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Nervous system and neuronal signaling o Nervous system (NS) has the ability to integrate information freedom of integration of incoming sensory input is the most marvelous feature of the nervous system o Function is to coordinate and regulate functions of other systems and maintain homeostasis o The nervous system is the most important system of the body which controls and coordinates the essential functions of the body o When a patient is pronounced brain dead, they are legally ‘dead’ in spite of other organs still functioning with or without medical aid Synonyms in neuroscience o Action potential Spike, nerve impulse, conduction signal o Autonomic NS Visceral NS Because controls a lot of the visceral organs o Axon Nerve fiber o Axon terminal Synaptic knob, synaptic button, presynaptic terminal o Cell body Cell soma, cyton, o Glial cells Neuroglia, glia o Interneuron Association neuron o Rough ER Nissl body o Sensory neuron Afferent neuron o Motor Efferent neuron How the NS controls the body o Controls the body by rapid communication of signals. Essential for maintenance of homeostasis and movement and many more functions Signals conducted at 100 m/s (maximum) Communication by neurons is based on changes in the membrane’s permeability to ions. When membrane becomes permeable, voltage changes and the signal is sent o Two types of membrane potentials are of major functional significance Graded potentials Local, cannot be conducted long distances Action potentials Long distance o Neurons are the functional units of the nervous system. Functional unit = smallest part of the system that can still perform the functions of that system o A typical neuron has three regions Soma or cell body Integrates the incoming information and sends commands via axon Dendritic region Specialized to receive information Axonal region Specialized to deliver information o Polio Almost completely phased out
Caused by polio virus When people are infected by the virus, the virus selectively damages motor neurons and healthy muscles are therefore unable to contract Skeletal muscles can only contract when stimulated by motor neurons Functions of the Nervous System o To sense the changes occurring both inside and outside of the body Change in environment is called stimulus Collected information about changed environment is called sensory input o To integrate and interpret the sensory input and make decisions about how to respond at each moment o To send instructions to effectors (muscles or glands) so to bring about appropriate response o Sensory input à integrating center à effector organs Divisions of the Nervous System o Central Nervous System (CNS) Consists of the brain and the spinal cord. Functions as the integrating center Cranial nerves 12 pairs Spinal nerves 31 pairs Different names based on where they originate in the spinal cord o Cervical, thoracic, lumbar, sacral, coccygeal o Peripheral Nervous System (PNS) Consists of nerves that enter or exit from the CNS All the nerves and parts of NS outside of CNS are included in this division Two divisions Sensory division o Concerned with sensing the stimulus o Called sensory neurons o Subdivisions Somatic sensory receptors Bringing information about position, touch, temperature, pain, and temperature Visceral sensory receptors Mostly in internal organs Processed in the brain stem so we are not aware of them Special sensory receptors Smell, taste, vision, balance and hearing
Sensory receptors are cells (unlike what you learned in chemical messengers’ chapter where the term receptor mean a protein which binds with a ligand) which can translate sensory information into changes in membrane potential. Sometimes sensory neurons are receptors, and they can receive the sensory signal o Olfactory epithelium consists of olfactory receptors 3% of our genes code for olfactory receptors Sometimes receptors are not sensory neurons but some non-neural cells o Like for example rods and cones of the eye. Rods and cones can detect like but they are not neurons Autonomic motor neurons, see figure below 2 neurons are present in this pathway, arranged in series Autonomic ganglion o Nodule like structure Cell bodies wrapped in glial tissue Neuron before the ganglion is called pre-ganglionic neuron Neuron after ganglion is called post-ganglionic neuron Reflex arc Sensory neuron (afferent pathway) à interneuron (in CNS) à motor neuron (efferent pathway)
