Nervous System and Behavioral Science.pdf

Lecture 1: Neuroembryology Early Embryonic Development of the CNS - week 3 and 4 - NS develops from the ectoderm - Notochord induces development of the neural plate - Lateral Edges accumulate and form neural folds -The neural neural groove grooveisisformed formedalong alongthe the longitudinal axis...

Lecture 1: Neuroembryology Early Embryonic Development of the CNS - week 3 and 4 - NS develops from the ectoderm - Notochord induces development of the neural plate - Lateral Edges accumulate and form neural folds -The neural neural groove grooveisisformed formedalong alongthe the longitudinal axis as the plate grows and widens - The neural neural folds foldsfuse fusealong alongthe themidline midline forming the neural tube - The process by which the neural neural tube tubeisis formed from the neural neural plate plateisiscalled called primary neurulation neurulation Fates of Neural Crest (Differentiate into groups of neurons Group 1 Group 2 Group 3 Sensory Neurons of CN Ganglia Autonomic Chromaffi Mesoderm Ganglionic n cells of al cells Cells the alongside Adrenal the neural Medulla tube SOMITES CN V, VII, IX, and X of the head region Postgangli onic neurons of the para and prevertebr al ganglia of the SNS Dorsal Root Ganglia, componen ts of the body Post Melanocyt Ganglionic es neurons of the PNS located in the visceral Organs Schwann cells that form meyline in PNS Group 4 Somites will develop into skeletal muscle, vertebrae, and the dermal layer of the skin Eye Development - week 4 and 5 the prosencephalon displays selective changes (diencephalon) - Formation of optic vesicle at the ventral aspect of the anterior forebrain - Optic vesicle expands outwards while connected to the forebrain by the constricted optic stalk - The fiber bundles formed anterior to the optic chiasm are are the optic nerves. Their continuation posterior to the chiasm is the optic tract Forebrain Development/ Diencephalon - Develops from swellings of the lateral aspects of the neural canal and mainly from the Alar plates - Forms the thalamus dorsally and the hypothalamus ventrally - The thalamus displays the greatest amount of growth and is the largest component of the diencephalon. A small bridge is formed between its two sides the Masssa Intermedia - Other structures associated w/ the hypothalamus are the optic chiasm, the mamillary bodies, and the infundibulum. Telencephalon - Lies in front of the lamina terminalis - Grows into the cerebral hemisphere from the dorsal aspect of the forebrain - Sac-like structures within each hemisphere develop into the lateral ventricles - During month 3-4 the cerebral hemispheres continue to grow anteriorly and dorsally forming the frontal lobe - It expands laterally and dorsally forming the parietal lobe - Posterior and ventral growth results in the development of of the temportal and occipital lobes - Contains the neocortex (6 histologically distincy leyers Telencephalon (cont) - The lateral ventricles are continuous w/ the 3rd ventricle through the interventricular foramina (of Monroe) - Pyrimidal cells are formed, and their axons form the internal capsule as well as the corpus callosum - Granule cells are formed They receive input from regions of the Thalamus - Proliferation of immature neurons in the floor of the telencephalon forms the major components of the basal ganglia (caudate nucleus, putamen, globus pallidus) - Hippocampal formation from medial surface forms the fornix. Spinal Cord Spinal Cord consists of three layers: - Ventricular Layer: Inner most proliferativve and the first to form - Mantle layer: Intermediate and 3rd layer to form. It contains the primary cell bodies of neurons and becomes the grey matter of the spinal cord. (contains Alar and Basal Plate) - Marginal Layer: Second layer to form and the outer most. *The central canal is formed from the closure of the posterior neuropore. * The sulcus limians is formed along the lateral margin of the neural canal forming the walls. It is the shallow groove that separates the Alar and basal plates of the mantle layer. Alar and Basal Plates - Alar plates – Formed from neurocytes that migrate dorsal to the sulcus limitans – contributing sensory path. - Basal Plates – Formed from neurocytes that migrate ventral to the sulcus limitans and contribute motor path. - Cells along the dorsal midline – Roof Plate - Cells along the ventral plate – Floor Plate - Cells in the intermediate position adjacent to the sulcus limitans will become autonomic neurons Mesencephalon – Midbrain 3 general region Tectal Region – Dorsal Tegmental Region – Intermediate Peduncular Region – Ventral - Neurocytes from the basal plate develops into motor neurons (CN III, IV) Metencephalon – Pons and cerebellum - Pons - Tementum - Dorsal - Basilar Pons – Ventral - Cerebellum: Derived from the dorsal aspect of the Alar plate - Cells from the central region – vermis - Cells from lateral region – Cerebellar hemispheres - Coordination of movements - Spatial Memory Brain Stem and Cerebellar Development - Roof plate expands, Alar plates lacted lateral to the basal plates - Motor structures medial to sensory structures; GSE medial to GSA - CNXII – Hypoglossal GSE – Motor – Innervates tongue - CNVIII – Vestibulocochlear special sensory afferent (SSA) - Cerebellum formation (D, E) medial fusion of the rhombic lip, w/ vermis at midline Myelencephalon – Medulla - The neural canal expands to become the 4th ventricle, roof plate expands, and Alar plate becomes lateral to basal plate - Motor and sensory neurons are arranged in columns in a medial to lateral fashion - Mesenchymal tissue in 4th ventricle becomes highly vascular, from the central portion of the roof it invaginates to become the choroid plexus. - In the 4-6 month of development the foramen of Luschka (pair) and foramen of magendie (single) are formed CC Neural Tube Defects - Early development can be affected by a deficiency of folate which is critical for synthesis of various amino acids. A deficiency prevents appropriate cell turnover at the time of neural tube closure - To prevent neural tube defects folic and supplements are recommended. CC Spina Bifida- Failure of Vertebral Canal Closure - Spina Bifida Occulta - One or more vertebrae fail to close, no involvement of meninges or underlying spinal cord, overlying skin is closed - Mostly benign discovery incidental - Spina Bifida Aperta/ Cystica : - Protrusion of only meninges (meningocele) or spinal cord w/ meninges (meningo – myelocele) CC Syringomyelia - A cavity formed in the region of the central canal. It is filled w/ CSF. It damages the crossing fibers of the spinothalamic tract resulting in segmental loss of pain and temperature CC Tethered Cord Syndrome - Anchoring of the lowest part of spinal cord to sacrum CC Encephalocele - Failure of portions of anterior neural tube to close CC Dandy Walker Syndrome - Congential absence of the lateral apertures (foramen of luschka) and the median aperture (forman of magendie) - Results in complete/ partial agenesis of the cerebellar vermis, cystic dilation of posterior fossa communicating w/ the 4th ventricle. CC Acenecephaly - Partial or complete absence of the brain because of failure of the anterior neuropore to close MRI of Cephalocele and a meningomyelocele Lecture 2: General Morphology 1 5 Parts of the Brain 1. Telencephalon 2. Diencephalon 3. Mesencephalon 4. Metancephalon 5. Myelencephalon Central Nervous System (CNS) – Terminology Brain - Telencephalon (Endbrain, cerebrum) - Diencephalon - Thalamus, Hypothalamus, Subthalamus, Epithalamus - Mesencephalon (Midbrain) - Metaencphalon (Pons and Cerebrum) BrainStem - Myelencephalon (Medulla) Embryological Origin / Ventricular System and Parts of the Brain - Lateral Ventricles (telencephalon) - Third Ventricl (Diencephalon) - Cerebral Aqueduct (midbrain) - Fourth Ventricle (Pons, Medulla, and Cerebellum( - Central Canal (Spinal Cord) Surface of the Telencephalon – Gyri and Sulci - Gyri and Sulci are the two main types of surface folds of the telencephalon - A gyrus is an elevation of the cerebral cortex - Sulcus is a groove or indentation that separates the gyri from each other Lobes of the Telencephalon – Frontal Lobe - Functions of the Frontal Lobe: - Voluntary Movement - Production of Language - Prodominantly left hemisphere - Higher executive functions - Planning - Initiating - Self monitor behavior Lecture 3: General Morphology Neurons (aka never cells) are functional building blocks of the nervous system. The diameter of a neuronal soma or cell body is between 10 to 100 micrometers. Axons can cover distance from a few micrometers in the immediate vicinity to slightly more than 1 meter (more than 3 feet). Most neuronal axons are myelinated. * Axons can be up to a meter long Grey matter: gets its darker tone from the a high [neuronal cells bodies], because of great RNA content, and a high density of capillaries supplying them w/ O2 and nuetrients White Matter: gets a paler tone from a high amount of myelin, a fatty substance, which provides electrical insulation of axon, improving their conduction velocity. Cerebral Hemispheres- Gray and White Matter - In the cerebral hemispheres most of the gray matter is located close to the surface, in outermost layer called cerebral cortex. - Gyri (elevations) and sulci (grooves) are the two main types of surface folds of the cerebral cortex. - Some of the gray matter forms distinct nuclei in the deeper layers of the white matter. - The deeper nuclei are called basal ganglia or basal nuclei Gray Matter Terminology CNS: Cerebral Cortex; superficial component of the gray matter of the cerebral hemisphere - Nucleus: Most common term for distinct lump of gray matter, usually w/ a distinct function (e.g. red nucleus, substantia nigra) - Reticular Formation: Describes network of smaller nuclei of the brainstem connected by fiber tracts, which gives it the appearance of a fishing net (e.g. pontine paramedian reticular formation) PNS - Ganglion: Clusters of neurons usually surrounded by non-neuronal tissue; can be either somatic or visceral (eg dorsal root ganglia (somatic), sympathetic chain ganglia (visceral) Gray Matter in Coronal and Horizontal Sections - White