Nervous system Brno, November 2019 • Reminder on composition of nerve tissue • Structure of gray matter of spinal cord, cerebellum, and telencephalon (iso- and allocortex) • Peripheral nervous system - ganglia and peripheral nerves • Earliest phases of development of nervous system • Histogenesis of neural tube • Development of brain and spinal cord Lecture 11 Nervous system - Histologically Made of 3 structurally different components: The nerve tissue Blood vessels capillaries, arterioles and venules that densely penetrate the nerve tissue The connective tissue - provides protection of both previous components is organized into: • meninges - envelope the brain and spinal medulla • epi-, peri- and endoneurium - connective tissue within nerves or on their surfaces • thin capsules - surround the cerebrospinal and autonomic ganglia Nerve tissue – General features Nervous tissue is made up of just 2 types of cells: • Neurons • Neuroglia - glial cells (supporting cells) • Neurons are the basic functional units of nervous tissue. • They are highly specialized to transmit nerve impulses. Neuron 1. Perikaryon (neurocyte) 2. Processes: (one-way signal conduction) - axon (always only one; centrifugal conduction) - dendrit(es) (centripetal conduction) Neuron - PerikaryonPosition: CNS – grey matter PNS – ganglia Shape: pyramidal, shpherical, ovoid, peer-shaped Size: 5 to 150 mm Organelles: • Nuclues – large + pale + prominent nucleoli • Nissl substance – rough ER • Neurofibrils (neurofilaments + neurotubules + actin) • Lipofuscin pigment clumps Neuron – Neurites / Processes 6 Dendrites Collaterals Axon (axon branching, telodendria) Neuron – Neurites / Processes Axon (nerve fiber)Dendrites • Conducts impulses towards the cell body • Typically short, highly branched & unmyelinated • Surfaces specialized for contact with other neurons • Contains neurofibrils & Nissl bodies • Receptive surface for synaptic junctions • Contain MAP-2 (distinction from axon) • Tens of thousands of synapses on large dendrites • Dendritic spines located on surface of some dendrites • Spines diminish with age and poor nutrition • 1 axon projects from cell body at axon hillock • Axon hillock - pyramid shaped region of the soma that is devoid of RER • Some axons are up to 100 cm • Initial segment = Spike trigger zone (a portion of axon from its origin to the beginning of myelin sheath) • At spike trigger zone trigger zone summation of excitatory and inhibitory impulses occurred • Collateral branches, Terminal arbor • Myelinated or Unmyelinated • Conduct impulses away from cell body • Swollen tips called synaptic knob (terminal button) contain synaptic vesicles filled with neurotransmitters • Cell membrane = axolemma • Cytoplasm = axoplasm White matter: areas of myelinated axons Gray matter: areas of unmyelinated axons, cell bodies, and dendrites Neuron – Classification 1 According to the number of the processes Multipolar several dendrites & one axon (most common cell type) Bipolar one main dendrite & one axon (in retina, vestibular and cochlear ganglion) Unipolar (pseudounipolar) one process only (develop from a bipolar) (always sensory, in spinal ganglia) 9 Neuron – Classification 2 According to the function Motor (efferent) neurons: • conduct impulses to muscles, neurons, glands Sensory (afferent) neurons: • receive sensation Interneurons: • local circuit neurons Synapse Definition Synapses are highly specialized intercellular junctions, which link the neurons of each nervous pathway • Axon terminal forms bouton terminal • Presynaptic membrane - contains mitochondria, and an abundance of synaptic vesicles with neurotransmitter • Presynaptic dense projections - are associated with synaptic vesicles form active sites of synapse • Synaptic vesicles (smaller + larger – storage) • Postsynaptic membrane - contains receptors and some dense materials • Synaptic cleft - 20-30 nm width, occupied by fine filaments • Glial cells increase synaptic efficacy • Asymmetric synapses are excitatory (a thick postsynaptic membrane and a 30 nm synaptic cleft) • Symmetric synapses are inhibitory (thin postsynaptic membrane and a 20 nm synaptic cleft) • Need special staining to see by light microscopy Synapse Classification according to the constitution Note: Neuromuscular junction – synapse between neuron and effector muscle fibre Axodendritic Axosomatic