B3M1 Lectures 1-3 PDF

NERVOUS SYSTEM SYSTEM COORDINATOR: DR. CECILLE ESPINO BLOCK 3 MODULE 1 (LECTURES 1-3) BASIC BIOMEDICAL SCIENCES I NOT FOR SALE | DO NOT UPLOAD IN ONLINE SITES...

NERVOUS SYSTEM SYSTEM COORDINATOR: DR. CECILLE ESPINO BLOCK 3 MODULE 1 (LECTURES 1-3) BASIC BIOMEDICAL SCIENCES I NOT FOR SALE | DO NOT UPLOAD IN ONLINE SITES THIS IS ILLEGAL | NEVER EVER SHOW THE DOCTORS THIS FILE ------------------------------------------------------------------------------------------------------------------------------------------------------- LECTURE #1: NEURO-EMBRYOLOGY Neural Crest By: Maria Cecilia Alvarez-Espino, MD, FPLS, FPSP o Gives rise to: Pseudounipolar ganglion cells of the spinal and cranial nerve ganglia Schwann cells (neurolemmal sheath cells that form myelin in the PNS) Multipolar ganglion cells of the autonomic ganglia Leptomeninges (pia-arachnoid cells) Chromaffin cells of the Suprarenal medulla Pigment cells (melanocytes) Odontoblasts (dentine-forming cells) Aorticopulmonary septum of the heart DEVELOPMENT OF THE NERVOUS SYSTEM Parafollicular cells (Calcitonin-producing C-cells) CNS (Central Nervous System) Skeletal and connective components of the pharyngeal arches o Begins to form in the 3rd week of embryonic development as the Placodes neural plate o Are localized thickenings of the cephalic surface ectoderm o The neural plate becomes the neural tube, which gives rise to the o Give rise to cells that migrate into the underlying mesoderm and brain and spinal cord develop into the sensory receptive organs of the Olfactory nerve (CN PNS (Peripheral Nervous System) I) and the Vestibulocochlear nerve (CN 8) o Consists of spinal, cranial, and visceral nerves and spinal, cranial, and Olfactory placodes- differentiate into neurosensory cells that give autonomic ganglia rise to the Olfactory nerve (CN I) o Is derived from 3 sources: Induce formation of Olfactory bulbs Neural Crest Cells- give rise to Peripheral ganglia, Schwann cells, Otic placodes- give rise to the following statoacoustic organs: and Afferent nerve fibers Organ of Corti and spiral ganglion Neural Tube- gives rise to all preganglionic autonomic fibers and all Cristae ampullares, maculae utriculi and sacculi, and vestibular fibers that innervate Skeletal muscles ganglion Mesoderm- gives rise to the dura mater and to the connective tissue Vestibulocochlear nerve (CN 8) investments of Peripheral nerve fibers (endoneurium, perineurium, Stages of Neural Tube Development and epineurium) o Vesicle development: DEVELOPMENT OF THE NEURAL TUBE (1) 3 Primary brain vesicles and Associated flexures Begins in the 3rd week and is completed on the 4th week Develop during the 4th week Neural Plate Gives rise to dilatations of the primary brain vesicles and 2 o Thickened pear-shaped region of embryonic ectoderm, located curvatures which are the following: between the primitive knot and the oropharyngeal membrane Prosencephalon (Forebrain) Neural Groove Associated with appearance of optic vesicles o Forms as the neural plate begins to fold inward Shows cerebral hemisphere o Is flanked by neural folds which are parallel Gives rise to: o Deepens as the neural folds begin to close over it Telencephalon (end brain) Neural Folds Diencephalon (between-brain) o Fuse in the midline to form the neural tube Mesencephalon (Midbrain) o Site of neural crest cell differentiation Remains as the Mesencephalon up to adulthood Neural Tube Rhombencephalon (Hindbrain) o Forms as the neural folds fuse in the midline and separate from the Gives rise to: surface ectoderm Metencephalon (afterbrain)- forms pons and cerebellum o Lies between the surface ectoderm and the notochord Myelencephalon (Medulla Oblongata) o Gives rise to the CNS, where: Cephalic flexure (midbrain flexure) Cranial part becomes the brain Located between prosencephalon and rhombencephalon Caudal part becomes the spinal cord Cervical flexure Cavity gives rise to the central canal of the spinal cord and Located between the rhombencephalon and the future spinal ventricles of the brain cord The 2 openings in the Neural tube connect the central canal with the amniotic cavity: Anterior neuropore- closes on the 4th week (day 25) and becomes the lamina terminalis Posterior neuropore- closes in the 4th week (day 27) (2) The 5 Secondary brain vesicles (with 4 ventricles) Becomes visible in the 6th week The brain vesicles are visible as the primordia of the 5 major brain divisions: Telencephalon Has lateral outpocketings that form the cerebral hemispheres Has ventral outpocketings that form the olfactory bulbs Has visible lateral ventricles  Diencephalon o Neuroepithelial (ventricular) layer- innermost layer; a monocellular 3rd ventricle, optic chiasm and optic nerves, infundibulum, and layer of ependymal cells that line the central canal and future brain mamillary eminences become visible ventricles Mesencephalon o Mantle (intermediate) layer- middle layer; consists of neurons and Contains a large cavity that will become Cerebral Aqueduct, glial cells, the central gray matter of the spinal cord; contains the alar this will remain to be the same structure in adulthood and basal plates Metencephalon o Marginal layer- outermost layer; contains nerve fibers of neuroblasts Separated from the mesencephalon by the rhombencephalic of the mantle layer and glial cells; produces the white matter of the isthmus spinal cord through the myelination of axons growing into this layer Separated from the myelencephalon by the pontine flexure SPINAL CORD Contains rhombic lips on the dorsal surface, that gives rise to Develops from the neural tube caudal to the 4th pair of somites the Cerebellum Alar and Basal Plates/Sulcus Limitans/Roof and Floor Plates Becomes the pons and cerebellum o Alar Plate Contains dorsal half of the 4th ventricle Dorsolateral thickening of the mantle layer of the neural tube Myelencephalon Gives rise to sensory neuroblasts of the dorsal horn [General Lies between the pontine and cervical flexures Somatic Afferent (GSA) and General Visceral Afferent (GVA) cell Becomes the medulla regions] Contains the caudal half of the 4th ventricle Receives axons, which become the dorsal roots, from the dorsal root ganglion Becomes the dorsal horn of the spinal cord o Basal Plate Ventrolateral thickening of the mantle layer of the neural tube Gives rise to the motor neuroblasts of the ventral and lateral horns [General Somatic Efferent (GSE) and General Visceral Efferent (GVE) cell regions] Axons from motor neuroblasts exit the spinal cord and forms the ventral roots Becomes the ventral horns of the spinal cord The Primary Divisions of the Developing Brain Primary vesicle Primary Division Subdivision Adult structures Forebrain vesicle Prosencephalon Telencephalon Cerebral hemisphere, (forebrain) Basal ganglia, Hippocampus Diencephalon Thalamus, Hypothalamus, Pineal body, Infundibulum Midbrain Mesencephalon Mesencephalon