Mater: Categories of Fiber Tracts - Projection Fibers Connect higher (such as cerebral cortex ) and lower (such as the spinal cord) elements of the CNS along the rosto-caudal axis - Commissural Fibers: Connect the two hemispheres of the cerebral cortex to each other (eg Corpus Callosum is the largest commissural fiber tract) - Associated Fibers Connect different parts of the cerebral cortex of one hemisphere. (eg the arcuate fasciculus, which connects Broco’s area (language production) and Wernicke’s Area (understanding of language) in the same hemisphere White Matter in Coronal and Horizontal Sections Commissures connecting Left and Right Hemispheres Commissures connecting Left and Right Hemispheres Association Fibers of the Arcuate Fasciculus Connect Brocoa’s and Wernicke’s Areas - Arcuate Fasciculus: NOT a surface feature; but is proximal to supramarginal and angular gyri - Brocoa’s Area is anterior: Produce - Wernicke’s area is posterior: Understanding White Matter Terminology CNS - In addition to the terms already introduced above, there are other common terms for white matter tracts in the CNS Fasciculus: Bundle of Nerve Fibers Fornix: Arched, C-shaped bundle of nerve fibers Funiculus: Bundle of Nerve Fibers Lemniscus: A thin, ribbon like band of nerve fibers Peduncle: A stalk like bundle of nerve fibers, connecting one part of the brain w/ another Stria: A narrow, streak-like bundle of nerve fibers PNS Nerve: Bundle of axons covered by CT in the peripheral nervous system (eg cranial nerves (optic nerve), spinal nerves (L2); More distal branches (such as ulnar nerve) Cerebral Peduncles are Part of the Midbrain and connect the Cerebral Hemisphere w/ the Rest of the Brainstem Cerebellar Peduncles connect Brainstem w// Cerebellum Gray and White Matter in Axial Spinal Cord Section - Gray Matter is in the center of the cord, surrounded by white matter - The gray matter is shaped like a butterfly, w/ dorsal and ventral horns forming the wings - Lateral horns of gray matter are found in the thoracic and lumbar spinal cord (part of ANS) - White matter contains ascending and descending fiber tracts CNS = Cerebral Cortex, Thalamus, Midbrain, Pons, Medulla, Spinal Cord Communications between CNS and PNS – Afferents and Efferents Afferents and Efferents – Terminology Overview Brain= Cerebral Cortex, Thalamus, Midbrain, Pons, and Medulla * Crainial and Spinal Nerves are afferent or efferent Brainstem = Midbrain, Pons, Medulla - Somatic Nervous System - Connects the CNS to the body’s muscles and sensory receptors of skin and muscles Somatic NS - Somatic Afferents (towards CNS) - Somatosensory System - Eg. touch, vibration, proprioception, pain, and temperature of the face (CN) and body (spinal Nerves) Special Senses: Vision and hear (CN) - Visceral Nervous System - Regulates the functions of the internal organs, such as the heart, lungs, stomach, intestines, and kidneys Somatic Efferents: (Away from CNS) - Somatic Motor System - Eg eye movements and tongue movements (CN) limb and body (SpinalN) Visceral NS - Visceral Afferent (Toward CNS) - General Visceral Afferents - eg. Sonsory Imformation from the internal organs (may follow SNS and PSNS). - Special Visceral Afferents - Smell and Taste (Via Cranial Nerve) Visceral Efferents (away from CNS) - Sympathetic NS - Thoraco-lumbar spinal cord origin (eg Dilation of the Pupil) - PSNS - Contriction of the pupil (CN) emptying of bladder (Spinal) Cranial Nerves of the Telencephalon and Diencephalon CN I: Olfactory Nerve - Location Running through cribiform plate, connecting olfactory epithelum w/ olfactory bulb/ tract/ telencephalon - Functions: Visceral afferents (Special Senses olfaction (smell) CN II: Optic - Location: Connecting the retina of the eye w/ the diencephalon Functions: Somatic afferents (special senses) Vision Cranial Nerve of Midbrain (anterior) Cranial Nerve of Midbrain (posterior) CN III: Oculomotor Nerve - Loci: Medial Upper midbrain, level of the superior colliculi - Function: Somatic efferents: eye movement Visceral Efferents: Near accommodation and pupillary constriction CN IV: Trochlear Nerve - Loci: Only CN at posterior brainstem; Medial lower brainstem close to inferior colliculi - Functions: Somatic Effects: movement of eye *Note proximity of Uncus to the midbrain structure (clinical relevance) Cranial Nerve of Pons (Anterior) Cranial Nerve of Ponto-Medullary Junction Cranial Nerve of Ponto-Medullary Junction CN V: Trigeminal Nerve - Loci: Lateral Aspect of mid-pons - Function: Somatic Afferents: Somatosensation of face (touch, vibration, proprioception, pain, and temp) of the face. - Efferents: Motor Innervation of muscle of mastication CN VI: Abducens Nerve - Loci: Medial Ponto-Medullary jnx - Function: Somatic Efferents: eye movements CN VII: Facial Nerve - Loci: Intermediate ponto-medullary jnx - Function: Somatic Efferents: Motor innervation of muscles of facial expression *NOTE: Based on unfolding of basal and Alar plate during development of the brainstem, location of motor nuclei is more medial while location of sensory nuclei is more sideways (lateral) Visceral Afferents:Special Senses: Gustation (taste) of the anterior tongue) Cranial Nerve of Ponto-Medullary Junction Cranial Nerves of the Medulla (Anterior) Cranial Nerves of the Medulla (Anterior) CN VIII: Vestibulocochlear - Loci: Lateral Ponto-medullary jnx - Function: Somatic afferents (cochlear portion): Audition (Hearing) Somatic Afferents: Vistibular portion: Balance and equilibrium) CN IX: Glossopharyngeal - LocI: Postolivary sulci - Function: - Somatic Afferents: Sensation of plate and posterior pharynx - Visceral afferents: (special: Gustation (taste) from posterior tongue - Visceral afferents: input from carotid sinus and carotid body (regulating cardiac function) CN X: Vagus Nerve - Loci: Postolivary Sulcus - Functions: - Somatic efferents: Motor innervation of pharynx and larynx - Visceral afferents: Special senses: Gustation (taste) from base of tongue. Cranial Nerves (Anterior) Cranial Nerves of the Medulla (Anterior) CN XI: Accessory Nerve - Loci: Posterior to the medullary olive and lateral cervical spinal cord - Function: Somatic Efferents: Motor innervation of trapezium (raising shoulders) and sternocleidomastoid muscle (head turning) CN XII: Hypoglossal Nerve Loci: Preolivary Sulcus Function: Somatic Efferents: Motor innervation of the tongue (including protrusion) Some (S) - Olfactory nerve (CN I) - Sensory (smell) Say (M) - Optic nerve (CN II) - Motor (controls eye movement) Money (MX) - Oculomotor nerve (CN III) - Mixed (controls eye movement, eyelid lifting, pupil constriction) Matters (M) - Trochlear nerve (CN IV) - Motor (controls eye movement) But (M) - Trigeminal nerve (CN V) - Motor (controls chewing) My (M) - Abducens nerve (CN VI) - Motor (controls eye movement) Brother (MX) - Facial nerve (CN VII) - Mixed (controls facial expressions, taste, tear production) Says (S) - Acoustic nerve (CN VIII) - Sensory (hearing and balance) Big (M) - Glossopharyngeal nerve (CN IX) - Motor (swallowing, taste) Brains (S) - Vagus nerve (CN X) - Sensory (various sensations from internal organs) Matter (MX) - Accessory nerve (CN XI) - Mixed (muscle movement, especially in the neck and shoulders) More (M) - Hypoglossal nerve (CN XII) - Motor (tongue movement) Spinal Cord – Lateral View - Upper extremeties are innervated by C4-T1 spinal cord segments (cervical enlargement) - Lower extremities are innervated by L1- L3 spinal cord segments (lumbar enlargement) Significance of Cervical and Lumbar Enlargements Cervical enlargements of the spinal cord is a prominent macroscopic expansion of lower cervical (and upper thoracic) spinal cord segments. The enlargement is due to the increased number of neuronns in control of complex movements of the upper extremities including fingers, hands, and arms, allowing us sophisticated manipulation of objects we are holding in our hands Lumbar enlargement of spinal cord is a prominent macroscopic expansion of lumbar (and upper sacral) spinal cord segments. The enlargement is due to the increased number of neurons in control of the powerful musculature of lower extremities, allowing us to walk, run, and jump Transition between Central and Peripheral Nervous System - The transitional zone between the CNS and PNS is known as Redlich-Obersteiner Zone - It is located at the jnx between cranial nerve roots and brainstem, or between spinal nerve roots and spinal cord - In this transition zone, myelination of axons changes from Oligodendrocytes (myelinating cells of CNS) to Schwann Cells (myelinating cells of the PNS) * Some demyelinating diseases selectively affect oligodendrocytes (CC multiple sclerosis) , and hence CNS fibers, while other demyelinating diseases selectively affect Schwann Cells (CC Guillain-Barre Syndrome), and hence PNS Transition between Central and Peripheral Nervous System - Redlich-Obersteiner Zone is posterior and anterior to spinal cord. (Yellow arrows below); the root entry zone of dorsal and ventral nerve roots, which is the transition zone between CNS and PNS Communication Between CNS and PNS – Motor Pathway Starts on right side of cerebral cortex and down until it crosses at the Medulla to the other side of spinal cord to muscle desired Touch Sensation also follows same path but travels in opposite direction Pain Pathway differs as perception of pain crosses in the spinal cord at the vertibral level CC: Motor Pathway Lesion - A lesion at or above the medulla will results in contralateral motor deficits while lesions bellow the medulla in the spinal cord will result in ipsilateral motor deficits CC: Touch Pathway Lesion - Similar to Motor Lesions; a lesion in the cerebral cortex, midbrain, pons, or medulla will result in contralateral loss of touch sensation While a lesion in the spinal cord or apendage will result in loss of feeling ipsilaterally CC: Pain Pathway Lesion - Since pain crosses in the spinal cord the a lesion on the apendage or after spinal cord will be ipsilateral while a lesion in the medulla, pons or midbrain will be contralateral DLA 1: Practical Clinical Neuroimaging I, II, III X- Ray: A broad beam of X-rays penetrate the body. Tissues absorb x-rays as a function of