Lecture 7- Neuronal Micronenvironment_voice (1).pdf

Neuronal Microenvironment Dr. Kelly C. S. Roballo [email protected] VCOM-Main Building Room 341 Learning Objectives 1) 2) 3) 4) 5) Compare the structure and function of the meninges and subarachnoid spaces. Describe the formation and reabsorption of cerebral spinal fluid (CSF). Describe how t...

Neuronal Microenvironment Dr. Kelly C. S. Roballo [email protected] VCOM-Main Building Room 341 Learning Objectives 1) 2) 3) 4) 5) Compare the structure and function of the meninges and subarachnoid spaces. Describe the formation and reabsorption of cerebral spinal fluid (CSF). Describe how the microenvironment interacts with neurons and how the brain stabilizes it to provide constancy for neuronal function. Describe cerebrovascular disorders such as stroke, aneurysm and migraine headache as to primary cause and effect and how excitotoxic mechanisms can lead to neuronal death (Also Lecture 8). Define the synthetic pathways, inactivation mechanisms and neurochemical anatomy and mechanisms of receptor transduction for Catecholamines, Acetylcholine, Serotonin, Histamine, GABA (gamma-aminobutyric acid), and Glutamate Read: Chapter 1 Tolbert Basic Clinical Neuroscience Brain Extracellular Fluid (BECF) & Cerebrospinal fluid (CSF) • Neuronal microenvironment includes the extracellular fluid (ECF), capillaries, glial cells, and adjacent neurons • The concentration of solutes in brain ECF (BECF) fluctuate with neural activity. Similarly, changes in BECF can influence nerve cell behavior • Blood-brain-barrier (BBB) protects BECF from fluctuations in blood composition • The cerebrospinal fluid (CSF) strongly influences the BECF composition • The surrounding glial cells “condition” the BECF The Meninges: A Review Remember the brain and spinal cord are covered by three membranes: • The innermost layer is pia mater • The middle is arachnoid mater (membrane)* between the arachnoid mater and pia mater is the subarachnoid space (filled with CSF) • The outermost layer is dura mater • Clinical connection: Meningitis (viral/bact) Blood Vessels and CSF Occupy the Subarachnoid Space Arteries and veins carrying blood to and from the brain parenchyma travel through the subarachnoid space. The red arrow points to the boundary between dura and arachnoid. The red bracket spans the subarachnoid space. The subarachnoid space is filled with cerebrospinal fluid (CSF). Brain Ventricles/Cerebrospinal Fluid A slice through the head at the level of horizontal line 3 in the diagram on the left is shown in the center panel. The panel on the right shows an MRI scan at approximately the same level as the center panel. The red arrows indicate portions of brain ventricles. These spaces are filled with cerebrospinal fluid (CSF). The spaces appear black in MRI scans. The four arrows pointing towards the right are indicating regions of the lateral ventricles; the one arrow pointing towards the left indicates the third ventricle. Ventricles and Subarachnoid Space • The ventricles of the brain are four small compartments • The two lateral ventricles are the largest and each communicate with the third ventricle via the interventricular foramen of Monro • The third ventricle communicates with the fourth ventricle by the cerebral aqueduct of Sylvius • The fourth ventricle is continuous with the central canal of the spinal cord • CSF escapes from the fourth ventricle and flows into the subarachnoid space via three foramina • Two laterally placed foramina of Luschka • Midline opening in the roof of the fourth ventricle, foramen of Magendie Cerebrospinal Fluid • CSF is a colorless, watery liquid which fills the ventricles of the brain and forms a thin layer around the outside of the brain and spinal cord in the subarachnoid space • CSF is secreted by a highly vascularized epithelial structure, the choroid plexus • The composition of CSF is highly regulated Cerebrospinal Fluid • Most of the CSF is produced by the choroid plexuses which are located in ventricles • Capillaries also form a small amount of CSF • CSF production is 500 ml/day >>> CSF volume of 140 ml is replaced three times a day • CSF percolates throughout the subarachnoid space, then absorbed into venous blood from the superior sagittal sinus Cerebrospinal Fluid • CSF percolates throughout the subarachnoid space, then absorbed into venous blood from the superior sagittal sinus Cerebrospinal Fluid Circulation https://www.youtube.com/watch?v=kaOphkMv2pM CSF Communicates with BECF • CSF can exchange freely with BECF across two borders: pia mater & ependymal cells • Ependymal cells line the walls of the ventricles and forms gap junctions between themselves • Macromolecules and ions can pass through this layer and equilibrate between the CSF and the BECF “Normal-Pressure” Hydrocephalus • Spinal tap reveals normal pressure readings, but MRI of the head will show enlargement of all four ventricles • An infection or inflammation of the meninges damages arachnoid villi, and causes impaired CSF absorption • Patients typically have progressive dementia, urinary incontinence, and gait disturbance • A CSF shunt to venous blood or to the peritoneal cavity helps reduce CSF pressure *Clinical correlation Secretion of CSF • Choroid epithelial cells are bound to one another by tight junctions, which makes the epithelium an effective barrier to free diffusion • Ion concentration of CSF is rigidly maintained • Micronutrients are selectively transported CSF forms in two steps: 1. 