Somatic NS (NS=nervous system) o Motor neuron release NT onto skeletal muscle and resulting in its contraction o At the neuromuscular junction with skeletal muscles, the motor neuron release NT ACh ACh-receptors here are specifically Nicotinic ACh receptors o Effector organ is skeletal muscles only, and the neurotransmitter is ACh Autonomic NS o Some scientists believe adrenal medulla is a modified sympathetic ganglion o Sympathetic NS Preganglionic neurons release ACh to the cholinergic receptors on the post GN Postganglionic neurons always release norepinephrine onto adrenergic receptors in the effector organs Two exceptions o In Sweat glands these neurons produce ACh o Chromaffin cells of adrenal medulla gland produce epinephrine and norepinephrine Effector organs are smooth muscles and glands Sympathetic NS aka thoracolumbar outflow o Parasympathetic autonomic NS Both neurons secrete ACh ACh acting on the heart will bind to Muscarinic ACh receptors Aka craniosacral outflow Parasympathetic vs. Sympathetic Autonomic NS Antagonistic At one time, one will be dominant to the other o Both always working but one dominates the other
Neurofibrils Run along the long axis of the neuron Made up of microtubules o One of the three filaments that make up the cytoskeleton The other two are microfilaments and intermediate filaments Microtubules are thickest, microfilaments are thinnest o Myelin sheath Fatty/phospholipid-rich sheath The purpose of the myelin sheath is to increase the speed of conduction of the signals In the brain the neurons are both nonmyelinated and myelinated o Synapse Functional junction between presynaptic cell and postsynaptic cell Tiny gap in between is synaptic cleft o Electrical signal cannot cross the gap o Action potential (electrical signal) has to cause release of chemicals that diffuse quickly across cleft to form new action potential signals in the next cell o Nodes of Ranvier Parts of axon are exposed to ECF at Nodes of Ranvier o Dendrites receive the signal, the cyton will process the signal, the cyton will elicit action potentials at the trigger zone, action potentials travel down axon. Action potential will make a gland secrete if post synaptic cells is a gland, or cause muscle contract if post synaptic cell is a muscle, or send further action potential down if the post synaptic cell is another neuron o Neurons are categorized based on structure and function Structure Pseudounipolar o Appear as if only 1 process but there are actually two o Somatic senses (sensory) Bipolar o Two relatively equal fibers extending off the central body o For smell and vision (special senses) Retina has bipolar layer
Multipolar o Highly branched but lack long extensions o Can make up 200-400,000 synapses o Interneurons Anaxonic o No apparent axon o Interneurons Types of neurons based on function Sensory N o Afferent o Transmit information to the CNS from receptors at their peripheral endings o Cell body and the long peripheral process of the axon are in the PNS Only the short central process of the axon enters the CNS o No dendrites (do not receive input from other neurons) Motor N o Efferent o Transmit information out of CNS to effector cells Particularly muscles, glands or other neurons o Cell bodies, dendrites, and a small segment of the axon are in the CNS Most of the axon is in the PNS Interneurons N o Function as integrators and signal changers o Integrate groups of afferent and efferent neurons into reflex circuits o Lie entirely within the CNS o Most abundant neurons 99% of all neurons are interneurons Interneurons > motor neurons > sensory neurons Glial cells o We have more glial cells than neurons in nervous system o Function of glial cells is to protect, bind, nourish, and support neurons o Have the ability to divide always Brain tumors are tumors of the glial cells because they can divide o 6 kinds of glial cells PNS has 2 types of glial cells Satellite cells o Support cell bodies in ganglion
In Alzheimer’s the neurons that produce ACh are dying and so the neuroscientists are trying to coax these cells to transform into neurons that can produce ACh In Parkinson’s disease the neurons that release dopamine are damaged Axonal transport o Neurons are microscopic but some are 4 feet long o NT has to be transported from cyton to axon terminal o Two types of transport mechanisms exist Anterograde transport Movement of material from the cyton to the axon terminal Brought about by motor proteins called kinesins à Retrograde transport Movement of material from the terminal to the cyton for recycling material Brought about by motor proteins called dyneins Electrical potential and Membrane permeability o How the neurons are going