Axoaxonic Neuroglia General features • non-neuronal cells of several types • support and protect the neurons • bind neurons together and form framework for nervous tissue • in fetus, guide migrating neurons to their destination • if mature neuron is not in synaptic contact with another neuron, it is covered by glial cells • prevents neurons from touching each other • gives precision to conduction pathways • only nuclei visible by light microscopy without special staining • there are several glial cells for each neuron Number of neurons: about 100 billions to 1 trillion Number of glial cells: 50x more then neurons Central neuroglia • Astrocytes • Oligodendrocytes • Microglia • Ependymal cells Peripheral neuroglia • Schwann cels • Satellite cells Neuroglia - Astrocytes Membrana limitans gliae… …superficialis …perivascularis • most abundant glial cell in CNS • covers entire brain surface and most non-synaptic regions of the neurons in the gray matter of the CNS • diverse functions:  form a supportive framework of nervous tissue  have extensions (perivascular feet) that contact blood capillaries that stimulate them to form a tight seal called the blood-brain barrier  convert blood glucose to lactate and supply this to the neurons for nourishment  nerve growth factors secreted by astrocytes promote neuron growth and synapse formation  communicate electrically with neurons and may influence synaptic signaling  regulate chemical composition of tissue fluid by absorbing excess neurotransmitters and ions  astrocytosis or sclerosis – when neuron is damaged, astrocytes form hardened scar tissue and fill space formerly occupied by the neuron  contains GFAP Neuroglia - Oligodendrocytes  smaller than astrocytes; darker, round nucleus, abundant RER, well developed golgi apparatus  form myelin sheaths in CNS  one cell serves more then one axon  cannot migrate around axons (unlike Schwann cells) must push newer layers of myelin under the older ones so myelination spirals inward toward nerve fiber  nerve fibers in CNS have no Schwann sheath (neurilemma) or endoneurium  each arm-like process wraps around a nerve fiber forming an insulating layer that speeds up signal conduction  damaged in multiple sclerosis oligodendrocyte Neuroglia - Microglia  smallest neuroglial cell  small, dark, elongated nuclei  possess phagocytotic properties  when activated – antigen presenting cell  originate in bone marrow (mesodermal origin) Neuroglia – Ependymal cells  line ventricles of CNS and central canal of spinal cord  cuboidal or low columnar shape  no basal lamina  secrete cerebrospinal fluid (CSF)  some are ciliated, facilitate movement of CSF  participate in formation of Choroid plexus Neuroglia – Central - Summary Copyright © The McGraw-Hill Companies, Inc. 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Ependymal cell Cerebrospinal fluid Neurons Astrocyte Perivascular feet Microglia Oligodendrocyte Capillary Myelinated axon Myelin (cut) Neuroglia in PNS – Schwann cells • cells that encircle all axons in PNS • provide structural and metabolic support to axons • provide guidance for axonal growth X Small diameter axons Enveloping by only cytoplasm Large diameter axons Wrapping by myelin sheaths only Schwann sheath – gray nerve fiber Schwann + myelin sheath – double contoured nerve fiber Neuroglia in PNS – Schwann cells Schwann sheath + Myelin sheath Double contoured nerve fiber = Neurilemma CNS is Brain and Spinal cord + PNS is everything else Nervous system – Peripheral x Central Central nervous system – Brain + Spinal cord AnteriorPosterior Telencephalon Cerebellum Mesencephalon - Midbrain Metencephalon - Pons Myelencephalon – Medula oblongata Spinal cord Diencephalon – Thalamus + Hypothalamus Brain stem • Diencephalon • Mesencephalon • Metencephalon • Myelencephalon Central nervous system – Neuronal organization Gray matter • Cell bodies • Nonmyelinated neurons (dendrites, proximal + distal ends of axons) • Neuroglia (plasmatic astrocytes, microglia) • Capillaries (Blood-Brain barrier) - forms the outer layer of the cerebrum cerebral cortex - also forms nuclei deep in the brain = clusters of neuronal cell bodies in CNS - collections of nuclei can form a centers (higher brain function) White matter • Myelinated axons of nerve cells • Neuroglia (oligodendrocytes, fibrilar astrocytes) • Blood capillaries (lesser