Tectum, Tegmentum, vesicle (midbrain) (midbrain) Crus cerebri Hindbrain Rhombencephalon Metencephalon Pons, Cerebellum vesicle (hindbrain) Myelencephalon Medulla oblongata HISTIOGENESIS Cells of the Neural Tube Wall- neuroepithelial cells that give rise to: o Neuroblasts- form all neurons found in the CNS o Glioblasts (Spongioblasts)- for the most part, are formed after the cessation of neuroblast formation (except for radial glial cells which o Sulcus Limitans develop before neurogenesis is complete) Is a longitudinal groove in the lateral wall of the neural tube that Form the supporting cells of the CNS appears during the 4th week of embryonic development Macroglia Separates the Alar-Sensory and the Basal-Motor plates Astroglia (astrocytes) Disappears in the adult spinal cord but is retained in the rhomboid Contain glial fibrillary acidic protein (GFAP), a marker for fossa of the brainstem astroblasts Extends from the spinal cord to the rostral midbrain Surround blood capillaries with their perivascular feet o Roof Plate Radial glial cells Is the nonneural roof of the central canal Are of astrocyte lineage and GFAP-positive o Floor Plate Provide guidance for migrating neuroblasts Is the nonneural floor of the central canal Oligodendroglia (oligodendrocytes) Contains the ventral white commissure Origin of myelination of CNS Ependymal cells- are ciliated Ependymocytes- line the ventricles and the central canal Tanycytes- located in the wall of the 3rd ventricle Transport substances from the CSF to the hypophyseal portal system Choroid Plexus Cells- produce CSF Are bound together by tight junctions (zonulae occludentes) Myelination representing the blood-CSF barrier o Commences in the 4th fetal month in the Spinal Cord motor roots o Microglia (glitter cells) Oligodendrocytes accomplish myelination of the CNS Scavenger cells of the CNS Schwann cells accomplish myelination of the PNS Arise from monocytes, not from glioblasts Myelination of the Corticospinal tracts is not completed until the end Invade the developing nervous system in the 3rd week with the of the 2nd year (i.e., when the corticospinal tracts become developing blood vessels myelinated and functional) Layers of the Neural Tube Wall Myelination of the association neocortex extends into the 3rd decade o Are formed within the wall of the primitive neural tube of life or during the age of 30.  Positional Changes of the Spinal Cord This is discovered when the mother will carry a child and would o Disparate growth results in formation of the cauda equina, consisting see the clothing of the child will be wet, but the wet area will be of the dorsal and ventral roots (L3-Co) that descend below the level of clear since CSF is clear. the conus medullaris and in formation of nonneural filum terminale, Syringomyelocele which anchors the spinal cord to the coccyx This condition is rare. A meningomyelocele is present, and in At 8 weeks, the spinal cord extends the entire length of the vertebral addition, the central canal of the spinal cord at the level of the bony canal defect is grossly dilated. At birth, the conus medullaris extends to the level of the 3rd Lumbar Spina bifida occulta is the most common defect. vertebrae (VL3) The next most common defect is myelocele, and many afflicted In adults, the conus medullaris terminates at the VL1-VL2 interspace infants are born dead. If the child is born alive, death from infection o During the first 2 months of intrauterine life, the spinal cord is the of the spinal cord may occur within a few days. same length as the vertebral column. Thereafter, the developing vertebral column grows more rapidly than the spinal cord; thus, at birth, the coccygeal end of the cord lies at the level of the third lumbar vertebra. o In the adult, the lower end of the spinal cord lies at the level of the lower border of the body of the first lumbar vertebra o As a result of this disproportion in the rate of growth of the vertebral column and spinal cord, the anterior and posterior roots of the spinal nerves below the first lumbar segment of the spinal cord descend within the vertebral canal until they reach their appropriate exits through the intervertebral foramina. o Moreover, the pia mater, which attached the coccygeal end of the spinal cord to the coccyx, now extends down as a slender fibrous strand from the lower end of the cord to the coccyx and forms the filum The photo above depicts the different congenital anomalies, such as spina terminale. bifida occulta (most common), meningocele, meningomyelocele, myelocele, o The obliquely coursing anterior and posterior roots of the spinal nerves and syringomyelocele and the filum terminale, which now occupy the lower end of the Most cases of spina bifida occulta require no treatment vertebral canal, collectively forming the cauda equina. A meningocele should be removed surgically within a few days of CONGENITAL ANOMALIES birth Practically any part of the nervous system can show defects of Infants with meningomyelocele should also be treated surgically. development, and these produce a wide variety of clinical signs and The sac is opened, and the spinal cord or nerves are freed and symptoms carefully replaced in the vertebral canal. The meninges are sutured Spina bifida, hydrocephalus, and anencephaly each occur about 6 times over the cord and the postvertebral muscles are approximated. per 1,000 births and are therefore the more common congenital As the result of advances in medical and surgical care, many infants anomalies with the severe forms of spina bifida now survive. Unfortunately, these children are likely to have lifelong disabilities and psychosocial Spina Bifida problems. The neurologic deficits alone may result in deformation of o In spina bifida, the spines and arches of one or more adjacent the limbs and spine and in bladder, bowel, and sexual dysfunction. vertebrae fail to develop. The condition occurs most frequently in the lower thoracic, lumbar, and sacral regions. Beneath this defect, the meninges and spinal cord may or may not be involved to varying degrees. The condition is a result of failure of the mesenchyme, which grows in between the neural tube and the surface ectoderm, to form the vertebral arches in the affected region. o Types of Spina bifida are as follows: Spina bifida occulta Meningocele in the lumbosacral region with the sac formation The spines and arches of one or more vertebrae, usually in the Hydrocephalus lumbar region, are absent, and the vertebral canal remains open o Hydrocephalus is an abnormal increase in the volume of cerebrospinal posteriorly fluid within the skull The spinal cord and nerve roots usually are normal. The defect is o The condition may be associated with spina bifida and meningocele covered by the postvertebral muscles and cannot be seen from o Hydrocephalus alone may be caused by stenosis of the cerebral the surface. aqueduct or, more