density. Absorbed x-rays undergo detection for representation as a negative image. X-rays of the head are most useful for assessing diseases of the skull. Only indirect inference can therefore be drawn regarding pathologies of low-density tissue. For example, internal erosion of the skull may indicate an expanding neoplasm. X-ray advantages and Disadvantages Advantages: Inexpensive, Common, Sensitive to skull fracture and dense foreign matter Disadvantage: Exposure to Ionizing radiation, Brain structures minimally visible. In Meylography, the spinal cord, nerve roots and the subarachnoid space are examined. The lyelogram is taken after injecting a contrast medium into the spinal subarachnoid space. Meylography reveals herniated (slipped) intervertebral disks and spinal tumors. Cerebral Angiography (Vasography) - Xray representation of blood vessels w/ contrast medium applied through a catheter Risk of allergic reaction; arterial spasm (cerebral infarction) Indicated for vascular malformations: Angioma (vascular tumor) aneurysm; vascular obstruction, stenosis =====> Frontal View 1. Internal Carotid Artery 2. Carotid Siphon 3. Anterior Cerebral Artery 4. Medial Cerebral Artery 5. Posterior Cerebral Artery Lateral View Lateral View 1. Carotid artery 2. Carotid Siphon 3. Anterior Cerebral Art 4. Medial Cerebral Art 5. Posterior Cerebral Art Digital Subtraction Angiography Angiogram showing middle cerebral arteriovenous malformation Native Xray is taken followed by conventional angiograph - The angiograph is digitally subtracted from the native X-ray, yielding a dark image of vessels w/ attenuation of dense structures (gets rid of the bone) Computed Tomography (CT-Scan) In cranial CT scan, an xray source rotates around the head of the patient. X-ray sensors located opposite to the source continuously measure the attenuation of the X-radiation. The data are used to calculate a horizontal “slice” (or tome) of the head. Indicated for infarctions and particularly recent intracranial hemorrhages are readily detected by CT. The procedure is initially performed w/o contrast agents, because contrast may resemble a bleed. A normal CT generally does not show an infarction in the acute stage but is commonly performed to exclude a hemorrhage. For dx tumors, CT w/ contrast can be used inexpensively but is less sensitive than MRI. Other indications for CT are increased intracranial Pressure (before Lumbar Puncture) and head trauma w/ facial or skull fractures. Can differentiate bone, white matter, grey matter, and fresh blood. *May Suboptimally represent brainstem structure Grey matter look white White matter looks grey Epidural Hemorrhage - CT reveals fresh blood, as in this left-sided epidural hemorrhage - Skull fracture may damage dural vessels, yielding a biconvex accumulation of blood Subarachnoid Hemorrhage - Blood in the subarachnoid space, as revealed in CT Subdural Hemorrhage - CT often reveals subdural hemorrhages which often reflect trauma-inducing tearing of the dura or tiny cerebral veins that traverse the dura from the subarachnoid space - Subdural hemorrhages often assume a cresent shape. Magnetic Resonance Imagery (MRI) - Magnetic moments of H+ protons aligned in strong magnetic field - Radio waves change alignment and synchrony of spin, w/ protons subsequently relaxing to their prior state - Relaxation yields signals that generate an image - T1 Signals (Fatty Acids) and T2 (water) Ht2O) revealing distinct aspects of anatomy and pathology T2 MRI - CSF is white - Weak differentiation of white and gray matter - Shows Edema and hence neuropathology T1 MRI - Differentiates grey-white and shows structures in detail (CSF is dark) - Infarctions are visible T2 Weighted MRI - Sensitive to pathology * A specialized MRI varient called FLAIR, which darkens the CSF, may better receal periventricular lesions from Multiple Sclerosis than a standard T2 weighted scan Comparison of T1 and T2 Weighted Scan in Tumor Detection - T1 weighted MRI w/o Contrast is often poor at localizing boundaries of tumors in brain - A contrast agent dramatically improves the capacity of the T1-weighted MRI to reveal the boundaries of the tumor, which are associated w/ compromise of the BBB - T2 weighted MRI poorly demonstrate tumors but can reveal inflammatory reactions in surrounding tissue. MRA MR Angiography - Contrast agent (Gadolinium) is introduced to the vascular system to reveal normal and abnormal blood vessels (e.g. expressing stenosis or aneurysms) MRI Advantages - Excellent structural Resolution - Sensitive to Edema - No ionizing rad - Relatively Common Disadvantages - Expensive - Cannot be used when paramagnetic metals in body (watch for cardiac pace-makers) Lecture 4: Neurons and Glia Major Nevous System Cell Types: Neurons and Glia Neurons: - Excitable: Generate and conduct action potentials (AP) - Main role is signaling – integration, communication Glia - Supportive of Neurons but also w/ signalling roles - Not excitable in classical sense (No AP) - But oscillations in intracellular Ca2+ (Ca2+ waves) promote release of gliotransmitters (Glutamate, ATP) - Cell types are categorized according to morphology, location, and functional properties Basic Structure of Neurons - Dendrites covered in dendritic spines make synaptic connections w/ other neurons - Nissl bodies in the soma contain RNA granules and ribosomes - Axons and dendrites are collectively known as neurites Morphology is related to signal reception and transmission: Taking a multipolar neuron such as a motor neuron as our example, we see the soma expressing w/ dendrites that may be covered in spines. The primary function of dendrites is to integrate chemical signals emitted from axons (typically from other neurons). The spines, if present, can serve as a post-synaptic targets Nissl Bodies are the histological sign of rER, a major site of protein synthesis The axon hillock (AH) is the site of initiation of AP. In many neurons, the AH arises from a conical elecation of the soma. The first 50-100 microns of the axon emerging from the AH is the axonal initaial segment. Unlike other eukaryotic cells, neurites do not readily support diffusion, so transport mechanisms are required for sufficient movement of material throughout the lengths of the axons and dendrites. Meylin is fused membrances of Schwann cells or oligodendrocytes forming an insulating shealth around axons, which may collateralize extensively. Synaptic boutons contain synaptic vesciles w/ stored neurotransmitter destined to undergo exocytosis. In neurons that release Catecholamines, serotonin, or peptides there are dense cored vesicles whereas in those like motor neurons that release Ach, the vessicle is clear. Components of the Cytoskeleton Microtubules: dimers of α and β tubulin added at the positive end of microtubules = Polymerization (involved in transport) (medial loci) - MAPs (microtubule associated proteins stabilize microtubules - Neurofilaments (NF) number determines axonal diameter - Microfilatments (MFs) mediate growth cone advance during growth and repair after injury. (lateral loci) Cytoskeletal Components - Crucial for neuronal growth and shape and for transport between soma and neurites Microtubules - Single microtubule is ~100 um in length 25nm in diameter - Composed of 13 protofilaments, formed from pairs of α and β tubulin - Polar structures creates a positive and minus end of polymer - Organized by microtubule- organized centers (MTOCs, contain γ-tubulin) - Stabilized by microtubule-associated proteins (MAPs) e.g tau protein. Neurofilaments - Most common filaments in neurons ~10 nm - Very stable w/ little turnover - Create the scaffolding of the cytoskeleton - Level of neurofilament gene expression controls axonal diameter Microfilaments - Braids of two thin strands of actin filaments; diamter ~5 nm - Anchored to membrane by mesh just beneath the cell membrane - Participate in growth cone advance during neuronal growth or repair. Axonal Transport Anterograde Transport - Kinesin – Microtubule associated ATPase) – Moves vesicle along microtubules toward positive end – AWAY FROM SOMA Retrograde Transport - Dynein – Protein MAP-ATPase – towards negative end of microtubules TOWARD SOMA Transport Proteins Kinesin - ATPase responsible for fast aterograde transport - Similar to myosin in muscle - Binding sites for attachment of large structures, e.g. vesicles and mitochondria - Movement toward towardMT MTpositive positiveend, end, ie ie nerve endingending nerve - Becomes inactivated in nerve ending and carried back to the soma by retrograde axonal transport to be reactivated Dynein - ATPase responsible for fast retrograde transport - Also the motor protein for movement of cilia and flagella - Movement towards towardsMT MTnegative negativeend endieie SOMA - Inactivated in SOMA, activated again in nerve ending Type of Transport Speed (mm/day) Anterograde (Kinesin-driven) Fast (100-500) Slow (1-10) Slow (0.1-1.0) Retrograde (Dynein -driven) Fast (200-300) Dendritic Transport, Axonal Flow Transport along dendrites - Axonic microtubules always have a negative end towards soma and positive end distal - Dendritic microtubules are of mixed orientation - ½ w/ +ve ends facing some , other half opposite - This may selectively direct movement of some materials to dendrites rather than down axons Axoplasmic Flow Occurs in Peripheral Nerve Axons Continuous movement of axoplasm occurs along axons at a rate of ~1mm/day, but this transport does not account for the ovbserved transport rates of proteins and organelles within axons. Faster axonal transport processes occur Axonal Transport Occurs at Different Rates w/o fast axonal transport, the soma and nerve ending would be unable to exchange materials at a satisfactory rate to retain the viability of the distant endings of the neuron. By contrast, the neurons electrical signalling ability is fast over the same Axoplasmic Flow distance. Even at the slowest conduction velocity of the - Continuous movement of axoplasmm AP (0/5 m/s) (ie 100,000x) faster than axonal along axons transport). - ~ 1mm/day - Retrograde transport for lysosomes and - Slower than axonal transport and endolysosomes degrade endocytosed material and does not explain axonal movement