density than in the gray matter) Brain - axons are bundled together to form white matter tracts conduct nerve impulses from gray region to gray region - three types of tracts (commisural, association, projection) Spinal cord - sensory and motor tracts (ascending and descending) Central nervous system – Distribution of grey/white matter Telencephalon + Cerebellum Gray matter: • covers surface of both hemispheres forming the folded plate - cortex • forms islands nearby ventricular system – telencephalic and/or cerebellar nuclei • centrally located also in brain stem White matter: • occupies the interior of hemispheres Spinal cord Gray matter: •centrally forms the core of the organ resembles letter H •at the periphery it is surrounded by funiculi of the white matter H X Central nervous system – Spinal cord - Anatomy Cervical enlargement - C4 to T1 nerves to and from upper limbs Lumbar enlargement – T9 to T12 nerves to and from lower limbs Cauda equina nerve bundle C1 L1 Approx. 40-50 cm • Cylindical strand • Narrowed conically • Bilaterally symmetrical • Central canal 31 segments + 31 pairs of spinal nerves Central nervous system – Spinal cord – White matter POSTERIOR anterior median groove posterior median septum Fasciculi = Funiculi (= Collumns) • Anterior – sensitive tracts + motoric tracts • Lateral – sensitive tracts + motoric tracts • Posterior – sensitive tracts Sensitive = Ascending Motoric = Descending Spinal cord – White matter - Tracts Only for demonstration purpose – no need of memorizing !!! Spinal cord – White matter WhitematterGraymatter Myelinated axons Spinal cord – Gray matter – Organization Posterior gray horn Lateral gray horn Anterior gray horn Define collumns from dorsal root to ventral root Spinal nerve Sensory neurons Motor neurons Motor neurons (radicular) • in the anterior (ventral) horns • stellate shape, 150 mm in diameter • send off long myelinated axons ending on muscle fibres Funicular cells • mainly in the posterior horns • their axons enter the white matter and connect to other segments of SC and to brain stem Interneurons • small neurons • diffusely distributed among motor and funicular cells Neurons in gray matter – all are multipolar Spinal cord – Gray matter – Organization Spinal cord – Gray matter Spinal cord – Gray matter – Motor neurons Spinal cord – Central spinal canal Central spinal canal Anterior median groove Posterior median (glial) septum Spinal cord – Central spinal canal Cerebellum Sagital section Dorsal view Corpus callosum Cerebellum Pons Cerebral cortex Thalamus Hypohalamus vermis hemispehere hemispehere Function •co-ordination of voluntary movements and helping to maintain balance •allows for smooth, co-ordinated movements by constantly adjusting muscle tone and posture Weight: 130 grams Surface area: 0,10 - 0,15 m2 Cerebellum – Gray matter Gray matter • Cortex at the surface (1 mm thick) • Nuclei in white matter (nucleus dentatus, emboliformis, globusus, and fastigii) White matter Cortex Cerebellum – White matter „Arbor vitae“ – white matter Cerebellum – Cortex Purkinje cell layer (stratum gangliosum) Molecular layer (stratum moleculare) Granule cell layer (stratum granulosum) Cerebellum – Cortex - Cells Purkinje cell layer (stratum gangliosum) • Perikaryons of Purkinje cells • Golgi (Bergman) glial cells Molecular layer (stratum moleculare) •Basket cells •Stellate cells Granule cell layer (stratum granulosum) • Granule cells • Golgi (Bergman) glial cells Cerebellum – Purkinje cells Cerebellum – Cortex – Cells and Fibers STELLATE CELLS Fibers Efferent • Axons of Purkinje cells - the only cells in cerebellum sending signals outside - always inhibitory signals Afferent • Mossy fibers – synapse with granule cells (Glomerulli cerebelares) • Climbing fibers – synapse with dendrites of Purkinje cells STELLAR CELLS Cerebellum – Cortex – Cells and Fibers Cerebellum – Cortex – Cells and Fibers a - granule cells b - Purkinje cells c - basket cells d - satellite cells f - mossy fibers g - climbing fibersRamon Y. Cajal Glomeruli cerebellares Cerebellum – Cortex – Cells and Fibers Glomeruli cerebellares (only few are shown) Telencephalon Gray matter • Cortex at the surface • Nuclei in white matter Hemisphere Hemisphere White matter • Among the cortex and nuclei Folding of cortex: gyri + sulci Telencephalon – Cerebral cortex Functions: • perception and