commonly, by the normal single channel being A small tuft of hair or a fatty tumor may be present over the defect. represented by many inadequate minute tubules Most cases are symptomless and are diagnosed by chance when o Another cause, which is progressive, is the overgrowth of neuroglia the vertebral column is x-rayed. around the aqueduct. Meningocele o Inadequate development or failure of development of the The meninges project though the defect in the vertebral arches, interventricular foramen, or the foramina of Magendie and Luschka, forming a cystic swelling beneath the skin and containing may also be responsible. cerebrospinal fluid, which communicates with the subarachnoid o Hydrocephalus may occur before birth, and if it is advanced, it could space obstruct labor. It usually is noticed during the first few months of life The spinal cord and nerves usually are normal because of the enlarging head, which may attain a huge size, Meningomyelocele sometimes measuring more than 30 inches in diameter. The normal spinal cord, or cauda equina, lies within the meningeal o The cranial sutures are widely separated, and the anterior fontanelle sac, which projects through the vertebral arch defect is much enlarged. The veins of the scalp are distended, and the eyes The spinal cord or nerve roots are adherent to the inner wall of the look downward. Cranial nerve paralyses are common. sac o The ventricles of the brain become markedly dilated. This ventricular Myelocele expansion occurs largely at the expense of the white matter, and the The neural tube fails to close in the region of the defect neurons of the cerebral cortex are mostly spared. This results in the An oval raw area is found on the surface; this represents the neural preservation of cerebral function, but the destruction of the tracts, groove whose lips are fused. The central canal discharges clear especially the corticobulbar and corticospinal tracts, produces a cerebrospinal fluid onto the surface. progressive loss of motor function.  Sensory Part of the Nervous System- Sensory Receptors o Most activities of the nervous system are initiated by sensory experience exciting sensory receptors, whether visual receptors in the eyes, auditory receptors in the ears, tactile receptors on the surface of the body, or other kinds of receptors. Hydrocephalus. Take note of the large size of the head. Example: Accidentally touching a hot stove can cause pain due to Anencephaly the heat received by the sensory receptors of the skin. This o In anencephaly, the greater part of the brain and the vault of the skull sensation will be received by the nociceptors (pain receptors) in the are absent form of free nerve endings. o The anomaly is caused by the failure of the rostral end of the neural o This sensory experience can either cause an immediate reaction tube to develop, and as a consequence, its cavity remains open from the brain, or a memory of the experience can be stored in the o In place of the normal neural tissue, there are thin-walled vascular brain for minutes, weeks, or years and determine bodily reactions at channels resembling the choroid plexus and masses of neural tissue. some future date o Although the eyes are present, the optic nerves are absent o This information enters the central nervous system through peripheral o The condition commonly involves the spinal cord, and the neural tube nerves and is conducted immediately to multiple sensory areas in: remains open in the cervical region 1. The spinal cord at all levels o The condition is commonly diagnosed before birth with sonography or 2. The reticular substance of the medulla, pons, and mesencephalon x-ray studies of the brain o Most anencephalic infants are stillborn or die shortly after birth. 3. The cerebellum 4. The thalamus 5. Areas of the cerebral cortex (sensory portion) A picture of an anencephalic baby. Take note of the absence of the back portion of the skull and a part of the brain. LECTURE #2: ORGANIZATION OF THE NERVOUS SYSTEM By: Maria Cecilia Alvarez-Espino, MD, FPLS, FPSP GENERAL DESIGN OF THE NERVOUS SYSTEM Central Nervous System Neuron: The Basic Functional Unit o Central nervous system (CNS) contains more than 100 billion neurons o Incoming signals enter this neuron through synapses located mostly on the neuronal dendrites, but also on the cell body. o Conversely, the output signal travels by way of a single axon leaving Motor Part of the Nervous System- Effectors the neuron. o The most important eventual role of the nervous system is to control o This axon has many separate branches to other parts of the nervous various bodily activities. system or peripheral body. o This is achieved by controlling: o A special feature of most synapses is that the signal normally passes 1. Contraction of appropriate skeletal muscles throughout the body only in the forward direction (from the axon of a preceding neuron to 2. Contraction of smooth muscle in the internal organs dendrites on cell membranes of subsequent neurons) 3. Secretion of active chemical substances by both exocrine and o This forces the signal to travel in the required directions for performing endocrine glands in many parts of the body specific nervous functions. o These activities are collectively called motor functions of the nervous system and the muscles and glands are called effectors because they are the actual anatomical structures that perform the functions dictated by the nerve signals o Operating parallel to this axis is another system: the autonomic nervous system, for controlling smooth muscles, glands, and other internal bodily systems o Skeletal muscles can be controlled from many levels of the central nervous system, including: 1. The spinal cord 2. The reticular substance of the medulla, pons, and mesencephalon o Parts of the neuron: 3. The basal ganglia Cell body (soma)- support center of the neuron 4. The cerebellum Dendrites- are shorter projections that receive messages from other 5. The motor cortex cells o Each of these areas plays its own specific role: Axon- a longer projection that passes messages (neural impulse) The lower regions (spinal cord) concerned primarily with automatic, away from the cell body owing to the terminal branches onto the next instantaneous muscle responses to sensory stimuli subsequent neuron Example: Spinal cord- flexor reflex or withdrawal reflex Neural impulse- electrical signaling traveling down the axon The higher regions with deliberate complex muscle movements Synapse- also called neuronal junction, the site of transmission of controlled by the thought processes of the brain electric nerve impulses between two nerve cells (neurons) or o The Motor Axis of the Nervous System between a neuron and a gland or muscle cell (effector). A synaptic When the impulse reaches the cerebral cortex, it will be interpreted connection between a neuron and a muscle cell is called a so that