to develop resting membrane potential Potential = electric potential difference o Electric potential is developed because of separation of charges Because of the separation they have potential energy because , they want to move back toward each other due to attraction When they move they generate Kinetic energy, energy due to movement Force increases with the quantity of charges separated and the when the distance of charge separation is reduced o Electrical potential difference or simply potential is measured in volts o Average resting membrane potential is -70 millivolts o Overall the cell is electrically neutral inside and outside Only charge differences exist on the inside and outside surface of the membrane Only a very thin shell of charge difference is needed to establish a membrane potential Sodium potassium pumps help in maintaining the resting membrane potential o Potassium equilibrium potential. See the illustration provided in PPT slides If two compartments ( A and B) are separated by a membrane only permeable to potassium; A compartment is filled with NaCl and B with KCl Potassium wants to move because of concentration gradient from B to A As this continues there comes a point where the negative charge in Compartment B is building due to K+ are moving into compartment A. This negative charge begins to atteact K+ back into its original compartment B. This movement due to electrical gradient. This back and forth movement continues. At equilibrium point, the number of potassium ions moving out into A is equal to those moving back into compartment B. So, there is no net movement of K+. When you place electrodes in compartment A and B, and measure the voltage it would be read –90mV. At the potassium equilibrium potential buildup of positive charge in Compartment A produces an electrical potential that exactly offsets the K+^ chemical concentration gradient -90 mV The membrane’s permeability to potassium is not the only one determining the resting potential. Equilibrium potential for potassium (EK+) +60 mV If reverse scenario and made it permeable to sodium and not potassium (cells do have the ability to change permeability of their membranes) Equilibrium potential for sodium (ENa+) Equilibrium potential for potassium is closer to resting membrane potential
Membrane is much more permeable to potassium than to sodium (20 times) Root cause of development of resting membrane potential is permeability of the membrane Causes establishment of concentration gradient (which eventually creates electrical gradient) o Distribution of major mobile ions across the plasma membrane of a typical nerve cell (concentration in mmol/L) Sodium Extracellular: 145 Intracellular: 15 Chloride Extracellular: 100 Intracellular: 7 Potassium Extracellular: 5 Intracellular: 150 So many negative ions inside the cell that try to keep potassium ions inside All due to membrane permeability o Electrical signals: Ion movement Resting membrane potential determined by K+^ , Na+ Cl- concentration gradient Cell’s resting permeability to K+, Na+, and Cl– Gated channels control ion permeability Mechanically gated Chemical gated Voltage gated Threshold voltage varies from one channel type to another o Electrical Signals: Nernst Equation Using this equation you can estimate membrane potential for a single ion Membrane potential is influenced by Concentration gradient of ions Membrane permeability to those ions Eion means equilibrium potential for any ion Z indicates the charge for the ion o Examples: K+ has 1, Cl- has 1, Ca2+ has 2 If you know concentration of ion on both sides of the membrane, then you can calculate potential for that ion. o Electrical Signals: are of two types. 1. Graded potentials and 2. Action potential Graded potential Most important function of the nervous system is to communicate information about stimulus Stimulus could be electrical, mechanical or chemical When neuron membrane is at rest, it is not permeable to Na+ When neuron is stimulated the membrane become permeable to Na+ Under resting condition membrane is permeable to K+ but not to Na+ When stimulated it becomes permeable to sodium Sodium channels will open Sodium will move inside The membrane potential becomes less negative (more positive) as positive Na+ moves inside This is depolarization. The membrane is now positive inside. The positive Na+ ions diffuse down the cell and can reach trigger zone. Change in potential will spread down the cell because the sodium ions are diffusing and affecting the membrane all the way down