conscious understanding of all sensations • integration of different sensory modalities • higher cognitive and advanced intellectual functions • responsible for features such as emotion, personality and intellect • involved in planning and executing complex motor activities Overall characteristics: • about 80% of the mass of the brain • surface area about 0.20 – 0.25 m2 • thickness about 2 - 5 mm • contains about 10 billion neurons Allocortex: • = archicortex + paleocortex • less layers of cells (e.g. olfactory cortex – 3 layers, hipocampus – 1 layer) Isocortex: • = neocortex (phylogenetically youngest) • only in mammals • 90% of the cortex in humans • 6 distinguishable layers of cells Telencephalon – Cerebral cortex – Neuron types + layers Pyramidal • efferent – projecting neurons • triangular perikaryon (different size) • axons with myelin sheets • axons travel to different cortical layers and to subcortical areas Non-pyramidal • variety of different cells • act as interneurons • axons stay in the layer with their perikayons (e.g. fusiform cells, granule (stellate) cells, horizontal cells (Cajal), vertical cells (Matinotti) 1. Molecular layer • horizontal cells (of Cajal) 2. Outer granular layer • small granular (stellate) cells 3. Outer pyramidal layer • pyramidal cells (various sizes) 4. Inner granular layer • small granular (stellate) cells 5. Ganglionic (internal pyramidal) layer • large pyramidal cells (various sizes) 6. Multiform layer • fusiform cells • small granular (stelůlate( cells • vertical cells (of Martinotti) Telencephalon – Cerebral cortex – Cell types + Plexuses 1. Molecular layer 2. Outer granular layer 3. Outer pyramidal layer 4. Inner granular layer 5. Ganglionic layer 6. Multiform layer Plexus of Exner Band of Bechterev External band of Baillarger Deep tangential plexus of Meynert Internal band of Baillarger Golgi stain Nissl stain Weigert stain Telencephalon - Isocortex Telencephalon - Isocortex Telencephalon - Isocortex Molecular layer Outer granular layer Telencephalon - Isocortex Ganglionic (internal pyramidal) layer Telencephalon - Isocortex Multiform layer White matter Telencephalon - Isocortex Heterotypic various divergences from the typical architecture (cell numbers/density, relative propoertions, thickness, fibers, vessels, …) Homotypic typical 6-layered architecture • cytoarchitectonic - the density of perikarya • myeloarchitectonic - the density of myelinated fibers • glioarchitectonic - the type and density of glial cells • angioarchitectonic - the density of blood capillaries or vascularization • synaptoarchitectonic - the density synapses in the isocortex Maps 1909 - K. Brodman 11 regions and 52 areas Meninges • membranes • protect CNS + contriubute to distribution of liquor • cover both brain and spinal cord (are continuos) Pachymeninx (hard) Dura mater Leptomeninx (soft) Arachnoid + Pia mater Dura mater Arachnoid Pia mater Meninges – Dura mater Cranial dura • Endosteal layer (periosteal; outer) - adhering to the inner surface of the bones of the skull • Meningeal layer (inner) - thinner fibrous tissue membrane, inner surface covered by mesothelial cells Spinal dura - continuation of the inner layer of cranial dura the outermost + robust (fibrous) Dura mater Venous (dural) sinuses separations of inner and outer layers at ceratin locations Meninges – Arachnoid Arachnoid • Neurothel (lamina neurothelialis) - adhering to the inner layer of dura mater, tight junctions – barrier between CSF and blood in dura mater • Trabeculae – delicate fibers covered by flat (meningeal) cells Subarachnoid space • enclosed between the arachnoid and pia mater • filled by cerebrospinal fluid (CSF) middle + spider web-like + avascular Dura mater Arachnoid Meninges – Pia mater the innermost + delicate + vascular + adheres to and follows the surface of brain Pia mater • Superficial layer- receives trabeculae of the arachnoid • Inner layer – elastic and reticular fibers, firmly attached to the under-lying nervous tissue, covered from outside with simple squamous cells of mesodermal origin Dura mater Arachnoid Pia mater Meninges – Spaces between the membranes Subdural space • between the arachnoid and the dura mater (potential space in the cranial region) Subarachnoid space • between the arachnoid and pia mater (large veins run through the subarachnoid space - e.g. cerebral