a proper or appropriate reaction or response will be neuromuscular junction. generated. From the cortex, it will go to the efferent pathway Myelin sheath- covers the axon of some neurons and helps speed Effectors: neural impulse Skeletal muscles Terminal branches of axon- form junctions with other cells Smooth muscles Exocrine and Endocrine glands  As it goes down to the levels of the spinal cord, the pain sensation Spinal Cord Level that has been interpreted in the cerebral cortex will cause the o We often think of the spinal cord as being only a conduit for signals immediate reflex action (flexor or withdrawal reflex) from the periphery of the body to the brain, or in the opposite direction Levels: from the brain back to the body. 1. Subcortical areas o This supposition is far from the truth. Even after the spinal cord has 2. Reticular form. (medulla, pons, and mesencephalon) been cut in the high neck region, many highly organized spinal cord 3. Basal ganglia functions still occur. For instance, neuronal circuits in the cord can 4. Cerebellum cause: 5. Motor cortex Walking movements As it goes to the higher regions of the brain, it will cause the muscles Reflexes that withdraw portions of the body from painful objects to perform the more complex activities that it will have. Reflexes that stiffen the legs to support the body against gravity Reflexes that control local blood vessels, gastrointestinal movements, or urinary excretion. Lower Brain or Subcortical Level o Many, if not most, of what we call subconscious activities of the body are controlled in the lower areas of the brain- that is, in the medulla, pons, mesencephalon, hypothalamus, thalamus, cerebellum, and basal ganglia. o For instance, subconscious control of arterial pressure and respiration is achieved mainly in the medulla and pons. o Control of equilibrium is a combined function of the older portions of the cerebellum and the reticular substance of the medulla, pons, and mesencephalon. o Feeding reflexes, such as salivation and licking of the lips in response to the taste of food, are controlled by areas in the medulla, pons, mesencephalon, amygdala, and hypothalamus (there is involvement of the limbic system). o In addition, many emotional patterns such as anger, excitement, sexual response, reaction to pain, and reaction to pleasure can still How the impulse is conducted from the sensory going to the motor areas occur after the destruction of much of the cerebral cortex (this is because it is still considered to be a subconscious activity). Higher Brain or Cortical Level o After the preceding account of the many nervous system functions that occur at the cord and lower brain levels, one may ask, what is left for the cerebral cortex to do? o The answer to this question is complex, but it begins with the fact that the cerebral cortex is an extremely large memory storehouse. o The cortex never functions alone but always in association with lower centers of the nervous system. o Without the cerebral cortex, the functions of the lower brain centers are often imprecise. The vast storehouse of cortical information usually converts these functions to determinative and precise operations. o Finally, the cerebral cortex is essential for most of our thought processes, but it cannot function by itself. In fact, it is the lower brain centers, not the cortex, that initiates wakefulness in the cerebral cortex, thus opening its bank of memories to the thinking machinery of the brain. For instance, during summer when it is very hot, this will be received by the o Thus, each portion of the nervous system performs specific functions, thermoreceptors in the skin, and the impulses would be conducted to the but it is the cortex that opens a world of stored information for use by brain, interpreted, and sent to the effector (the sweat glands). The sweat the mind. glands will then cause cooling by surface evaporation (perspiration) hence PROCESSING OF INFORMATION- “INTEGRATIVE” FUNCTION OF THE the body will go back into homeostasis. NERVOUS SYSTEM MAJOR LEVELS OF CENTRAL NERVOUS SYSTEM FUNCTION One of the most important functions of the nervous system is to process incoming information in such a way that appropriate mental and motor responses will occur. More than 99% of all sensory information is discarded by the brain as irrelevant and unimportant. o Example: When listening to a lecture. More often than not, your attention will only be drawn to the person who will be giving the lecture and whatever noise in the surroundings will be relegated to the There are 3 levels of the CNS function subconscious. After it is received by the sensory receptors, the impulses will go to the For instance, one is ordinarily unaware of the parts of the body that are spinal cord level. Through the afferent fibers, it goes further to the in contact with clothing, as well as of the seat of pressure when sitting. lower brain level, and then up to the higher brain level. Likewise, attention is drawn only to an occasional object in one’s field of After it is interpreted in the higher brain level, it will go down through the vision, and even in the perpetual noise of our surroundings is usually efferent fibers, into the effector organ relegated to the subconscious. Three major levels of the central nervous system have specific functional But, when important sensory information excites the mind, it is characteristics: immediately channeled into proper integrative and motor regions of the 1. The spinal cord level brain to cause desired responses. This channeling and processing of 2. The lower brain or subcortical level information is called the integrative function of the nervous system. 3. The higher brain or cortical level  Thus, if a person places a hand on a hot stove, the desired ELECTRICAL CHEMICAL Distance between pre and instantaneous response is to lift the hand. And other associated post synaptic cells 3.5 nm 20-40 nm responses follow, such as moving the entire body away from the stove, Cytoplasmic continuity between pre and post Yes No and perhaps even crying or shouting with pain. synaptic cells Ultrastructural components Pre synaptic vesicle and active Gap-junction channels zones; Postsynaptic receptors Agent of transmission Ion current Chemical transmitter Synaptic delay Significant: at least 0.3 ms, Virtually absent usually 1-5 ms or longer The purpose of the nervous system is to process any incoming Direction of transmission Usually bidirectional Unidirectional Function Mediate either excitatory or information or stimulus and be able to have an appropriate motor inhibitory actions; Send simple depolarizing response or desired response. signals Long-lasting changes in electrical properties of postsynaptic cells; Role of Synapses in Processing Information More complex behaviors o The synapse is the junction point from one neuron to the next neuron. o Parts of a Synapse A neuron