Organization of the Nervous System. Physiology of neurons and glial cells.

Transcription

1 LECTURE 1 NERVOUS SYSTEM PHYSIOLOGY Organization of the Nervous System. Physiology of neurons and glial cells. Assoc. Prof. Ana-Maria Zagrean MD, PhD Physiology & Neuroscience Div. azagrean@gmail.com

2 Physiology 2 nd year Semester 1 Curricula Nervous system physiology 6 lectures Cardiovascular physiology 7 lectures Lectures Monday, 8:00-11:00 Practical laboratories Thursdays, from 14:00 (seria 2) & 17:00 (seria 1) Neuroscience Optional Lecture October-December, 2014 Info at

3 Nervous System Physiology 1. Organization of the Nervous system. Physiology of neurons and glial cells. 2. Excitability and ionic transport part 1 3. Excitability and ionic transport part 2 4. Synaptic transmission in the nervous system. Neurotransmitters. 5. Physiology of the neuro-muscular system. 6. Somatic sensory system: touch, proprioception, pain. Sensation and sensory processing: Physiology of sight & hearing. Recommended bibliography: Guyton & Hall Textbook of Medical Physiology Boron & Boulpaep Medical Physiology, Updated 2012 Ed. Dale Purves Neuroscience, 5 th Edition Medical Physiology principles for clinical medicine, R.A. Rhoades, 4 th Ed., 2013

4 Nervous system How is organized, develop, function to generate behavior these questions can be explored using the tools of genetics and genomics, molecular & cellular biology, anatomy and systems physiology, behavioral observations and psychology. This exploration rises a major challenge: to integrate the diverse knowledge derived from these various levels of analysis into a coherent understanding of brain structure and function.

5 Nervous system Myriad cell types, and many more interconnections Mechanisms of excitability and plasticity Physiological role of the neural circuits defined in the behaviorally meaningful contexts.

6 Nervous system At cellular level neurons & glia neural circuits Neural circuits primary components of neural systems that process specific types of information Neural systems serve one of three general functions: 1. sensory systems (inform about the state of the organism and its environment) 2. motor systems (organize and generate actions) 3. associational systems link sensory & motor components provide the basis for higher order brain functions (perception, attention, cognition, emotion, language, rational thinking, creativity ) understanding human beings, their behavior, their history, and perhaps their future

7 Organization of the nervous system: from where to start We need a leap in our understanding: from the organism to the human being How much we would struggle to look inside there is still a veil that let us imagine, sense, feel, create the thinking inside the thinking.

8 Different perspectives on the brain To the unaided eye, the most striking feature of the human brain is its curvy pattern of bumps and grooves. But within those curves is a latticework of nerve fibers that cross each other at roughly right angles (method used here is called diffusion spectrum imaging that infer the position of nerve fibers in the living human brain from the way water flows through and around them). These scans revealed an orderly texture of fibers a much simpler organization than many scientists would have suspected (

9 Connectomics - Human Connectome Project White Matter Connections Obtained with MRI Tractography From: Gigandet X, Hagmann P, Kurant M, Cammoun L, Meuli R, et al. (2008) Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography. PLoS ONE 3(12): e4006. doi: /journal.pone

10 Dale Purves, Neuroscience, 5 th Ed. Genetics and the Brain Genomics has brought insight into how nuclear DNA provides instructions for the assembly and operation of the brain Human genome: about 20,000 genes (coding & regulatory DNA) 14,000 genes expressed in the developing/mature brain about 8,000 genes are expressed in all cells and tissues a great deal of brain specific genetic information resides in the regulatory DNA sequences that control timing, quantity, variability, and cellular specificity of gene expression individual genes vary in the level of expression in specific brain regions and cells (i.e. the amount of mrna expressed) foundation of the diversity & complexity of brain functions! Gene mutations & brain pathology (Huntington D, Alzheimer D, Parkinson D )

11 Dale Purves, Neuroscience, 5 th Ed. Genetics and the Brain Genetics & Genomics understand physiopathology develop new therapies But relationship between genotype and phenotype is not just the result of following genetic instructions, and genetic information alone cannot explain how the brain operates in normal individuals, or how disease processes disrupt normal brain functions. the need to understand the cell biology, anatomy and physiology of the nervous system constituent cells and the circuits they form.