veins) Subdural space Subarachnoid space Epidural space • between the dura mater and the vertebral canal in the spinal column (potential space in the cranial region) Epidural space Cerebrospinal fluid Brain ventricles (chambers) 2x lateral ventricles + 1x third ventricle + 1x fourth ventricle • connect to central canal which runs to spinal cord • contain cerebrospinal fluid (CSF) • CSF is produced by ependymal cells of chorid plexuses Lateral ventricles Third ventricle Fourth ventricle Cerebrospinal fluid - Circulation Arachnoid villus Dural sinus Arachnoid villi • fingerlike projections into the dural venous sinuses • mediate gradual reabsorbtion of CSF into the blood Peripheral nervous system - Components Definition: Made up of transmission pathways carrying information between the CNS and external/internal environments. Afferent (sensory) pathways: Carry information to the CNS. Efferent (motor) pathways: Carry information from the CNS. Includes: • Cranial nerves (12 pairs) • Spinal nerves (31 pairs) • Peripheral nerves • Ganglia • Sensory receptors Peripheral nervous system – Overall organization Somatic (voluntary) nervous system (SNS) • neurons from cutaneous and special sensory receptors to the CNS • motor neurons to skeletal muscle tissue Autonomic (involuntary) nervous systems (ANS) • sensory neurons from visceral organs to CNS • motor neurons to smooth & cardiac muscle and glands 1.sympathetic division (speeds up heart rate) 2.parasympathetic division (slow down heart rate) Enteric nervous system (ENS) • involuntary sensory & motor neurons control GI tract • neurons function independently of ANS & CNS Connective tissue layers composing nerves: • Endoneurium - surrounds axons - primary nerve bundles • Perineurium - surrounds fascicles – secondary n. bundles • Epineurium - surrounds the entire nerveNeurilemma Consists of 100’s to 100,000’s of myelinated and unmyelinated axons (nerve fibers). Peripheral nervous system - Nerves Peripheral nervous system - Nerves Peripheral nervous system – Nerves epineurium perineurium endoneurium Peripheral nervous system – Nerves myelin sheetsaxons Peripheral nervous system – Nerves Nodes of Ranvier Peripheral nervous system – Ganglia = aggregations of cell bodies of neurons located outside of CNS Sensory ganglia • associated with cranial nerves (V, VII, IX, X; cranial ganglia) and with all spinal nerves (dorsal root ganglia) • contain pseudounipolar neurons • neurons are enveloped by satellite cells Autonomic ganglia • associated with nerves of the autonomic nervous system • contain medium-sized multipolar neurons • neurons are motor by function (smooth and cardiac muscle, glands) • neurons are enveloped by satellite cells Peripheral nervous system – Ganglia Sensory ganglion Autonomic ganglion About the same magnification Spinal cord + Dorsal root ganglion Ventral horn Lateral horn Dorsal horn Dorsal root ganglion Autonomic ganglion Parasympathetic ganglia in the wall of the gut Nerve tissue regeneration - PNS Axons and dendrites may be repaired if: • Neuron cell body remains intact • Schwann cels remains active and form tube • Scar tissue does not form too rapidly injury Breakdown of axon Breakdown of myelin sheath Schwann cells divide Axon begins to grow (1.5 mm/day) Navigaion by Schwann cells Collaterals will die Nerve tissue regeneration - CNS Stem / progenitor cells resiging in some areas of adult brain Life-long plasticity of CNS • Sprouting new dendrites • Synthesis of new proteins • Changes of synaptic contacts Gastrulation Formation of the three germ layers Ectoderm: outside, surrounds other layers later in development, generates skin and nervous tissue. Mesoderm: middle layer, generates most of the muscle, blood and connective tissues of the body and placenta. Endoderm: eventually most interior of embryo, generates the epithelial lining and associated glands of the gut, lung, and urogenital tracts. Nerve tissue – Ectoderm Nerve tissue – Neural plate Neural Induction In addition to patterning the forming mesoderm, the primitive node also sets up the neural plate Endoderm + Mesoderm BMP-4 Ectoderm to Skin Notochord BMP-4 antagonists Ectoderm to Nerve tissue noggin chordin follistatin X Nerve tissue – Neural tube Neurulation Folding and closure of the neural plate • neural folds close • neural crest delaminates and migrates away • closure happens