has terminal branches of the axon, and this will connect to Pre-synaptic Terminals the next neuron by way of the synapses. Also known as: terminal knobs, buotons, end-feet, synaptic knobs o It is important to point out that synapses determine the directions that Synaptic cleft: 200-300 Å width the nervous signals will spread through the nervous system. Some Synaptic vesicles: with neurotransmitter synapses transmit signals from one neuron to the next with ease, Mitochondria: provide ATP whereas others transmit signals only with difficulty. Voltage-gated Ca++ channels o Also, facilitatory and inhibitory signals from other areas in the Post-synaptic neuron nervous system can control synaptic transmission, sometimes Receptor proteins: 2 components: opening the synapses for transmission and at other times closing them. Binding components o In addition, some postsynaptic neurons respond with large numbers of Ionophore components (2 types) output impulses, and others respond with only a few. Chemically activated ion channels: o Synapses perform a selective action, often blocking weak signals Na+ channels- excitatory while allowing strong signals to pass, but at other times selecting and K+ channels and Cl- channels- inhibitory amplifying certain weak signals, and often channeling these signals in Enzymes: active internal metabolic system to: many directions rather than only one direction. Increase in no. of receptors Decrease in no. of receptors Modulators 2nd messengers A synapse has a pre-synaptic terminal and a post-synaptic terminal o Information is transmitted in the form of nerve action potentials - “nerve impulses”, through a succession of neurons, one after another o Synaptic functions of neurons: Each impulse may be blocked in its transmission from one neuron to the next. Physiologic anatomy of the synapse where it has a pre-synaptic terminal It may be changed from a single impulse to repetitive impulses. and postsynaptic neuron It may be integrated with impulses from other neurons. MECHANISM: ACTION POTENTIAL CAUSES TRANSMITTER RELEASE This is where the information would be transmitted in the form of (PRE-SYNAPTIC KNOB) action potentials. Pre-Synaptic Terminal Synapse is the junction point from one neuron to the next. It is an advantageous site of substance or the control of signal transmission. Described as “interneuronal junction.” Almost all synapses in the CNS transmit signals through a neurotransmitter substance, and is known as chemical synapse. o Types of Synapses Chemical Synapses o Initially, due to the introduction of the stimulus, there is a nerve Utilized for almost all signal transmission in the CNS impulse that causes depolarization of the presynaptic terminal. Neurotransmitter secreted by the presynaptic neuron that may o Hence, with the depolarization of the presynaptic terminal, there will either excites, inhibits, or modifies the activity of the post-synaptic now be an influx of sodium and calcium. neuron. o With influx of both sodium and calcium, there will be a binding of Always transmit signals in one direction: calcium with the protein receptors, which would be the release sites. o With the binding of calcium with the protein receptors, the local transmitter vesicles will now bind with the presynaptic membrane, hence resulting to the exocytosis of the neurotransmitter to the synaptic cleft. Post-Synaptic Terminal Electrical Synapses Direct channels that conduct electricity from one cell to the next. Most are gap junctions- allow free movement of ions from the interior of one cell to the next. o Neurotransmitter will bind with the binding components of the receptor Transmits signals in either direction (bidirectional). proteins (post synaptic membrane) o Due to the binding, the ionophores will then be activated: Chemical activation- which causes the opening of the channels, which can be: Excitatory transmitter- opens the Na+ channels Inhibitory transmitter- opens the K+ and Cl- channels Enzyme activation- increase or decrease of receptors Factors that decrease quantity of Ca++ entering pre-synaptic terminals that decrease transmitter release: o Weak action potential (A.P.) caused by partial depolarization of presynaptic terminal o Decreased Ca++ in ECF = hypocalcemia o Decreased permeability of presynaptic terminal to Ca++ Fates of Transmitter substances after it has opened certain ion Distribution of Sodium, Potassium, and Chloride channels in the post-synaptic membrane: Neuron at Resting Membrane Potential: -65 mV o Diffusion into surrounding fluids More Sodium outside o Enzymatic destruction: More Potassium inside ACH + cholinesterase (causes the destruction of acetylcholine) = More Chloride outside choline and acetate Resting vs. Excited vs. Inhibited o Transmitter re-uptake Excited Neuron: -45 mV at Resting Membrane Potential Active transport back into pre-synaptic terminal Inhibited Neuron: -70 mV Receptors in the Postsynaptic Membrane o Origin of Resting Membrane Potential (Neuronal Soma) Na-K pump o Excitatory Extrusion of more Na+ to the outside than K+ to the interior (3:2) Opening of Na+ channels Interior of the cell is more negative since (-) charged ions inside the Depressed conduction through Cl- or K+ channels or both soma cannot diffuse outward (protein ions, PO4 or phosphate Various changes in the internal metabolism to excite cell activity compounds) o Inhibitory o Uniform distribution of potential inside soma Opening of Cl- ion channels Highly conducive to the electrolytic resolution of the intracellular fluid Increase in conductance of K+ ions out of the neuron of the soma Activation of receptor enzymes that inhibit cellular metabolic Any change in potential in any part of intrasomal fluid will result in functions almost exact equal change in potential at all points inside the soma. CHEMICAL AND PHYSIOLOGICAL NATURE OF TRANSMITTER Very highly conductive electrolyte solution in the ICF of soma SUBSTANCE Very large diameter of soma would result in almost no resistance to Factors that determine the effects of Neurotransmitters conduction of electrical current. o Nature of transmitter EPSP (Excitatory Postsynaptic Potential) o Nature of receptors in post-synaptic membrane o Increase in voltage above the normal Resting Membrane Potential Classes of Neurotransmitters o Transmitter acts on membrane excitatory receptor = increase o Class 1: ACH membrane permeability to Na+ & K+ o Class 2: Amines (epinephrine, norepinephrine, dopamine, serotonin) o Mainly the Na+ influx would neutralize negativity inside the membrane o Class 3: Amino Acids (GABA, glycine, etc.) e.g., from -65 mV to -45 mV Class 1, 2, 3- Small molecule rapidly-acting transmitters; acute EPSP + +20 mV responses of N.S. ACTION POTENTIAL (A.P.) o Class 4: Neuroactive peptides o Begins in the axon hillock: 7x more concentration of voltage-gated Neuropeptides- Slowly-acting neurotransmitters; More prolonged Na+ channels