2. Ultrafiltration of plasma across the capillary wall into the extracellular fluid (ECF)-underneath the basolateral membrane of the choroid epithelium Choroid epithelium cells secrete fluid into the ventricle CSF production occurs with a net transfer of NaCl which drives water isosmotically Composition of Cerebrospinal Fluid SOLUTE PLASMA (mM OF PROTEINREE PLASMA) CSF (mM) CSF/PLASMA RATIO Na+ 153 147 0.96 K+ 4.7 2.9 0.62 Ca2+ 1.3 (ionized) 1.1 (ionized) 0.85 Mg2+ 0.6 (ionized) 1.1 (ionized) 1.8 110 113 1.03 24 22 0.92 0.75 (ionized) 0.9 1.2 PH 7.40 7.33 Amino acids 2.6 0.7 0.27 7 g/dl 0.03 g/dl 0.004 290 290 1.00 Cl- Proteins Osmolality (mOsm) The Extracellular Space • The average width of the space between brain cells is 20 nm • Glial cells express neurotransmitter receptors, and neurons have extrajunctional receptors capable of receiving messages sent via BECF • Numerous trophic molecules secreted by brain cells diffuse in the BECF to their target cells Cerebral Edema Net accumulation of water within the brain • Cell swelling in the absence of net water accumulation in the brain does not constitute cerebral edema • For ex: intense neural activity causes a rapid shift of fluid from the BECF to the intracellular space, with no net charge in brain water content *Clinical correlation • If the cerebral edema is generalized, it can be tolerated until intracerebral pressure exceeds arterial blood pressure • Sensors in the medulla detect the increased intracerebral pressure and can partially compensate by increasing arterial pressure Blood-Brain Barrier • CNS blood vessels exclude certain substances from brain tissue: • “blood-brain barrier” • The brain needs to be protected from the constituent variations of blood Leaky regions of the BBB Blood-Brain Barrier • Neurons within the circumventricular organs are directly exposed to blood solutes and macromolecules • Part of neuroendocrine control system for maintaining osmolality, appropriate hormone levels etc. • Humoral signals are integrated by connections of circumventricular organ neurons to endocrine, autonomic, and behavioral centers within the CNS The BBB function of brain capillaries • Brain capillary endothelial cells are fused to each other by tight junctions • The tight junctions prevent watersoluble ions and molecules from passing from the blood into the brain via paracellular route • Electrical resistance of the cerebral capillaries is 100 to 200 times higher than other systemic capillaries Headache Headache is one of the most common neurologic symptoms. Although usually benign, it occasionally signals life-threatening conditions. Interestingly, there are no pain receptors in the brain parenchyma itself. Therefore, headache is caused by mechanical traction, inflammation, or irritation of other structures in the head that are innervated, including the blood vessels, meninges, scalp, and skull. The supratentorial dura (most of the intracranial cavity) is innervated by the trigeminal nerve (CN V), while the dura of the posterior fossa is innervated mainly by CN X, but also by CN IX and the first three cervical nerves. The side of the headache often, but not always, corresponds to the side of pathology. *Clinical correlation Differential Diagnosis of Headache • Vascular headache • Pseudotumor cerebri • Migraine • Low CSF pressure • Cluster headache • Toxic or metabolic derangements • Tension headache • Meningitis • Other causes • Epidural abscess • Acute trauma • Vasculitis • Intracranial hemorrhage • Trigeminal or occipital neuralgia • Cerebral infarct • Neoplasm • Carotid or vertebral artery • Disorders of the eyes, ears, • dissection • Sinuses, teeth, joints, or scalp • Venous sinus thrombosis • Post-ictal headache • Hydrocephalus The Specialized BloodNeural Barriers Blood-Brain Barrier pp 1-8| Cite as An Overview of the Blood-Brain Barrier, 2018 Look Chapter 5 -Blumenfeld Nervous System SUPORTING CELLS Glial Cells Glia Greek word meaning glue The three major types of glial cells in the CNS are astrocytes, oligodendrocytes, and microglial cells Glial cells are about 10-fold more numerous than neurons (10:1), and they can proliferate throughout life Glial Types GLIAL CELL TYPE SYSTEM LOCATION GFAP Fibrous CNS White matter