o Sodium potassium ATPase also helps in bringing the potential back to its normal value VGKC exist in only two states, 1. open and 2. closed) Trigger Zone Graded potential enters trigger zone Voltage-gated Na+^ channels open and Na+^ enters axon Positive charge spreads along adjacent sections of axon by local current flow Local current flow causes new section of the membrane to depolarize The refractory period prevents backward conduction of action potential. ; loss of K+ repolarizes the membrane Graded Potential Action Potential Type of Signal Input signal Conduction signal Where it occurs Usually dendrites and cell body Trigger zone through axon Types of gated ion channels involved Mechanically, chemically or voltage-gated channels Voltage-gated channels Ions involved Usually Na+, Cl-, Ca2+ Na+ and K+ Type of signal Depolarizing (Na+) or hyperpolarizing (Cl-) Depolarizing Strength of signal Depends on initial stimulus; can be summed Is always the same (all or none phenomenon); cannot be summed What initiates the signal Entry of ions through channels Above-threshold gradient potential at the trigger zone Unique characteristics No minimum level required to initiate Threshold stimulus required to initiate Two signals coming close together in time will sum Refractory period: two signals too close together in time cannot sum Initial stimulus strength is indicated by frequency of a series of action potentials Excitatory postsynaptic potentials, EPSPs. When a stimulus is applied to a neuron, and if it results in depolarization then it is called excitatory stimulus and the change in membrane potential is called EPSP. Depolarizing graded potential is when you apply a stimulus and it cause the potential to drift towards -55mV. Usually opening of Na+ channels, Ca++ channels can cause EPSPs. Inhibitory Post Synaptic Potentials, IPSPs. When a stimulus is applied to a neuron, and if it results in hyperpolarization then it is called inhibitory stimulus and the change in membrane potential is called IPSP. Hyperpolarizing graded potential is when you apply a stimulus and it cause the potential to drift way from -55mV. So, it becomes harder for this neuron to generate AP as this is an inhibitory stimulus. If Cl- is applied and causes opening of chloride channels and chloride enters the cell it will make the inside more negative and will be hyperpolarizing What will be the fate of membrane potential if potassium channels open Hyperpolarization Potassium leaves the cell and that makes inside more negative How can the body tell what is a strong stimulus and what is a weak stimulus Frequency of action potentials o Will help us decode the strength of the initial stimulus Summed means added together Refractory Periods (RP) Absolute RP- AP propagate towards the axon terminal and not backwards during absolute RP. The reason for tis is, the VGNC are in inactivated state and VGKC are in open state making it impossible to stimulate the membrane in this time.
Relative refractory period- with the application of suprathreshold stimulus another AP can be formed on the membrane. The reason for this is some of VGNC are reverted back to closed state and some VDKC are in closed form. Conduction of AP along the axon o Saltatory conduction In this method of conduction action potentials appears to jump from one node to the next as they propagate along a myelinated axon At trigger zone action potentials are elicited and sodium ions enters For spreading of action potentials down the axon terminal o Sodium has to diffuse laterally in the axon and reach the adjacent node This diffusion of Na+ causes depolarization of membrane at adjacent Node of Ranvier to threshold -55mV When membrane is depolarized to -55mv then a new action potential is generated due to opening of VGNC and VGKC. Density of voltage-gated channels in nodes of Ranvier is very high enabling formation of AP This process repeats again and again until AP gets to the end of axon Ions can only depolarize in the forward direction of the axon because VGNC are in inactivated state Saltatory conduction is only seen in myelinated neurons and appears as if the action potentials are jumping from node to node Saltatory means to leap o Electrical signals: Speed of action potential Speed of action potential in neuron is influenced by Diameter of axon o Larger axons conduct faster Easier for sodium ions to move without getting resistance Resistance of axon membrane to ion leakage out of the cell Myelinated axons are faster o Resistant to leakage because nonpolar fat Don’t have to generate action potentials at each and every point along the axon o Electrical signals: Chemical factors Effect of extracellular potassium concentration on the excitability of neurons Potassium levels in the blood are very important Normokalemia o Normal potassium levels in the blood