than soma actions; Much more potent than the small molecule rapidly-acting EPSP to elicit A.P. at the axon hillock would require +15 to +20 mV transmitters At soma = +30 mV DALE Principle o Travels peripherally along axon, soma, and dendrites o Release of only a single type of transmitter substance by each neuron ELECTRICAL EVENTS DURING NEURONAL INHIBITION and the release of this same transmitter at all of its separate terminals. Inhibitory Postsynaptic Potential (IPSP) ELECTRICAL EVENTS DURING NEURONAL EXCITATION Large motor neurons in spinal cord Resting Membrane Potential (RMP) of the neuronal soma o (-) 65 mv. o Concentration difference of ions across neuronal somal membrane: “Short-Circuiting” of the Membrane Na+: ECF = 142 mEq/L; ICF = 14 mEq/L o Neuronal Inhibition without necessarily causing IPSP Na-K pump- continually pumps out Na+ into the ECF o Produces postsynaptic Inhibition Nernst potential (EMF) = +61 mv Allows Na+ to normally diffuse INWARD (inside the cell) K+: ECF = 4.5 mEq/L; ICF = 120 mEq/L K+ pump- pumps K+ INWARD Nernst potential = -86 mv Presynaptic Inhibition Tends to move K+ OUTWARD (towards the ECF) o Caused by “presynaptic” synapses that lie on terminal nerve fibrils Cl-: ECF = 107 mEq/L; ICF = 8 mEq/L before they themselves terminate on the following neuron Membrane is highly permeable to Cl- ions o Secrete a transmitter that depresses voltage of Action Potential at Negative voltage (-65 mv) inside soma repels Cl- to the OUTSIDE Synaptic Membrane (Partial depolarization) (towards the ECF) Decreased Ca++ that enters the terminal Nernst potential = -70 mV Decreased transmitter released by the terminal Therefore: Cl- normally tend to diffuse INWARD (towards the ICF) Decreased excitation of neuron (post-synaptic)  SUMMATION OF EPSP AND IPSP o Most anesthetics increase the neuronal membrane threshold for Spatial Summation excitation and thereby decrease synaptic transmission at many points o Occurs when activity is present in more than one synaptic knob at the in the nervous system. Because many of the anesthetics are same time especially lipid soluble, it has been reasoned that some of them might o Effect of summing simultaneous postsynaptic potentials by excitation change the physical characteristics of the neuronal membranes, of multiple pre-synaptic terminals on widely spaced areas of the making them less responsive to excitatory agents. membrane (several pre-synaptic terminals simultaneously stimulated) Example: When a person is administered with general anesthesia, Temporal Summation the person will be in a state of sleep and will be less responsive in o Occurs if repeated afferent stimuli cause new EPSPs that would any form of excitatory stimulus. produce depolarization Effect of Acidosis or Alkalosis on Synaptic Transmission o Involves single presynaptic terminal o Most neurons are highly responsive to changes in pH of the One presynaptic terminal but are repeatedly excited or stimulated surrounding interstitial fluids. hence producing EPSPs that would produce an action potential. o Normally, alkalosis greatly increases neuronal excitability. NOTE: If the EPSP in both spatial and temporal summation is large For instance, a rise in arterial blood pH from the 7.4 (normal) to 7.8 enough to reach a firing level, a full-pledged action potential is to 8.0 often causes cerebral epileptic seizures because of increased produced. excitability of some or all of the cerebral neurons. This can be RELATION OF STATE OF EXCITATION OF THE NEURON TO RATE OF demonstrated especially well by asking a person who is predisposed FIRING to epileptic seizures to overbreathe. The “excitatory state” of a neuron is defined as the summated degree The overbreathing blows off carbon dioxide and therefore elevates of excitatory drive to the neuron. If there is a higher degree of excitation the pH of the blood momentarily, but even this short time can often than inhibition of the neuron at any given instant, then it is said that there precipitate an epileptic attack. is an excitatory state. o Conversely, acidosis greatly depresses neuronal activity Conversely, if there is more inhibition than excitation, then it is said that A fall in pH from 7.4 to below 7.0 usually creates a comatose state. there is an inhibitory state. For instance, in very severe diabetic or uremic acidosis, coma When the excitatory state of a neuron rises above the threshold for virtually always develops. excitation, the neuron will fire repetitively as long as the excitatory state remains at that level. LECTURE #3: MEMBRANE ACTION POTENTIAL AND SPECIAL CHARACTERISTICS OF SYNAPTIC TRANSMISSION NEUROMUSCULAR TRANSMISSION Fatigue of Synaptic Transmission By: Ana Lisa Biliran, MD o When excitatory synapses are repetitively stimulated at a rapid rate, Membrane Potential: difference in electric charge between the interior the number of discharges by the postsynaptic neuron is at first very and exterior of a cell great, but the firing rate becomes progressively less in succeeding milliseconds or seconds. This is called the fatigue of synaptic transmission. o The mechanism of fatigue is mainly exhaustion or partial exhaustion of the stores of transmitter substance in the presynaptic terminals. MEMBRANE POTENTIALS ACROSS A SELECTIVELY PERMEABLE o The excitatory terminals on many neurons can store enough excitatory MEMBRANE transmitters to cause only about 10,000 action potentials, and the Diffusion Potential: potential difference generated across a membrane transmitter can be exhausted in only a few seconds to a few minutes when a solute diffuses down its concentration gradient of rapid stimulation. o Parts of the fatigue process probably results from two other factors as well: Progressive inactivation of many of the postsynaptic membrane receptors Slow development of abnormal concentrations of ions inside the postsynaptic neuronal cell Effect of Hypoxia on Synaptic Transmission o Hypoxia- the cutting off of the oxygen supply. o Nerve fiber that is only permeable to potassium o Neuronal excitability is also highly dependent on an adequate supply Potassium is more abundant in the inside of the nerve compared to of oxygen. the outside (it goes from high concentration to low concentration; o Cessation of oxygen for only a few seconds can cause complete naturally, potassium will go from inside to outside). inexcitability of some neurons. This is observed when the brain’s blood Potassium has positive (+) charge; it will keep the inside of the nerve flow is temporarily interrupted, because within 3 to 7 seconds, the fiber negative (-). person becomes unconscious. Inside the nerve fiber are anions, which are negative substances Ex. A patient from a drowning incident will have hypoxia, causing the (e.g., phosphates, proteins). inexcitability of neurons. The patient will go in an unconscious state. o Nerve fiber that is only permeable to sodium Effect of