redundant cellular components are degraded. These rates for proteins and organelles. materials are packaged in large membrane-bound organelles that are part of the lysosomal system. - Retrograde Axonal transport: Some viruses use retrograde transport to infect neurons. e.g herpes, and Material Transported rabies wich gain access to neuronal cells bodies by Vesicles, Mitochondria entry into axons in the skin. The rabies replicate well in Soluble Proteins (calmodulin) the cell body and enzymes - Interuption of axonal transport leads to death of axons distal to the site of injury in a process call Wallerian Cytoskeletal molecules (Tubuline, actin, NF Protein) likely in relation to disrupted axonal transport mechanisms. In Alzheimer’s disease, the MAP Tau is Lysosomes, enzymes, recycled deranged, leading to the intracellular formation of vesicular membranes, NGF neurofibrillary triangles, thereby disrupting microtubular (CC: Viruses (Herpes, Rabies)) structures and axonal transport. Morphotype Influences Signal Reception and Transmission - One way to classify neurons is by the total # of neurites. One class of neurite is the dendrite and the other is the axon. Most neurons have several dendrites and only one axon (which may collateralize). The morphological types are pseudo-unipolar, bipolar, and multipolar, The names relating to the pattern of neurites extending from their cell bodies Most neurons in the brain are multipolar. Motor neurons in the spinal ventral and lateral horns of the SC, autonomic ganglion cells. Mostly inhibitory of the CNS and referred to as Golgi type II. Multipolar neurons w/ long axons are called Golgi Type I; multipolar neurons w/ short axons are often inhibitory and are called Golgi Type II Bipolar-retinal sensory, olfactory, and inner ear. Have two processes one axon and one dendrite Pseudo-unipolar: spinal sensory neurons have one process, which divids into a central branch and a peripheral branch. Each branch has structural and functional characteristics of an axon. They are called pseudo-unipolar because they are originally bipolar. The two processes fuse during development to form a single process that bifurcates at a distance from cell body. There are peripheral sensory neurons, the cell bodies of which aggregate to form spinal and cranial nerve ganglia Functional Classification of Neurons - Afferent (sensory) – From PNS to CNS - Efferent (motor) – CNS to PNS - Interneurons – Connect and modulate inputoutput of afferent and efferent neurons in CNS and PNS Characterization of axons by myelination and diameter - Axons are commonly myelinated - Myelination speeds axonal conduction of AP and reduces energy needs for concentration gradients - Neurons can be grouped or categorized according to their axonal diameter and myelination - Both correlate w/ conduction velocity - Class I: Largest and most rapidly conducting fibers - Class II and III: Intermediate diameter - Class IV: Unmyelinated and smallest diamter Excitatory and Inhibitory Neurons - Excitatory Neurons - Cause Post-Synaptic Excitation (depolarization) - Inhibitory Neurons - Cause post-synaptic inhibition (hyperpolarization) - Transmitter effect depends on post-synaptic receptors - e.g. Dopamine D1 family couple to G(s) and increase cAMP - vs Dopamine D2 family coupled to G(i) and decrease cAMP Not uncommonly, neurons are described as either excitory or inhibitory. Transmitter released by excitory neurons tends to depolarize membranes of other neurons; transmitter released by inhibitory neurons tend to polarize or stabilize membranes of other neurons. It is noteworthy, however, that receptors (not transmitters) ultimately dictate excitatory vs Inhibitory effects of transmitters (or the neurons from which the transmitters are released) Neuroglia - Glia = Greek for Glue - Glial cells outnumber neurons in the NS Key Role - Maintaining the ionic milieu of nerve cells - Modulating the rate of nerve signal propagation (myelination) - Modulating synaptic activity by controlling the uptake of neurotransmitters at or near the synaptic cleft - Providing a scaffold for neural development (radial glia) - Participating in recovery from neural injury 4 Main types in CNS - Astrocytes - Oligodendrocytes - Microglia - Ependymal cells Astrocytes - Restricted to brain and spinal cord (CNS) - Most common CNS glial cells type Key functions - Component of BBB - Scar formation - Regulate chemical content of extracellular space - Limit spread of neurotransmitter from synapses - Uptake of neurotransmitters after release from nerve terminals - Recycling neurotransmitters such as Glu, GABA - Uptake of excess K+ released following APs - Disperse K+ throughout a greater volume: spatial buffering Astrocytes: Restricted to brain and SC; largest of glial cells, have elaborate local processes that give cells star-like appearance (hence the prefix astro), function is to maintain in a variety of ways an appropriate chemical environment for neural signaling as explained in the following slides. Astrocytes provide support for neurons: - A barrier against the spread of NT from synapses, uptake of NT after release from nerve terminals such as Glu, GABA, where they are processed for recycling. Uptake of excess K+ released following nerve impulses in the EC space. Astrocytes take up K+ via membrane pumps and transport and dissipate it over a wider area as the have an extensive network of processes. Astrocytes are also connected via gap junctions, which can assist further in K+ spatial buffering. Astrocytes and K+ Regulation - K+ increases after impulse propagation in neurons - High K+ interferes w/ AP generation - Excess K+ is taken into astrocytes via - Na/K ATPase - Na/ K/ Cl- co-transporters (NKCC) Spatial Buffering - Astrocytes then distribute K+ throughout a greater volume - Range enhanced by gap junctions between astrocytes Neuronal activity tends to raise [K+] in the extracellular fluid and, if a significant rise occurs, it will interfere w/ neuronal signaling by depolarizing neurons. Astrocytes have large # of open K+ channels facilitating removal of K+ ions from the extracellular fluid. K+ ions taken up at region of the cell are distributed throughout the cytoplasm of the cell and intro neighboring cells via gap junctions. This sharing of K+ ion load is called K+ spatial buffering. High [K+] interferes w/ impulse generation. Neuronal Energy Support - Main source of neuronal energy is circulating glucose - Astrocytes store glycogen and supply neurons w/ lactate - Alternative energy source for ATP generation - Exhausted within ~ 10 minutes Astrocytes store Glycogen and Supply Neurons w/ Lactate - In CNS, Astrocytes are the main storage depot for glycogen which can be converted to lactate and transferred to neurons as an alternative source for ATP production. Neurons pick up lactate from ECF via the transporter protein MCT2 and use it to generate energy in the form of ATP molecules - If blood supply is interrupted, the normal supply of glucose to the CNS will be terminated. Neuronal activity can survive this loss but only until the glycogen is used up (~ 10 minutes after blood supply interruption Microglia - CNS Macrophages - Smaller than astrocytes/ neurons Key Functions - Phagocytosis - Removal of debris - Synaptic Pruning - Immune activation - Produce pro-inflammatory cytokines during neuronal injury Two main States - Resting/ surveillance: extensive branching processes - Activated: Rounded, possible w/ phagocytic inclusions Myelinating Glia - Oligodendrocytes are found in the CNS - Schwann cells are the myelinating glia of the PNS - Myelination provided by flattened cytoplasm, wraps up to 100 membrane/ myelin layers around axons - Interrupted by nodes of Ranvier (1um) every 1000 um. Oligodendrocytes: In CNS, they wrap their membranes around long segments of axons to lay down a layer of myelin composed of up to about 100 membrane layers. The myelin acts as an electrical insulator and reduces capacitance of the axonal membrane and thereby elevates conduction velocities of impulses. The small region (1 um) of unmyelinated membrane between adjacent myelinated segments are called Nodes of Ranvier. Oligodendrocytes myelinate several segments on the same axon and segments of several axons in its vicinity. Each myelinated segment is about 1000 um long. Schwann Cells: In the PNS, They myelinate axons. Each cells myelinates only one segment of an axon. So, each myelinated peripheral axon is insulated by a large pop of Schwann cells. During myelination in the PNS Schwann cells rotate around the axon. Schwann Cells Facilitate Regeneration of Severed Axon: When an axon is cut in a peripheral nerve, Schwann cells retract from the isolated distal axonal segment, increase in number and form a guide tube. They also secrete GF to induce axonal growth of the proximal axonal segment along the guide tube to it target cell Axon instructs the Schwann cell to myelinate it: The axon destined to become myelinated sends an appropriate signal to the Schwann cell to induce wrapping and myelination. Small diameter axons introduced experimentally to Schwann cells do no induce them to form myelin. Ependymal Cells - Originate from ventricular zone in the neural tube 2 Types: - Choroidal Ep cells: In choroid plexus: CSF secretion - Tight junctions: CSF components must pass trans-cellular - Extrachoroidal Ependymal cells (ependymocytes) - Ciliated ependymal cells (lining ventricular system) - Propel CSF through ventricles and spinal cord - Gap junctions for exchange between CSF and interstitial fluid Other non-neuronal cells exist in the brain, such as ependymal cells (modified epithelial cells) which provide the lining of the fluid-filled ventricles. There are two types of ependymal cells, Group 1 choroidal epithelial cells of the choroid plexus and group 2 extra-chorodal cells Group 1 have tight junctions excluding passage of H2O and solutes by the paracellular route across the choroid plexus, forming the Blood-CSF barrier. Group 2 ependymocytes line the ventricles of the brain and central canal of the spinal cord and are in contact w/ the CSF. They are joined together by gap jnx. Group 1: Secretory cells of the Choroid Plexus. Virtually all the solutes and