Increase in NT amounts causes responses to be present for longer time One action potential arriving from pre-synaptic cell may or may not bring about response in postsynaptic cell o Inhibitory postsynaptic potentials (IPSP) When chloride or potassium channels are opened that cause hyperpolarization of the membrane, and these potential is more negative than RMP and are called IPSP o Kinds of Neurotransmitters Over 100 Acetylcholine NT of CNS In brain there are several neurons that secrete ACh In parasympathetic nervous system both pre and postsynaptic neuron will release ACh Oldest NT to be discovered NT released to skeletal muscle in neuromuscular junction (exclusive) Synthesis of ACh o Choline + Acetyl CoA à ACh Choline is a type of vitamin B Choline acetyl transferase is the enzyme involved o Made in the cytoplasm and then packed into vesicles When calcium enters there is exocytosis of ACh Two kinds of ACh receptors o Nicotinic receptors Bind nicotine as well as ACh Blocked by curare (antagonist) Linked to ionic channels Response is brief and fast Located at neuromuscular junctions, autonomic ganglia, and to a small extent in the CNS Mediate excitation in target cells Postsynaptic Ionotrophic pathway When ACh binds with nicotinic it is always excitatory o Muscarinic receptors Bind muscarine Blocked by atropine (antagonist) Linked to 2nd^ messenger systems through G proteins Response is slow and prolonged Found on myocardial muscle, certain smooth muscle, and in discrete CNS regions Mediate inhibition and excitation in target cells Both pre and postsynaptic Metabotrophic pathway When ACh binds with muscarinic it can be inhibitory or excitatory Alzheimer’s disease o A disease in which a marked deterioration occurs in the CNS, the hallmark of which is a progressive dementia o One of the characteristics of this disease is a marked decrease in ACh concentrations in the cerebral cortex and caudate nucleus Myasthenia gravis o A disease of the neuromuscular junction in which the receptors for ACh are destroyed through the actions of the patient's own antibodies o Autoimmune disease Biogenic amines Derived from amino acids Catecholamines
o Formed from the amino acid tyrosine and share the same two initial steps in their biosynthetic pathway. Examples-Dopamine, Norepinephrine, epinephrine o Adrenergic receptor are for Norepinephrine and epinephrine. There are two types of adrenergic receptor- alpha and beta. When epinephrine or norepinephrine binds with alpha receptors on smooth muscles then it causes contractions and if bound to beta receptors on smooth muscles it causes dilation. Seratonin (5-hydroxytryptamine, 5-HT)-formed from Typtamine Histamine Some amino acids can act as NT Glutamate is the most predominant excitatory NT of the brain GABA is inhibitory NT o Gamma aminobutyric acid o Glycine is another inhibitory NT Aspartate is excitatory but not as predominant as glutamate Neuropeptides Small chains of amino acids Endogeneous opioids, oxytocin, tachykinins Miscellaneous Gases o Nitric oxide Purines o Adenosine, ATP Integration of information o Spatial summation Summation of post synaptic potentials when simultaneously multiple synapses on a neuron are depolarizing or hyperpolarizing All changes have to happen simultaneously Examples: If 3 excitatory synapses on a neuron cause depolarizing graded potential o These Graded potentials arrive at trigger zone together and sum to create a suprathreshold signal o An action potential is generated If 1 inhibitory and 2 excitatory neurons fired on a neuron o The summed potentials are below threshold so no action potential is generated No action potential if magnitude of IPSP is equal or greater than EPSP See diagram in the book o Temporal summation In this type of summation, high frequency of action potentials at a single synapse elicits postsynaptic potentials that overlap and summate with each other. The effect is generated at a single synapse as a way of achieving action potential when the stimuli are given at high frequency. Examples: No summation o Two graded potentials will not cause an action potential if they are far apart in time Summation causing action potential o If two subthreshold potentials arrive at the trigger zone within a short period of time, they may sum and create an action potential o Stimuli are close o Stimuli happen at the same time in succession