Drugs on Synaptic Transmission Sodium is one of the most abundant extracellular ions (it goes from o Caffeine, theophylline, and theobromine, which are found in coffee, high to low concentration; sodium will go inside the nerve fiber) tea, and cocoa, respectively, all increase neuronal excitability, Sodium causes the nerve fiber to become positive (+). presumably by reducing the threshold for excitation. Eventually, there will come to a point that it will reach equilibrium o Strychnine is one of the best known of all agents that increase Nerst Potential excitability of neurons. However, it does not do this by reducing the o Diffusion potential across a membrane that exactly opposes the net threshold for excitation of neurons; instead, it inhibits the action of diffusion of a particular ion through the membrane some normally inhibitory transmitter substances, especially the Nerst Equation inhibitory effect of glycine in the spinal cord. Therefore, the effects of the excitatory transmitters become overwhelming, and the neurons become so excited that they go into rapidly repetitive discharge, resulting in severe tonic muscle spasms. o Calculate the Nernst potential for any univalent ion (1 ion) at the Experiment: Strychnine is injected in the throat area of the frog and the frog will go into severe chronic muscle spasms until it dies o Nernst potential is the potential inside the membrane o The sign of the potential is + for negative ions, – for positive ions o Example: Potassium (+ ion) Na+-K+ Pump- the net membrane potential when considering all the Concentration inside= 10; concentrate outside= 1 factors are operative at the Mv (C) = 61 mV (equilibrium potential is 61) NEURON ACTION POTENTIAL Hypokalemia (less potassium in the blood)- increase potassium efflux; farther from threshold and less likely to cause action potential (more negative) and causes muscle weakness Hyperkalemia (increased potassium)- closer to threshold and more likely to cause action potential (more positive) Potassium has a greater role in the resting membrane potential compared to sodium. 1. Resting Stage Goldman Equation 2. Depolarization Stage- Na+ ions in 3. Repolarization Stage- K+ ions out Voltage-Gated Sodium Channel o Necessary for depolarization and repolarization of the nerve membrane during the action potential o Calculates membrane potential on the inside of the o Activation and Inactivation membrane when two univalent positive ions, Na+ and K+, and one univalent negative ion, Cl- are involved o Key Points Na+, K+, and Cl- are the most important ions involved in the development of membrane potentials in nerve and muscle fibers Voltage is proportional to the membrane permeability for that particular ion Positive ion concentration gradient from inside the membrane to the Activation gate is closed, inactivation gate is opened outside causes electronegativity inside the membrane When it reaches a threshold of about -55 mV, this causes activation Na+ and K+ channels undergo rapid changes during transmission of gate to open so Na will come in. a nerve impulse whereas the permeability of the chloride channels Eventually it will get from -70 to +35 mV, and repolarization occurs. does not change greatly during this process In repolarization, inactivation gate closes, Na stops coming in, Resting Membrane Potential In Different Cell Types several factors come to play, and will soon go back to -70 mV. Inactivation The conformational change that flips the inactivation gate to the closed state is a slower process than the conformational change that opens the activation gate Membrane potential beings to return toward the resting membrane state, the repolarization process Inactivation gate will not reopen until the membrane potential returns to or near the original resting membrane potential level o An experiment was done by using a micropipette and placed inside the sample crane. Another electrode was used to determine the Voltage-Gated Potassium Channel resting potential. o Increases the rapidity of repolarization of the membrane RESTING MEMBRANE POTENTIAL OF NEURONS o Activation During the resting state, the gate is closed and K cannot pass through the channel. Once it opens, it will activate repolarization and will go from +35 mV to -70 mV. Sodium-Potassium Pump plays a role o Voltage Clamp Method o It goes against the concentration gradient so energy is required in the They conducted an experiment on the voltage clamp method and process (uses ATP). was able to provide evidence that when action potential activates, o 3 sodium is pumped out while 2 potassium is pumped in which makes Na comes in. When Na channels starts closing, K channel opens the inside of the cell negatively charged. since K channel opens more slowly. Eventually it goes back to o Origin of the Normal Resting Membrane Potential resting membrane potential. Events that Cause the Action Potential Potassium Diffusion Potential- If K ions were the only factor causing the resting potential, using the Nerst equation, the resting potential inside the fiber would be equal to -94 mV. (A) Sodium Diffusion- Using the value in the Goldman equation, and considering only Na and K, it gives a potential inside the membrane o Rate of opening of the K+ channels is much slower than that of the mV. (B) Na+ channels  Other Ions During the Action Potential o Applies to all normal excitable tissues (neurons, skeletal muscle cells) o Anions o For continued propagation of an impulse to occur, the ratio of action potential to the threshold for excitation must at all times be greater than 1 o The greater than 1 requirement is called the safety factor for propagation Negatively charged ions inside the nerve axon that cannot go IMPORTANCE OF ENERGY METABOLISM through the membrane channels Sodium and potassium ionic gradients should be re-established after Responsible for the negative charge inside the fiber when there is a action potentials are completed net deficit of positively charged K+ and other positive ions Sodium ions diffuse to the inside during depolarization and potassium o Calcium Ions ions diffuse to the outside during repolarization. These ions must be Calcium serves along with sodium in some cells to cause most of returned to their original state by the Na+-K+ pump. the action potential PLATEAU IN SOME ACTION POTENTIALS Calcium pump transports calcium ions from the interior to the exterior of the cell membrane Voltage-gated calcium channels (slow channels) have a more sustained depolarization whereas sodium channels (fast channels) initiate action potentials Calcium channels are found in cardiac muscle and smooth muscle Deficit of Calcium Ions causes Increased Permeability of Sodium Channels Sodium channels becomes activated by a small increase of the membrane potential from its normal, very negative level. Depolarization Calcium ion concentration needs to fall only 50% below normal o