Positive Protoplasmic CNS Gray matter Weakly positive Radial glial cells CNS Throughout brain during development Positive Müller cells CNS Retina Positive Bergmann glia CNS Cerebellum Positive Ependymal cells CNS Ventricular lining Positive Oligodendrocytes CNS Mainly white matter Negative Microglial cells CNS Throughout the brain Negative Satellite cells PNS Sensory and autonomic ganglia Weakly positive Schwann cells PNS Peripheral axons Negative Enteric glial cells ENS Gut wall Positive Astrocytes Astrocytes • Astrocytes modifies and controls the immediate environment of neurons • Fibrous astrocytes have long, thin and well-defined processes • Protoplasmic astrocytes have shorter, frilly processes • The cytoskeleton of all the astrocytes composed of a unique protein “glial fibrillar acidic protein (GFAP)” • During development, radial glial cells are present: • Create an organized scaffolding by spanning the developing forebrain from the ventricle to the pial surface • Müller cells are retinal astrocytes • Bergmann glial cells are located in the cerebellum Astrocytes • Astrocytes contain all the glycogen present in the brain • The brain’s glucose needs is supplied by blood, in the absence of glucose from blood, astrocytic glycogen could sustain the brain for about 5 minutes • Astrocytes break glycogen down to glucose and even further to lactate, which is metabolized by nearby neurons substrate buffering Astrocytes Help Regulate [K+]o Astrocyte Vm is about -85mV, compared to resting neuronal Vm of -65mV, thus glial membranes have higher K+ selectivity (equilibrium potential for K+ is -90 mV) The accumulation of extracellular K+ that is secondary to neural activity serve as a signal to glial cells which is proportional to the extent of the activity Small increases in [K+]o cause astrocytes to increase their glucose metabolism and provide more lactate for active neurons Astrocytes couple to each other via Gap Junctions The network of astrocytes functionally behaves as a syncytium • Strong coupling ensures that all cells in the aggregate have similar intracellular concentrations of ions and small molecules • The coupling among astrocytes also play a role in controlling [K+]o via spatial buffering The K+ taken up by an astrocyte in a region of high [K+]o can move through astrocytes via gap junctions, and exit into a region of low [K+]o Role of Astrocytes in the glutamate-glutamine cycle • Astrocytes synthesize at least 20 neuroactive compounds, including glutamate and GABA • Glutamate precursor glutamine is manufactured only in astrocytes, by astrocyte-specific enzyme glutamine synthetase • Glutamine is released by astrocytes to the BECF to be taken up by neurons • Glutamine is also important for the GABA synthesis • Neuronal glutamic acid decarboxylase converts glutamine to GABA • After its use as neurotransmitter by neurons, some of glutamate is taken by up into astrocytes via high-affinity uptake systems • This system maintains extracellular glutamate concentration around 1uM • If transmembrane ion gradients break down under pathologic conditions, high-affinity uptake systems may work in reverse • Excessive accumulation of glutamate in the BECF –induced by ischemia, anoxia, hypogylcemia, or trauma- can lead to neural injury • In anoxia and ischemia, the sharp drop in cellular ATP levels inhibits the Na-K pump and leads to large increases in [K+]o and [Na+]i • These changes result in membrane depolarization along with a burst of glutamate release from vesicles • The inability of astrocytes to remove glutamate from the BECF under these pathologic conditions makes extracellular glutamate levels too high to become toxic for neurons Oligodendrocytes The primary function of oligodendrocytes in the CNS is to provide and maintain myelin sheaths on axons • Oligodendrocytes in white matter has 15 to 30 processes, each connecting a myelin sheath to the oligodendrocyte’s cell body • Oligodendrocytes and myelin contain most of the enzyme carbonic anhydrase in the brain • Carbonic anhydrase is important in CO2/HCO3- buffer system • pH imbalance in the brain reduces seizure threshold • Oligodendrocytes are also involved with iron metabolism Microglial Cells • Microglial cells derive from cells related to the monocyte/macrophage lineage • Microglia represent 20% of the total glial cells within CNS • These cells are rapidly activated by injury to the brain, proliferate and become phagocytic • Microglia are also the most effective antigen-presenting cells within the brain Schwann Cell (PNS) In the Peripheral nervous system, a single Schwann cell provides a single myelin segment to a single axon of a myelinated nerve The constituent proteins in PNS myelin and CNS myelin are somewhat different Evaluation of the host immune response and functional recovery in peripheral nerve autografts and allografts KCS Roballo · 2019