12 The Nervous System components: brain, spinal cord, nerves, sensory receptors Responsible for sensory perceptions, mental activities, stimulating muscle movements, secretions of many glands Subdivisions Central nervous system (CNS) Peripheral nervous system (PNS) Somatic & Autonomic Nervous Systems, including Enteric NS

13 Nervous System Subdivisions! All elements of the nervous system work closely together in a way that has no clear boundaries.

14 Nervous System subdivisions interplay

15 Organization of the Nervous System: CNS, PNS & ANS Central nervous system (CNS): - brain (including cranial nerve II and retina) and spinal cord; - covered by the meninges (3 layers: pia mater, arachnoid, and dura mater); - special features: oligodendrocytes provide myelin; axons cannot regenerate Peripheral nervous system (PNS): - parts of the nervous system that lie outside the dura mater; - consists of peripheral ganglia (including cell bodies); sensory receptors; afferent & efferent peripheral portions of spinal nerves, cranial nerves (except CN II that is included in the CNS) and all peripheral portions of ANS. - special features: Schwann cells provide myelin; axons can regenerate Autonomic nervous system (ANS): - anatomically includes parts of CNS & PNS; - regulates & controls visceral functions through reflex arcs (visceral afferent/ sensory neurons, control centers in the CNS that receive input, and visceral motor output). - special feature: functionally distinct system

16 Central nervous system (CNS) interfaces Extracellular brain environment is maintained by a regulated molecular exchange between blood and the CNS, through several restricted borders/barriers: (1) blood - brain barrier (BBB) Brain endothelial capillaries (2) blood - choroids plexus epithelium - cerebral spinal fluid (CSF) (3) blood - nerves (4) blood - retina (5) blood - labyrinth.

17 CNS blood flow connections Cerebral capillary: BBB Choroid plexus capillary: blood-csf barrier Arterial blood CSF ependim Brain ECF Blood capillary in circumventricular organs (no BBB, important for neuropeptide transport, enables brain to sense and regulate blood composition) Brain intracellular compartment neurons neuroglia

18 Cerebral circulation Cerebral blood supply by two pairs of arteries: - the right and left internal carotid arteries anterior 2/3 of the corresponding cerebral hemispheres, - the right and left vertebral arteries, which join to form the basilar artery brain stem and posterior portion of the hemispheres Internal carotid arteries and the basilar artery join via anastomotic channels to outline the arterial circle of Willis around the optic chiasma, at the base of the brain Circle of Willis anterior, middle, and posterior cerebral arteries pial arteries that expand over the surface of the hemispheres, form anastomoses, and branch into penetrating arterioles, which further divide to continue with the capillaries

19 Cerebral circulation & BBB Total capillary length in the brain: roughly 400 miles Most neurons in the adult human brain are not more than 20 µm from a capillary the blood-brain barrier s (BBB) impact on neural tissue.

20 Cerebrospinal fluid (CSF) -ventricles of the brain -cisterns around the outside of the brain -the subarachnoid space around both the brain and the spinal cord Volume = 150 ml, daily production = 500 ml Formation of CSF: 2/3 as secretion from the choroid plexuses in the four ventricles, but mainly in the two lateral ventricles; 1/3 as secretion by the ependymal surfaces of the ventricles and by the arachnoidal membranes Function: mechanical protection; 1400 g 50 g distribution of neuroendocrine factors volume buffer : regulate ICP when tissue/ intracranial blood volume rises Monroe-Kelly doctrine: V-CSF+V-blood+V-brain tissue = const.