Voltage-activated Na+ channels (fast channels) before spontaneous discharge occurs in some peripheral nerves, o Voltage-activated Ca2+-Na+ channels (L-type calcium channels, slow often causing muscle tetany channels) Muscle tetany is sometimes lethal because of tetanic contraction Plateau of the respiratory muscles o Prolonged opening of slow Ca2+-Na+ channels Initiation of the Action Potential o Voltage-gated potassium channels RHYTHMICITY OF SOME EXCITABLE TISSUES- REPETITIVE DISCHARGE Repetitive self-induced discharges occur normally in the heart, in most smooth muscle, and in many of the neurons of the CNS. These rhythmical discharges cause the following: 1. Rhythmical beat of the heart 2. Rhythmical peristalsis of the intestines; 3. Neuronal events such as the rhythmical control of breathing Veratridine o Large nerve fibers and skeletal muscle fibers, which normally are o A positive feedback cycle opens the sodium channels highly stable, discharge repetitively when they are placed in a solution that contains this drug, which activates sodium ion channels, or when o Initiation of the action potential occurs only after the threshold potential the calcium ion concentration decreases below a critical value, which is reached increases the sodium permeability of the membrane A sudden rise in membrane potential of 15-30 mV in a large nerve Re-Excitation Process- Necessary for Spontaneous Rhythmicity fiber, from -70 mV up to about -55 mV causes the explosive o For spontaneous rhythmicity to occur, the membrane must be development of an action potential. This level of -55 mV is said to be permeable enough to sodium ions (or to calcium and sodium ions the threshold for stimulation. through the slow calcium-sodium channels) to allow automatic PROPAGATION OF THE ACTION POTENTIAL membrane depolarization. o The resting membrane potential in the rhythmical control center of the heart is only -60 to -70 mV, which is not enough negative voltage to keep the sodium and calcium channels totally closed. Therefore, the following sequence occurs: 1. Some Na+ and Ca+ ions flow inward 2. Increases membrane voltage in the positive direction which further increases membrane permeability 3. More ions flow inward 4. Permeability increases until an action potential is generated 5. At the end of the action potential, the membrane repolarizes 6. After a delay of milliseconds or seconds, spontaneous excitability causes depolarization again and a new action potential occurs spontaneously Action potential travels in all directions away from the stimulus until the entire membrane has become depolarized The depolarization process travels along the entire length of the fiber. This transmission of the depolarization process along a nerve or muscle fiber is called a nerve or muscle impulse. All-or-Nothing Principle o Once an action potential has been elicited at any point on the membrane of a normal fiber, the depolarization process travels over o Why does the membrane of the heart control center not depolarize the entire membrane if the conditions are right, but it does not travel immediately after it has become repolarized, rather than delaying for at all if conditions are not right nearly 1 second before the onset of the next action potential?  The reason behind this is because of the potassium conductance o At point C, the stimulus is even stronger and the local potential has as seen in the graph. This curve shows that toward the end of each barely reached the threshold level required to elicit an action potential, action potential, and continuing for a short period thereafter, the but this occurs only after a short “latent period.” membrane becomes more permeable to potassium ions. o At point D, the stimulus is still stronger, the acute local potential is also SIGNAL TRANSMISSION IN NERVE TRUNKS stronger, and the action potential occurs after less of a latent period. Myelinated Nerve Fiber Refractory Period o Absolute Refractory Period: Second action potential cannot be elicited even with a strong stimulus o Relative Refractory Period: Action potential can be initiated with a stimulus that is greater than normal o A typical small nerve has many large nerve fibers that constitute most Inhibition of Excitability of the cross-sectional area. There many more small fibers lying o Stabilizers between the large ones. The large fibers are myelinated, and the Membrane stabilizing factors can decrease excitability small ones are unmyelinated. The average nerve trunk contains Example: High extracellular fluid calcium ion concentration about twice as many unmyelinated fibers as myelinated fibers. decreases membrane permeability to sodium ions and o Axon: Central core of the nerve fiber; where the action potential simultaneously reduces excitability. conducted in its membrane Stabilizer: Calcium ions o Axoplasm: Viscid intracellular fluid that fills the center of the axon o Local Anesthetics (Procaine and Tetracaine) o Schwann Cell: Insulates nerve fiber; contains sphingomyelin Sphingomyelin is an excellent electrical insulator that decreases ion flow through the membrane about 5000-fold o Myelin Sheath: Surrounds the axon o Node of Ranvier: At the junction between 2 successive Schwann cells along the axon; small uninsulated areas where ions still can flow with ease through the axon membrane between the extracellular fluid and Act directly on the activation gates of the Na+ channels, making it intracellular fluid inside the axon much more difficult for these gates to open and thereby reducing Saltatory Conduction membrane excitability Nerve impulses fail to pass along the anesthetized nerve (usually thin, unmyelinated nerves) o Even though almost no ions can flow through the thick myelin sheaths of myelinated nerves, they can flow with ease through the nodes of Ranvier. Therefore, action potentials occur only at the nodes. o The action potentials are conducted from node to node by saltatory conduction. That is, electrical current flows through the surrounding extracellular fluid outside the myelin sheath, as well as through the axoplasm inside the axon from node to node, exciting successive nodes one after another. Thus, the nerve impulse jumps along the fiber, which is the origin of the term saltatory. Velocity of Conduction in Nerve Fibers o The velocity of action potential conduction in nerve fibers varies from as little as 0.25 m/sec in small unmyelinated fibers to as much as 100 m/sec (more than the length of a football field in 1 second) in large myelinated fibers. EXCITATION- THE PROCESS OF ELICITING THE ACTION POTENTIAL Threshold for Excitation and Acute Local Potentials o A weak stimulus at point A causes the membrane potential to change from -70 to -65 millivolts, but this change is not sufficient for the automatic regenerative processes of the action potential to develop. o At point B, the stimulus is greater, but the intensity is still not enough.