H2O that pass from blood to CSF via the choroid plexus must pass through the cytoplasm of these cells. Group 2: These cells are ciliated and line the brains ventricles and spinal cord canal. They assist w propelling and circulation of CSF within the CNS. Moreover, solutes and H2O may pass readily around the cells via the paracellular route. This permeable route allow effective exchange between CSF and interstitial fluid. Regeneration and Degeneration of Axons PNS: Wallerian degeneration distal to axonal transection - Proximal segment may form sprouts - Schwann cells proliferate - Form a guide tube - Release nerve Growth Factor - Remyelinate the regenerating axon (2mm/day) CNS: Oligodendrocytes and astrocytes inhibit axonal regeneration - Do not form guide tubes - Nogo protein block axon growth - Alzheimers disease feature derangement of Tau Protein CC: Multiple Sclerosis - Autoimmune demyelinating disease of CNS - Blurring, partial loss of vision – CNII - Muscle weakness – corticospinal tracts - Incoordination – cerebellum CC: Guillain- Barre Syndrom: Inflammatory demyelinating disease of PNS - Affects myelin sheath and axons - Symmetrical ascending paralysis CC: Tumore of Glial Origin - ~50% of brain tumors and 25% of spinal tumors Lecture 5: Transport in the CNS CNS Fluid Distribution - 40% is in extracellular space 480 - 60% in intracellular space 720 In total there is ~1200 mL of CNS fluid - CSF - Produced by secretion via choroid plexus - Circulates within a defined anatomical space - Ventricles, central canal (bulbar and spinal), subarachnoid space CSF Function - Maintenance of constant EC Fluid Environment - Removal of metabolites from the brain - Regulation of pulmonary ventilation (change in pH) and cerebral blood flow (CBF) - Cerebral Perfusion Pressure = MAPICP - Cushioining and protection of the brain (reducing chances for contact w/ the skull) - Buoyancy: weight of the brain reduced from ~1400 gm to ~50 g, decreasing P on basal structure CSF is similar to plasma mostly - Less Protein (pathology indicator) - a little less glucose - less K+. Ca2+, pH - More Mg2+, Cl-, - SAME osmolarity, Na+ Lumbar Puncture (Spinal Tap) - Location of spinal tap - Adults: L3/L4 - Children: L4/ L5 - Dx Purpose - Estimate of ICP - Normal ICP: 5-15 mmHg Pathological Evaluation of ICP - ICP Measurement - Ventricular catheter (most accurate) - Subdural Screw/ Bolt - Epidural Pressure sensor (no drainage option) - Pathologically elevated ICP: > 15 mmHg (200 mmH2O) CC adverse effect of a rise in ICP - Nausea - Increase BP - Bradycardia - Papilledema The BBB 1. There are tight junctions between Endothelial cells 2. Astrocytes end feet (pedocyte) around endothelial BBB- Main Transport: Transcellular Route - Diffusion rate across the bilayer depends on lipid solubility - Transport Mech across the BBB - Diffusion, facilitated diffusion and Active Transport - Lipid soluble molecules diffuse across the BBB via the phospholipid part of the endothelial cell membrane - Glucose crosses the BBB by facilitated diffusion via GLUT1 in the endothelial cell membrane - L-DOPA also crosses the BBB by facilitated diffusion, via a carrier for neutral AA - Glycine crosses the BBB (from brain to BLOOD) via secondary active co-transport w/ Na+, causing transfer of glycine in a Na+ dependent fashion Since paracellular route is close, substance must pass via the transcellular route. Most of the cell membrane is occupied by the phospholipid bilayer component. Transport across this bilayer commonly depends on the solute’s solubility in lipid. Solutes that readily dissolve in lipid will cross the endothelial cell membranes. The oil/water partition coefficient expresses the degree to which solutes will move into lipid from (aq) environment. The higher the coefficient, the more effective the transfer from H2O to lipid will be. Small Hydrophobic molecules, blood gases, small uncharged polar molecules, H2O, urea, and glycerol all diffuse readily across phospholipid bilayer. The line in the graph shows the expected relative extraction of solute from cerebral blood into brain tissue as a function of the partition coefficient. Note that glucose and L-dopa do not lie on the curve. Glucose is transported into the brain via GLUT1 transporters (facilitated diffusion) and L-DOPA through a neutral AA carrier. Phenobarbitol, while lipophilic, has a relatively low extraction ratio. This is because the substance is pumped out of the by in ATPase- dependent transporter Many pathologies can increase BBB Permeability - HTN - Trauma - Ischemia - Infection - Hyperosmolality - Inflammation Circumventricular Organs -Brain regions where capillary endothelial cells lack tight junctions - Region where access of neurons to Blood Plasma is crucial for function (sensory or secretory) - Eg Blood Pressure and osmolarity detection by Subfornical organ Secretion and Circulation of CSF - The ventricular Lining is not Uniform in Structure and Function - Extra choroidal cell Ependymal Cells Lining Ventricles - Paracellular Transport of CSF into interstitial Space - GAP junctions - Subfornical organe - Subcommissural organe - Organum vasoculosum lamina terminalis (OCLT) - Neurohypophysis (post pituitary - Median Eminence - Pineal Body - Area Postrema - Secretory Epithelium of Choroid Plexus - Transcellular CSF secretion, pumps and transporters, H2O through aquaporin channels CSF is Secreted, Circulated, and Absorbed - CSF is absorbed by arachnoid villi - CSF P > Venous P - Arachnoid villi act as one-way valves - CSF production ~500 mL/day - Total CSF Volume ~1400 mL - Replaced ~ every 7 hours Imaging Interpretation of Brain Ventricles - Pathological Condition Subarachnoid Hemorrhage Guillain-Barre Syndrome Metastatic Cancer of the Meninges Tubercular Meningitis Viral Meningitis Bacterial Meningitis Protein + Glucose N Cells Presence of RBCs ++ N Presence of few WBC + N/- Presence of Increased # of WBCs Tumor Cells + + + - Increase of WBCs Excessive # of WBCs Presence of increase WBCs (polymorphonuclear leukocytes CC Non-communicating Hydrocephalus - CC Obstruction of Right Interventricular Foramen - Obstruction of Cerebral Aqueduct TX: Ventriculoperitoneal (VP) Shunting: Brain ventricle and the other end in the abdominal cavity CC Obstructing Aqueduct - A cystic peneal region mass (yellow dotted line) has prolapsed anteriorly and obstructed the superior aspect of the aqueduct (red). Hydrocephalus is present w/ inferior bowing of the floor of the third ventricle and ballooning of the supraoptic recess (blue) and infundibular recess (purple) CC: Congenital Hydrocephalus: obstruction of Cerebral Aqueduct ==> Noncommunicating (obstuctive) Hydrocephalus is the most frequent type due to blockage of the flow of CSF within the ventricular system. In this case CSF is unable to pass between ventricles system into the subarachnoid space, due to obstruction of interventricular foramina, cerebral aqueduct or outflow foramina of fourth ventricle - In infant: increase CSF Pressure => Enlargement of the ventricles by expanding the skull because the cranial sultures are not yet closed => Large head size. - SX: infants: seizures, sleepiness, irritability, and downward deviation of the eyes (“sun setting” of the eyes) In older children and adults: HA, Nausea, vomiting, vision problems, sun setting gaze, difficulty maintaining balance, problems w/ gait, poor coordination, urinary incontinence, lethargy, drowsiness, irritability, and change in personality or cognition, inc memory loss CC Hydrocephalus Ex Vacuo - Brain Tissue Atrophy, Increased CSF Occupancy CC: Communicating Hydrocephalus - Mismatched absorption and production of CSF leading to enlargement of all ventricles Communicating Hydrocephalus can arise from imparied absorption of CSF by the superior sagittal sinus. This may reflect accumulations of cells in the subarachnoid space that impede passage of CSF through the arachnoid villi. A rare form of communicating hydrocephalus results from tumors of choroid plexus (papillomos) w/ excess CSF secretion unmatched by rate of CSF drainage. Excess CSF secretion causes enlargement of all ventricles. Hydrocephalus Ex Vacuo is associated w/ neurodegenerative dz. Cellular loss, as is seen in Alzheimer’s and Huntington’s Dz, permits enlargement of ventricles, as CSF passively occupies ever-increasing ventricular volume. Communicating Hydrocephalus w/ Normal ICP - Episodic increase in ICP - Expansion of ventricles distorts brain tissue - Affect mainly the elderly In non-communicating hydrocephalus, a tracer dye injected into the lateral ventricle does not appear in the lumbar CSF, indicating that there is an obstruction to the flow of CSF in the ventricular pathways. If the movement of the CSF into the dural venous sinuses is impeded or blocked by an obstruction at the arachnoid villi, hydrocephalus developed in this manner is called a communicating hydrocephalus (nonobstructive hydrocephalus). In communicating hydrocephalus, a tracer dye injected into the lateral ventricle appears in the lumbar CSF, indicating that there is no obstruction to the flow of CSF in the ventricular or extraventricular pathways. Solute and Water Transport Between Blood and Brain - Cerebral and Spinal Arterial Blood - BBB: Capillary Wall - Blood-CSF Barrier: Choroid Plexus Exchange Brain Interstital Fluid and CSF (Ventricles and Subarachnoid) - Cell membrane Brain IC Fluid - Permeable wall of venules (shared) - Brain Venules and Superior Sagital Sinus - Cerebral and Spinal Venous Blood Brain Edema - Increase CNS fluid volume and/or disturbance of blood supply. Osmotherapy is a key treatment. Feature Vasogenic Cytotoxic Origin Increased Capillary Permeability Cellular Swelling Location White Matter Grey and White Matter Composition of Plasma filtrate Increased edema fluid (w/ plasma intracellular protein water and Na+ Capillary Increased Normal (intact Permeability to (compromised BBB) Large BBB) Molecules Clinical Disorders Brain Tumor, abscesses, truama, hemorrhage Hypoxia, water intoxication, ischemia Edema is an accumulation of fluid in the EC or iC within the brain. Disturbances of blood supply that interfere w/ the normal well-regulated exchange of solutes and water between blood and brain, can