first in middle of the tube and then zips rostrally and caudally • anterior neuropore closes around day 25 • posterior neuropore closes around day 28 Nerve tissue – Neural crest Neural crest the “4th germ layer” Signals from: • Mesoderm • Adjacent skin • Neural plate Neural crest cells • Down-regulate cadherin • Delaminate from neuroepithelium • Transform into migratory mesenchymal cells • Give rise to many cell types Nerve tissue – Neural crest derivates Melanocytes •migrate to the epidermis Neuroblasts • psedounipolar neurons of spinal ganglia • multipolar neurons of autonomic ganglia • chromaffin cells of the adrenal medulla Spongioblasts • Schwann cells • satellite cells Ectomesenchymocytes • migrate into the branchial arches • replace the mesenchyme of mesodermal origin Nerve tissue – Histogenesis of neural tube • initial state - pseudostratified columnar epithelium • initially cells divide in whole thickness of the wall • later mitotic activity is reduced only tocells situated near the luminal aspect of the neural tube • neural tube develops 2 zones: germinative (inner) + marginal (outer) • cells of the germinative zone continue dividing and migrate peripherally to form mantle layer • ependymal layer = ependyma • mantle layer = gray matter - differentiate into primitive neurons - neuroblasts and spongioblasts (glioblasts) • marginal layer = white matter (contains no cells) Nerve tissue – Neural tube The early neural tube is a pseudostratified epithelium • The “apical” portion abuts the central canal • The “basal” portion abuts the surrounding tissue (e.g. somites, notochord, etc.). • Cell division occurs in the apical portion. S G2 M G0 G1 Nerve tissue – Neural tube – Cell differentiation Ependymal layer: • ependymal cells (ependymocytes) Mantle layer: • neuroblasts - to neurons • spongioblasts (glioblasts) – to: o astrocytoblasts o olidodendrocytoblasts Marginal layer: • no cells Nerve tissue – Morphogenesis Brain – develops from the proximal segment of the neural tube that is broadened from the very beginning Spinal cord – develops from the narrower caudal segment of the neural tube Nerve tissue – Brain development Brain develops from the cranial part of the neural tube at 4th week - 3 primary brain vesicles •Forebrain - prosencephalon •Midbrain - mesencephalon •Hindbrain - rhombencephalon Nerve tissue – Brain development vesicles are not followed each to other linearly, but are bent in the sagittal plane Cephalic flexure - permanent Occipital (cervical) flexure - after 2 months it is on straightening, so is not evident in the adulthood Nerve tissue – Brain development • 5th week • 5 secondary vesicles • Pontine flexure – remains to adulthood Nerve tissue – Brain development Nerve tissue – Brain development Early brain development results in: • deflection of the brain base • constitution of five final brain sections Definitive position compared to the baseline situation is highly complicated due to different growth rates of individual sections. Nerve tissue – Brain development - Ventricles Prosencephalon Mesencephalon Rhombencephalon Ventriculi laterali cerebri Mesencephalon Aquaeductus cerebri Metencephalon Myelencephalon Diencephalon Telencephalon Ventriculus tertius Ventriculus quartus You must memorize ! Nerve tissue – Spinal cord development • it develops from the caudal part of neural tube • cells of mantle layer proliferate and produce 2 sheets - the dorsal alar plate and ventral basal plate, which are separated by longitudinal groove called the sulcus limitans To remember: • alar plate - gives rise to dorsal horn • basal plate - gives rise to ventral horn Nerve tissue – Spinal cord development Axons of neuroblasts of anterior horns unite with peripheral processes of corresponding spinal ganglia neuroblasts and together leave the spinal canal as a trunk of spinal nerve. Nerve tissue – Spinal cord development in adults in newborns Positional changes of the spinal cord •initially, length of spinal cord correlates with length of the vertebral canal •during further development, the vertebral canal grows more rapidly than spinal cord so that its caudal end gradually comes to lie at relatively higher levels of the canal •in adults, it usually terminates at the inferior border of the first lumbar vertebra Thank you for your attention ! Questions and comments at: ahampl@med.muni.cz