptor separate from channel • G proteins • 2 nd messenger system – c. AMP – other types • Effects – Control channel – Alter properties of receptors – regulation of gene expression ~ University of Jordan 44

G protein: direct control • NT is 1 st messenger • G protein binds to channel – opens or closes – relatively fast ~ University of Jordan 45

G protein: direct control R G GDP University of Jordan 46

G protein: direct control R G GTP Pore University of Jordan 47

G protein: Protein Phosphorylation A C R G GDP PK University of Jordan 48

G protein: Protein Phosphorylation A C R G GTP ATP c. AMP PK University of Jordan 49

G protein: Protein Phosphorylation A C R G GTP ATP P c. AMP PK University of Jordan Pore 50

Transmitter Inactivation • • • Reuptake by presynaptic terminal Uptake by glial cells Enzymatic degradation Presynaptic receptor Diffusion Combination of above University of Jordan 51

Summary of Synaptic Transmission University of Jordan Purves, 2001 52

Some Important Transmitters University of Jordan 53

(1) Acetylcholine (ACh) as NT University of Jordan 54

Acetylcholine Synthesis choline acetyltransferase choline + acetyl Co. A ACh + Co. A University of Jordan 55

Acetylcholinesterase (ACh. E) • Enzyme that inactivates ACh. – Present on postsynaptic membrane or immediately outside the membrane. • Prevents continued stimulation. University of Jordan 56

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The Life Cycle of Ach University of Jordan 58

Ach - Distribution • Peripheral N. S. • Excites somatic skeletal muscle (neuro-muscular junction) • Autonomic NS Ganglia Parasympathetic NS--- Neuroeffector junction Few sympathetic NS – Neuroeffector junction • Central N. S. - widespread Hippocampus Hypothalamus ~ University of Jordan 59

Ach Receptors • ACh is both an excitatory and inhibitory NT, depending on organ involved. –Causes the opening of chemical gated ion channels. • Nicotinic ACh receptors: –Found in autonomic ganglia (N 1) and skeletal muscle fibers (N 2). • Muscarinic ACh receptors: –Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands. University of Jordan 60

Acetylcholine Neurotransmission • “Nicotinic” subtype Receptor: – Membrane Channel for Na+ and K+ – Opens on ligand binding – Depolarization of target (neuron, muscle) – Stimulated by Nicotine, etc. – Blocked by Curare, etc. – Motor endplate (somatic) (N 2), – all autonomic ganglia, hormone producing cells of adrenal medulla (N 1) University of Jordan 61

Acetylcholine Neurotransmission • “Muscarinic” subtype Receptor: M 1 – Use of signal transduction system • Phospholipase C, IP 3, DAG, cytosolic Ca++ – Effect on target: cell specific (heart , smooth muscle intestine ) – Blocked by Atropine, etc. – All parasympathetic target organs – Some sympathetic targets (endocrine sweat glands, skeletal muscle blood vessels - dilation) University of Jordan 62

Acetylcholine Neurotransmission • “Muscarinic” subtype: M 2 – Use of signal transduction system • via G-proteins, opens K+ channels, decrease in c. AMP levels – Effect on target: cell specific – CNS – Stimulated by ? – Blocked by Atropine, etc. University of Jordan 63

Cholinergic Agonists • Direct – Muscarine – Nicotine • Indirect – ACh. E Inhibitors ~ University of Jordan 64

Cholinergic Antagonists • Direct Nicotinic - Curare Muscarinic - Atropine University of Jordan 65

Ligand-Operated ACh Channels N Receptor University of Jordan 66

G Protein-Operated ACh Channel M receptor University of Jordan 67

(2) Monoamines as NT University of Jordan 68

Monoamines • Catecholamines – Dopamine - DA Norepinephrine - NE Epinephrine - E • Indolamines Serotonin - 5 -HT University of Jordan 69

Synthesis of Monoamine NT Tyrosine tyrosine hydroxylase L-Dopa decarboxylase Dopaminergic Neurons Dopamine dopamine hydroxylase Adrenergic Norepinephrine Neurons phenylethanolamine-N -methyltransferase Epinephrine Adrenal Glands

Mechanism of Action ( receptor) University of Jordan 71

Norepinephrine (NE) as NT • NT in both PNS and CNS. • PNS: – Smooth muscles, cardiac muscle and glands. • Increase in blood pressure, constriction of arteries. • CNS: – General behavior. University of Jordan 72

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Adrenergic Neurotransmission • 1 Receptor – Stimulated by NE, E, – blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary glands – vasoconstriction, sphincter constriction, pupil dilation University of Jordan 74

Adrenergic Neurotransmission • 2 Receptor – stimulated by, NE, E, …. . – Membrane of adrenergic axon terminals (presynaptic receptors), platelets – inhibition of NE release (autoreceptor), – promotes blood clotting, pancreas decreased insulin secretion University of Jordan 75

Adrenergic Neurotransmission • 1 receptor – stimulated by E, …. – Mainly heart muscle cells, – increased heart rate and strength University of Jordan 76

Adrenergic Neurotransmission • 2 receptor – stimulated by E. . – Lungs, most other sympathetic organs, blood vessels serving the heart (coronary vessels), – dilation of bronchioles & blood vessels (coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus University of Jordan 77

Adrenergic Neurotransmission • 3 receptor – stimulated by E, …. – Adipose tissue, – stimulation of lipolysis University of Jordan 78

(3) Amino Acids as NT • Glutamate acid and aspartate acid: – Excitatory Amino Acid (EAA) • Gamma-amino-butyric acid (GABA) and glycine: – Inhibitory AA University of Jordan 79

(4) Polypeptides as NT • CCK: – Promote satiety following meals. • Substance P: – Major NT in sensations of pain. University of Jordan 80

(5) Monoxide Gas: NO and CO • Nitric Oxide (NO) – Exerts its effects by stimulation of c. GMP. – Involved in memory and learning. – Smooth muscle relaxation. • Carbon monoxide (CO): – Stimulate production of c. GMP within neurons. – Promotes odor adaptation in olfactory neurons. – May be involved in neuroendocrine regulation in hypothalamus. University of Jordan 81

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