cause edema. Edema may be local or general. Brain edema may be vasogenic or cytotoxic. Vasogenic edema arises from damage to brain capillaries rendering them more permeable that normal, compromising the BBB, and allowing fluid to accumulate in the white matter and runs along axonal tracts (increase in IC fluid compartment). This could arise due to trauma or focal inflammation. Tumor- facilitated release of release of vasoactive and endothelial destructive compounds (e.g. arachidonic acid, excitory neurotransmitters, eicosanoids, bradykinin, histamin, and free radicals). Cytotoxic Edema arises while the BBB remains intact and is caused by in inaduquate blood supply to neurons and glia. When the Na/K pumps are deprived of ATP, the ionic gradients dissipate, and the cells swell w/ ensuring damage. Water intoxication is another source of cytotoxic edema. During edema, the astroglial cells are capable of regulating their cellular volume after the initial swelling, and thus may suffer less damage than the other CNS cells. This renders them capable of regulating the neuronal microenviroment during the onset of damage. The most common tx is osmotherapy. Lecture 6: Meninges and Arteries - 4 layers of cranial meninges (periosteal dura, Dural venous sinus, arachnoid, and pia mater - The periosteal dura mater adheres to the inner surface of the skull. Arteries supplying the meninges thus dwell against and indent the skull. - Dural folds (formed by the inner or meningeal layer of dura) dwell between the major subdivisions of the brain, forming large septa (falx cerebri, tentorium cerebelli) - Dural Venous sinuses (large valveless vessels) often lie between the two layers of dura mater. - Thin avascular arachnoid lies under the dura mater. - Pia mater is highly vascular and covers the outer surface of the brain. Cranial Meninges Epidural hemorrhages commonly reflect the traumatically induced rupture of meningeal arteries (eg middle meningeal artery), w/ a fractured bone cutting the vessel. Subdural Hemmorhhages commonly reflect trauma induced ruptures of the delicate veins that traverse the meningeal layer of the dura from the subarachnoid space (bridging veins). Leaking blood separates the stiff periosteal dura from the skull, yielding a characteristic biconvex (lenticular; lens-shaped) mass adjacent to the fracture. Bleeding arising from tearing of the meningeal dura are also subdural. Hematoma is contained by the penetrations of the periosteal dura into the sutures of the skull. Pressure arising from the accumulating blood compresses/ distorts the brain. Danger typically peak within hours of arterial involvement but may go fatally unrecognized. B/c the Pressure in the venous sys is much lower than in the arterial system, crescent shaped subdural masses of blood often develop slowly before manifestion arise (hours to week) Chronic subdural hematoma is a risk in older persons, even after minor head trauma, w/ presentation often being ascribed to other conditions (alzheimers) Subarachnoid Bleeding from the many arteries the reside between the arachnoid and pia mater (surrounded by CSF within the subarachnoid space). These vessels may rupture with trauma or spontaneously (e.g. aneurysm). The leaking blood assumes a tree-like appearance, while following sulci and other contours of the subarachnoid space. SX: intense headache, stiff neck, and photophobia due to meningeal irritation are characteristic of subarachnoid hemorrhage Intracranial hemorrhages reflect rupture of intraparenchymal branches of subarachnoid arteries, such as the Lenticulostriate arteries (black box bellow), which branch from the middle cerebral artery, supplying the internal capsule and basal ganglia. The small penetrating branches of major arteries are vulnerable to rupture (ventricular system may fill w/ blood) Internal Carotid and Vertebral Arteries - The arteries travel independently until entering the cranium, wherein they interface directly or indirectly via the anastomotic arterial circle of Willis - The right common carotid artery arises from the brachiocephalic trunk, and the left arises from the aortic arch. At the level of the thyroid cartilage, the common carotids bifurcate, yielding the external and internal carotid arteries. The internal carotid arteries ascend through the deep neck, the carotid canals of the petrous bones and the cavernous sinus. They emit the ophthalmic and posterior communicating arteries. They divide, terminating as the anterior and middle cerebral arteries. The vertebral arteries are the 1st branches of the subclavian arteries. They ascend through the transverse foramina of the upper 6 cervical vertebrae and enter the skull through the foramen magnum. They commonly emit the posterior inferior cerebellar arteries (PICA), which usually spawn the posterior spinal. The vertebral arteries then emit the anterior spinal arteries before unifying to form the basilar artery. - The basilar artery gives rise to the anterior inferior cerebellar arteries (AICA). The superior cerebellar arteries arise from the basilar artery, just prior to its bifurcation into the 2 posterior cerebral arteries at the midbrain. - The arterial circle of Willis is formed by a group of arteries that surround the optic chiasm, optic tract, mammillary bodies, and the remaining ventral hypothalamus. Their perforating branches supply deep structures. Cerebral Arteries - Vertebral and internal carotid arteries anastomose at the basal diencephalon (by forming the circle of willis) - The vertebral arteries supply the basilar, cerebellar, and cerebral arteries Anterior and Middle Cerebral arteries are the terminal divisions of the internal carotid artery, which reaches the ventral surface of the brain lateral to the optic chiasm. Arising from the junction of the internal carotid and middle cerebral arteries is the posterior communicating artery, which will join the vertebral arterial circulation - Anterior cerebral artery runs medially and anterior to the optic chiasm. Bridging the two anterior cerebral arteries is the anterior communicating artery. - Major branches of the anterior cerebral arteries pass to the medial aspect of the frontal and parietal lobes, anterior perforated substance, septum pellucidum, and corpus callosum (often feeding all but the most posterior zones of this commissure) - Striate arteries (early branches of the anterior cerebral artery) supply the basal ganglia and anterior limb of the internal capsule. - The middle cerebral artery extends laterally in the lateral fissure over the insula, sending branches to the lateral aspect of frontal, temporal, and parietal lobes. Dueing its early course, the middle cerebral artery emits the lenticulostriate arteries, which target the basal ganglia and the entire internal capsule. These arteries are particularly vulnerable to rupture and are a major source of intracerebral (periventricular) hemorrhage. Anterior and Middle Cerebral Arteries - Internal carotid arteries feed the middle and anterior cerebral arteries - Middle cerebral arteries emit the lenticulostriate arteries - The anterior communicating artery connects the anterior cerebral arteries. The posterior cerebral arteries are the terminal branches of the basilar artery. They receive the posterior communicating arteries from the internal carotid. They travel laterally and dorsally around the midbrain to reach the thalamus and third ventricle. Cerebral branches supply medial temporal, occipital, and parietal structures. Cerebral Arteries: Lateral Distribution - The middle cerebral artery dominates the lateral cerebral surface. Posterior Cerebral Arteries - Posterior cerebral arteries arise from the basilar artery, anastomosing w/ the internal carotid system via the posterior communicating arteries. Cerebral Arteries - Vertebral and internal carotid arteries anastomose at the basal diencephalon (by forming the circle of willis) - The vertebral arteries supply the basilar, cerebellar, and cerebral arteries. Cerebral Arteries: Medial Distribution - The anterior cerebral artery feeds the anteromedial cerebral surface. - The posterior cerebral artery feeds the posteromedial cerebral surface - Blood typically reaches the brainstem, cerebellum and even parts of the diencephalon via the (subarachnoid) vertebral arteries. Branches from the vertebral arteries then distribute the bulbar blood, converging at the caudal pons to form the midline basilar artery. The vertebral arteries will supply blood to the cerebellum via three branches. Vertebral Arteries Supply the Ventral Brainstem Midbrain - Posterior Cerebral (PCA) - Superior Cerebellar (SCA) Pons - Basilar (BA) - Anterior inferior cerebellar (AICA) - Superior Cerebellar (SCA) Medulla - Vertebral (VA) - Posterior Spinal (PSA) - Posterior inferior cerebellar (PICA) - Anterior Spinal Spinal Meninges - Spinal meninges lack the periosteal Dura Spinal Meninges - Lateral Extension of the pia form denticulate ligaments, which fuse w/ the arachnoid and dura, lending stability Arterial Supply of the Spinal Cord - Segmental branches of the vertebral arteries and aorta supply the anterior spinal and a pair of posterior spinal arteries via spinal medullary arteries - Spinal anastomoses are rich and involve an arterial vasocorona - Radicular arteries may also contribute, following nerve roots to the cord SMALL GROUP 2 DLA 2: Excitable Cells Na+ and K+ Movements during the Impulse - During initiation, a few voltage-gate ligand Na+ Channels are open. - When enough open there is depolarization threshold - This creates a cascade the opens a lot of Na+ Voltage gate chaneels w/ Na+ going in electrochemical gradient. (V(E)- E(Na+) - Rising Phase High intracellular resistance -> Short Length constant Large Diameter Axon -> Large Cross-sectional area -> Low intracellular resistance -> Long Length Constant Action Potential Initiation - Input Integration - Graded potential generate AcP in their sum exceeds the depolarization threshold at a special Axonal region - Threshold = voltage that is sufficient to open Voltage- Gated Channels Na(V) activation gate - S4 trans-membrane domain contains voltage sensitivity: Positively charged AA serve are the activation (m) gate and are repelled outwards by increased internal positively tied to depolarization - Impulse Initiation Zone (IIZ) Near Axonal hillock (start of axon, or near sensory nerve ending in sensory neuron) - Contains the highest density of Voltage Gates Na+ Channels - Most excitable part of Neuron - Site of AP initiation Na(V) Structure- Function Relationship - 4 α- subunits each having 6 trans-membrane domains - S4 is positively charged, confers voltage sensitivity - S5 and S6 line the inner ion pore - Rings of AA around pore confer ion sensitivity - Intracellular loops: inactivation gate (D3-D4 short link) and phosphorylation sites (long intracellular links) Na(V) inactivation Gate Outward movement of S4 trans-membrane domain w/ depolarization also exposes AA on the internal S4-S5 links that bind the IFMT (isoleucine, phenylalanine, methionine, and threonine) motif in the short D3-D4 Intracellular link. After rapid depolatization during AP, the bound inactivation (h) gate terminates the influx of Na+ Distribution of Voltage-Gated Channels - Unmyelinated axon: Uniform sparse distribution of Na(V) - Myelinated axon: Na(V) concentrated at the Node of Ranvier Rapid Conduction in Myelinated Axons Unmyelinated Axon (top) - Current from depolarized region depolarizes adjacent region, allowing slow propagation of the AP Myelinated Axon (bottom) - Current from a depolarized Node of Ranvier does not readily leads via adjacent membrane, owing to electrical myelin dependent insulation - But the current is sufficent to depolarize the membrane exposed at the next node, allowing the action potential to “JUMP” (saltate) from rapidly from node to node Saltatory Conduction - Wtap short axon segments - Formed by Schwann cells in PNS, Oligodendrocytes in CNS - Rich in lipids, act as electrical insulators AP ‘jumps’ from one unlyelinated node of Ranvier to the next, between the myelinated sections - More energy efficient and much faster propogation of AP Myelination, Size, and Conduction Velocity Disorders of Myelination - Disease that lead to lyelin sheath damage, slow or blocking AP conduction Some examples: - CNS: CC Myelinoclastic disorders (myelin being destroyed - Autoimmune (e.g. Multiple Sclerosis(MS)) CC Leukodystrophic disorders (myelin is not produced properly) - eg. CC CNS neuropathies due to B12 deficiency - PNS: Effects of Local Anaesthetics on Na(V) - RX: Lidocaine binds to the open pore w/ high affinity - Lidocaine prevents the return of the domain III Voltage Sensor to the resting state after repolarization - Net effect is a preferential Na(V) block in actively firing neurons, where open Na(V) channels are available for binding Lidocaine Suppresion of AP by Lidocaine - Blue Trace (A): AP is afferent during muscular stretch - Purples Trace (B): Absence of AP due to Lidocain-induced blockage of Voltage-gated Na+ channels * Lidocaine holds Na+ gate in parital open/close position and doesn’t allow any passage keeping the Membrane potential at base in Sensory Receptors (analgesia) CC Guillain- Barre Syndrome CC: Chronic inflammatory demylinating polyneuropathy, - Both Autoimmune conditions targeting Schwann Cells SX: muscle weakness, loss of muscle control, ataxia, loss of sensation, paresthesias (abnormal sensation) Clinical Implications - Local anesthetics may preferentially act on firing and depolarized neurons - Use-dependent suppression of AP - Selective for rapidly firing neurons Related Anti-Seizure Drugs RX: Phenytoin, Carbamazepine, Na Valproate - Bind to and stabilize inactive configuration of Na(V), blocking Na+ Flux - Action is “use-dependent’ because they preferentially affect firing or depolarized cells (more inactivated Na(V) channels are present) - Similar to Local Anesthetic like Lidocaine - Specific binding preferences may differ but common effect is suppression of trains of AP - Important anti-seizure drugs - Dose-dependent blocking of pain but not normal sensation - Can Stabilize Mood Lecture 8: Synaptic Transmission Electrical Synapses - Synchronize electrical activity among cells Properties: - Mediated by gap junctions - Voltage-Sensitive - Pass ions directly between cells - Intercellular communication rapid * Made by connexon which is composed of 2 hemichannels Chemical Synapses - Most common synaptic contact among mammalian neurons - Presynnaptic cells release chemicals that bind to receptors - Post-synaptic receptors mediate altered postsynaptic neuronal function - Presynaptic receptors regulate exocytosis - Synapses can persistently change in function to mediate learning. Chemical Synapses: Location and Function - Axosomatic Synapse: Neuron-1 axon binds to Soma (body) of Neurons-2; often reduce probability of AP at target neuron Axo-dendritic: Neuron-1 axon binds to dendrite of Neuron-2; Influence likelihood of AP at target cell: Distal synapses tend to be excitory; proximal synapses tend to be inhibiitory Axoaxonic Synapse: The axon of Neuron-1 binds to the synaptic bulb of neuron-2 and diminish the magnitude of AP and reduce transmitter released. Tripartite Synapse - Astrocytes take up glutamate released by neurons - Then converts glutamate to glutamine - Glutamine returned to neurons for conversion back to Glutamate ACh Receptors: Ionotropic vs Metabotrophic - Ionotrophic: Nicotinic open Na+, K+ channels and change flux rapid (milliseconds) - Metabotropic: Muscarinic: Metabolic changes (eg phosphorylation); Slower effects (seconds to minutes) Metabotropic Receptors - Receptor coupled to G-proteins - Ligand binding dissociates α subunit from βγ complex - α subunit can be stimulatory or inhibitory - Effects on ion channels, metabolism and gene expression The 5 Step of Life Cycle of Neurotransmitters/ Neuroactive Peptides 1 Produced in rER 2. placed in propeptide and enzyme containing vesicle (golgi) 3. Axonal transport 4. Cleavage of propeptide to smaller peptide neurotransmitter 5. Exocytosis 6. Diffusion and Digestion The 5 Events that Underlie the Interval Between a Presynaptic Impulse and Postsynaptic Responses to Neurotransmitter -- Synaptoc Delay: 0.5 to 100 mS -* Arrival of AP 1. Activation of Voltage Gate Ca2+ channel 2. Fusion of Vesicle and release of transmitter into cleft 3. Diffusion of transmitter across cleft to postsynaptic neuron 4. Transmitter-receptor binding 5. Ionic flux or induction of enzyme activity * Postsynaptic Response ## AP depolarize and Ca2+ is transported to synaptic cleft where is induces exocytosisi of neurotransmitter out of presynaptic cells these open Na+ channels in postsynaptic buton and Na+ enters that cell depolarizing and exciting it. Quantal Size vs Quantal Content - Quantal size = smallest post-synaptic response (related to transmitter released from a single vesicle) - Quantal Content = Number of Quanta/ impulse - Mean Quantal Content = Mean size of EPP/ Mean size of mini EPP Example: - NMJ Quantal Content (QC) = 200 (vesicles exocytosed per impulse) -In other synapses QC = 1, 1 impulse = one vesicle released - Some cases QC = 0 = failed release Magnesium Block: Replace Ca2+ w/ Mg2+ (blocks voltage gated Ca2+ channels) * Overall reduces Ca2+ in response to stimulus and reduced EPPs Quantal Release of Neurotransmitter - 4000- 10,000 ACh molecules p/ vesicle - Total NT release = p*n - p = probability of release - n = number of vesicles - p inreases w/ increased intracellular Ca2+ - p is greater than 0 in absence of stimulation , ie some spontaneous vesicle release at NMJ Chemically Altered Release 1 Modulating ACh Release RX: Tetrodotoxin,, Saxitoxin block Na+ channels on axon RX; ω-Conotoxin: block Ca2+ in axon button RX: Botulinum Toxin block exocytosis of ACh RX: Neostigmine, Physeostigmine, Sarin, and Tabun: Inhibit the breakdown (hydrolysis) of ACh in synaptic cleft RX: Tubocurarine, α-Bungarotoxin: Block ACh receptor on post synaptic neuron Chemically Altered Release 2 RX : CC: Botulinum Toxin - Protease produced by bacterium Clostridium botulinum - Clinical SX: - Diplopia (double vision) - Dysphagia (difficulty swallowing) - Xerostomia (dry mouth) - Dysarthria (difficulty speaking) - Muscle Weakness – limbs and trunk - Respiratory paralysis - Theratpucti application - Treatment of Dystonia - Cosmetic: BOTOX * Protease breaks down synaptobrevin, therefore no visicle docking and no ACh release Irreversible Chemically Altered Release 3 RX CC Tetanus Toxin - β – Bungarotoxin: Snake venom, that binds to cytoskeleton, inhibiting phosphorylation of synapsin 1; No Vesicle release - Tetanus Toxin: Clostridium tetani, degrades synaptobrevin, inhibits glycine release; sustained powerful contraction (hypertonia); irreversible Chemically Altered Release 4 Drugs Affecting Quantal Dynamics - RX Aminoglycosides antibiotics (Neomycin, Streptomycin) - Block presynaptic Ca2+ channels (reversible in extracellular Ca2+ increased) - High concentration can nAChR RX: 4-aminopyridive (K+ Channel Blocker) Increase duration of AP Chemically Altered Release 5 RX: 4- Aminopyridine Therapy - CC: Lambert- Eaton Syndrome - Risk factor: Cancer (Small-cell carcinoma of the Lung (SCCL) - Causes muscle weakness if untreated and sustained or repeated effort briefly increases strength Lambert- Eaton Syndrome is autoimmunity to Ca2+ uptake channels Graded Potentials and EPSP - Neurotransmitter release produces sub-threshold graded potentials, brief local changes in dendrites and cell bodies but not axons. Current spreads w/ decrement according to length constant. EPSP Spatial and Temportal Summation - Spatial Excitory Postsynaptic Potential - Has multiple pre-synaptic inputs - Temporal Excitory Post Synaptic Potential that how has one high frequency input Both have additive summation of input Summation: EPSP and IPSP Govern Overall --- Firing Rate --- ESPS Spatial = Multiple Presynaptic Inputs - EPSP Temportal - ISPS (Inhibitory Post Synaptic Potential - Promotes Hyperpolarization - Record of resulting Membrane Potential (m) Excitaroy – Glutamate Inhibitory – GABA Changes likelihood of AP firing - Spatial Summation - Activity from different pre-synaptic neurons converge onto one neuron => Changes likelihood of AP firing Examples of NT Removal / Degradation - Transporters remove most NTs from synaptic cleft - Except Gas, ACh, and peptides - Monoamines (NE, EPI, DA, 5-HT) removed by pumps, the recycled and degraded - Degraded by MAO in pre-synaptic terminal, glia, liver - Degraded in dendrites, glia, liver by COMT (DA, NE, EPI) Although Transmitter release occur briskly, cellular effects may linger for 20 ms or many minutes Except for ACh, peptides, and Gases, all other transmittesr are rapidly removed from the synaptic cleft by transporters in the nerve ending or astroglia. EG glutamate when take up by transportesr in Astrocytes, has it own neuronal transporter Peptide transporters are found in BBB cells. Diffusion and extracellular proteases also contribute to removal of all peptides. Overall however, clearance from synaptic zones occurs slowly. DLA 3: Neurotransmitter Pathways and Roles Traditional Criteria for Neurotransmitter - Synthesized by PreSynaptic Neurons - Stored in preparation for release - Released by pre-synaptic neurons in Ca2+ dependent fasion - Specialized receptors (typically postsynaptic) effect stereotyped transmitter and analogue dependent physiological changes - Mechanism for removal of transmitter from synapse Small- Molecule Neurotransmitters Neuropeptides Gaseous Neurotransmit ters ACh #Excitory AA Glutamate Aspartate #Inhibitory AA GABA Glycine Opiod Peptides Β-Endorphin Enkephalins Nociceptin Nitric Oxide #Biogenic Amines Catecholamines Dopamine, NE, EPI Tachykinins: Substance P #Indoleamine Serotonin (5- HT(5-Hydroxytryptamine) #Imidazole amine Histamine #Purines ATP, Adenosine * High molecular weight neurotransmitters (neuroactive peptides) are vastly more numerous Steps involved in the synthesis, transport, and release of Neurotransmitters - Vesicular Loading - Energy Driven Pump loads Vesicles w/ H+ Ions - Antiport substitutes transpmitter for H+ Steps Involved in the Synthesis and Release of Glutamate ##Synthetic Pathway 1 -- Krebs (TCA) Cycle 1. Glucose enters the neuron by facilitated diffusion 2. Intracellular glucose is metabolized via Krebs Cycle 3. α-oxoglutarate transaminase yields glutamate ##Synthetic Pathway 2 – Glutamine synthase from glutamate in glia or Astrocytes to be recycled. 1. Terminal and astrocytic glutamate transporters take up extracellular glutamate 2. Glutamine synthetase metabolizes glutamate to form flutamine in Astrocytes 3. Glutamine exits Astrocytes and enters neurons through glutamine transporters 4. Intraneuronal glutaminase converts glutamine to glutamate for reloading into vesicles 5. Glutamate taken up by neuronal terminals is also subject to vesicular reloading Synthesis and Removal of AA Transmittesr: GABA 1. Glutamic Acid Decarboxylase converts Glutamate to GABA 2. GABA enters vesicles 3. After release, GABA transporter take up GABA for reuse 4. Glia take up GABA, where GABA transminase degrades GABA to Glutamate 5. Glutamine synthase converts Glutamate to Glutamine 6. Glutamine returns to neuron for re-synthesis of glutamate then GABA PLP (B6) is a coenzyme Synthesis and Removal of AA Transmittesr: Glycine 1. Glycolysis of glucose yields 3phosphoglycerate and subsequently serine 2. Serine transhydroxymethylase folate (B9) dependent convert Serine to Glycine 3. Membrane spanning transporters take up synaptic glycine Synthesis and Removal of ACh 1. Glucose enters cell through facilitated diffusion 2. Cytoplasmic Glycolysis generated pyruvate 3. Pyruvate enters Mt - Donates acetyl group to coenzyme-A - Acetyl coenzyme-A returns to cytoplasm 4. Choline retrieved from the synapse interacts w/ acetyl CoA in presense of ACh Transferase to yield ACh 5. ACh enters vesicle 6. ACh -esterase hydrolyzes ACh (resultant choline taken up for reuse) *Choline is present in plasma. ACh formation is limited by the intracellular concentration of choline, which is determined by uptake of choline into the nerve ending. Synthesis and Removal of Catecholamin Transmitters: Dopamine 1. Tyrosine Actively transported into catecholaminergic neurons. 2. Tyrosine hydroxylase converts tyrosine to LDOPA 3. DOPA decarboxylase converts L-DOPA to Dopamine (DA) 4. DA loaded into vesicles for release 5. Reuptake-1: Actively transported DA into presynaptic neurons a. Some DA reloaded into vesicles b. Remainder metabolized by MAO 6. Reuptake -2: Actively transported DA into postsynaptic neurons a. Metabolized by COMT - Remaining synaptic DA diffuses and is absorbed by blood for peripheral Synthesis and Removal of Noreepinephrine 1. DA enters vesicles w/ dopamine-β-Hydroxylase, which converts DA to NE 2. Reuptake-1: Actively transports NE into presynaptic neuron - Some NE reloaded into vesicles - Remainder metabolized by MAO 3. Reuptake-2: Actively transports NE into post synaptic cell for metabolism by COMT 4. Remaining synaptic NE diffuses and is absorbed by blood for peripheral metabolism Synthesis and Removal of Epinephrine Synthesis and Removal of Serotonin 1. NE in vesicles leads into the cytoplam where it is converted EPI by phenylethanolamine-Nmethyltransferase (PNMT) 1. Tryptophan Hydroxylase converts cytoplasmic Tryptophan to 5-hydroxytryptophan 2. Reuptake-1 actively transports EPI into pre synaptic neurons - SOME EPI reloaded into vesicles - Remainder metabolized by MAO 3. Reuptake-2: actively transports EPI into postsynaptic cell for metabolism by COMT 4. Remaining synapptic EPI diffuses and is absorbed by blood for peripheral metabolism 2. Aromatic AA decarboxylase converts 5-hydroxytryptophan to Serotonin (5-hydrotryptamine (5-HT) 3. Serotonin actively transports into vesicles for storage and the release 4. Synaptic serotonin can undergo reuptake or metabolism by MAO to 5hydroxyindoleacetyldehyde 5. Aldohyde DH then converts 5hydroxyindoeacetyldehyde to 5-hydroxyindoleacetic acid for urinary excretion Neuroactive Peptides: β-endorphin Finish the PART II OF THIS DLA - Lecture 9: Neurotransmitter Pathways and Roles Cholinergic Projections: Arousal and Memory ACh Receptors: ionotrophic vs Metabotropic 1. The basal forebrain constellation of cholinergic neurons include the basal Nucelus of Meynery it is anterior to the midbrain and has projections around entire cerebral cortex: and midbrain and is responsible for leaning and memory Ionotrophic (Nicotinic) ion flux (Na+, K+) rapid 2. The dorsolateral pontine tegmental constellation of cholinergic neurons are located in the Pons, and spread through the midbrain. Medulla, and Cerebellum: It main role is in arousal Metabotropic: muscarinic G-coupled protein receptor (slow); phosphorylation stuff Central ACh: Pathology and Therapeutics - CC: Alzheimer’s Disease - Nucleus Basalis of Meynert degenerates - AchE inhibitor approved for Treatment - DOES NOT MODIFY DZ Peripheral Cholinergic Neurons - Somatic and Preganglionic Efferent Fibers are Myelinated - Smooth, cardiac and gland muscle have a presynatpic nerve that secretes ACh onto N2 receptors - Skeletal muscles has ACh go onto N1 receptors and directly on Neuromuscular jnx The Neuromuscular Junction - Acetyl CoA join w/ Choline w/ enzyme Choline acytltransfers - Cholinesterase in synaptic cleft quickly degrades ACh, preventing desensitization and tetany Peripheral ACh: Pathology and Theraputics CC: Myasthenia Gravis - Distrupts the cholinergic transmission of neuromuscular junction TX: AChE (esterase) inhibitors CC: SLUD (Salivation, Lacrimation, Urination, Defecation - Over-activation of target of the Cholinergic post-ganglionic fibers Glutamate: Pathology and Theraputics CC: Seizures - Heightened release of glutammate through hypersynchronization of neuronal population - NMDA antagonist inhibit Ca2+ influx to post synaptic neuron CC: Weakness: Reduced release of Glutamate into bulbar and spinal motor nuclei - EX Upper Motor Neuron Syndrome Glutamate Receptors - Ionotropic Glutamate Receptors - AMPA and Kainate Receptors induce Na/ K flux after Glutamate binds - EPSP summation unblocks the NMDA channels pore → Ca2+ Flux - Metabotropic Glutamate Receptors - Group 1: (e) 1,5 - Group 2: (I) 2,3 - Group 3: (I) 4,6-8 Gamma – Amino butyric Acid (GABA) Made from Glutamate - Nuclei annd Projections - GABAergic interneurons are unbiquitous GABAergic Pathways = Striatum -> Substantia Nigra → Superior Colliculus and thalamus → Medial Vestibular Nuclei → Spinal Cord Cerebellar Cortex Deep → Deep Cerebellar nuclei Glutamate Neurotransmitter Sys - Made from glutamine and recycled in glial cells w/ Glutamine synthase - Vesicle Exocytosis GABA Pathology and Theraptics CC: Seizures: Heighted release of Glutamate through hypersyncronization of neuronal population TX: GABA agonist can inhibit hyperexcitable cells CC: Mediated throgh altered excitability of limbic cells TX: Benzodiazepines (Augment GABAergic transmision (reduced excitability Glycine - Nuclei and Projections - Neurons tend to be small nuclei inhibitory interneurons - Common in spinal and bulbar motor nuclei - 1 Receptor Type Ionotropic w/ Cl- channel RX: Blocked by Strychnine Glycine Pathway and Theraputics Tetanus vs Strychnine poison CC: Tetanus Toxin: Prevents release of inhibitory neurotransmitter (glycine) * Muscle can’t relax Tetanus enters threw axon end and uses retrograde toxin transport to reach another axon end CC: RX: Strychnine: Blocks binds on glycine to receptor * Glycine is released but stuck in in cleft space ***BOTH Leads to strong muscle contraction Glycine: Pathology and Theraputics CC Tetanus - Toxic protease suppresses release of glycine from bulbar and spinal interneurons - Lower motor neurons are disinhibited -TX Deplying muscle-relaxing strategies directed at central or peripheral targets CC: Strychnine poisoning - The alkaloid blocks glycine receptors on lower motor neurons, reducing Cl- influx - Lower motor neurons are disinhibited Catecholamines 1. Tyrosine - Tyrosine Hydroxylase (Catecholamine Marker) 2. DOPA - DOPA Decarboxylase 3. Dopamine - DOPAMINE Hydroxylase 4. NorEpinephrine - Phenylethanolamine N- Methyl- Transferase (PNMT) 5. Epineephrine ### If cells is positive for DBH (Dopamine Beta Hydroxylase) but Negative PNMT the cell only makes NorEpinephrine Dopamine: CNS Pathways and Receptors - Substantia Nigra and Ventraltegmentral are in midbrain and the Nigro-Striatal and Mesolimbic carry their axon signal (respectively) to the Striatal and Mesocortical projections - Reward, mood, and movement - Dopamine acts on all Metabotropic Receptos D1