21

22 In the PNS, nerves have their blood vessel supply

23 Nervous System: structure 1) CENTRAL NERVOUS SYSTEM (CNS): brain spinal cord Covered by meninges 2) PERIPHERAL NERVOUS SYSTEM (PNS): cranial nerves spinal nerves 2 types of nervous tissue cells: neurons: sensory, motor, interneurones/association neurons non-neuronal/neuroglial cells: astrocytes, microglia, oligodendocytes / Schwann cells, ependymal cells Spinal cord

24 Cells of the Nervous System: Cellular diversity of the brain Human brain is estimated to contain 100 billion neurons and several times as many supporting cells glial cells. The nervous system has a greater range of distinct cell types - whether categorized by morphology, molecular identity, or physiological activity - than any other organ system

25 Neuroglial cells variable structures that are suited for their diverse functions provide a physiological environment for neurons can function as signaling cells! Cells of the nervous tissue Nerve cells: neurons and neuroglial cells. ~10 11 neurons in the human brain and 10 x more neuroglia Neurons have special shapes, physiological properties, and connections (~1000 synapses/each neuron & other connecting mechanisms!) information transmission throughout the nervous system unique patterns of connectivity & regional specialization tremendous complexity of NS

26 26

27 Typical neuron has 4 regions: cell body, dendrites, axon, presynaptic terminals each region is specialized for its particular function information flows in a single direction Neuron Cell Body Location Most are found in the central nervous system Gray matter cell bodies and unmylenated fibers Nuclei clusters of cell bodies within the white matter of the central nervous system Ganglia collections of cell bodies outside the central nervous system

28 The structure of a typical neuron (1) cell body/ soma /perikaryon (nucleus, ER, Golgi complex, mitochondria ) (2) dendrites of various complexity: tapered, limited length, contain membrane rec. for neurotransmitters; dendritic spines The dendrites & cell body are the main areas for receiving information through the membrane receptors that bind and respond to the neurotransmitters released by neighboring cells. (3) the axon: - axon hillock, a cone-shaped initial segment = the spike initiation zone (unmyelinated region where AP initiates) - axon can extend for >1m, can be myelinated (electrical insulation, fast impulse spread), high density of Na + channels - contain axoplasm, microtubules and microfilaments that confer structural stability and axonal transport. (4) the presynaptic terminals: rapid conversion of the neuron's electrical signal into a chemical signal or another kind of signal.

29

30 Neuronal compartmentalization Neurons are polarized cells and have distinct membrane protein at each of the distinct domains of the Two plasma major membrane. classes of MAPs are found in the brain: high-molecular-weight proteins (MAP-1, MAP-2) and lower Protein synthesis occurs mainly in the cell body, less molecular in dendrites, weight and tau smooth proteins. and rough ER & Both classes of MAPs associate with Golgi system are absent in the axon. microtubules and help link them to other Mitochondria: present in the cell soma and cell components. presynaptic terminal, also trafficking in the axon. MAP-2 is found only in cell bodies and dendrites. Anterograde and retrograde axoplasmic transport Dephosphorylated of molecules tau in proteins vesicles are along confined entirely to axons. In cultured microtubules is mediated by microtubuleassociated proteins (MAPs ): neurons, suppressing the expression of tau protein prevents formation of the 1. kinesin for anterograde transport: always axon without altering formation of the dendrites. move toward the (+) end of microtubules, away from the cell body 2. dynein for retrograde transport: provides a mechanism for target-derived growth factors, as NGF, to reach the nucleus of a neuron where it can influence survival! Quantum content

31 "signaling endosome" Axoplasmic Transport

32 Features of Axoplasmic Transport Transport Type Fast anterograde Speed (mm/day) Mechanism ~ 400 Saltatory movement along microtubules by the motor molecule kinesin (ATP dependent) Material Transported Mitochondria Vesicles containing peptide and other neurotransmitters, some degradative enzymes Fast retrograde Slow anterograde ~ Saltatory movement Degraded vesicular along microtubules membrane by the motor Absorbed exogenous molecule dynein (ATP material (toxins, viruses, dependent) growth factors) ~0.2-8 Not clear; possibly by molecular motors Cytoskeletal elements (e.g., neurofilament and microtubule subunits) Soluble proteins of intermediary metabolism Actin

33 Heterogeneity of cell morphology is likely related to the different functions of the different neurons Structure function relation:

34 Neurons and synapses - from cells to networks Neural coding at cellular or network level Specific circuits / systems Input/processing/output From experience to educated output

35 Classification of neurons based on their structure (Borone)

36 Classification of Neurons

37 Classification of Neurons based on their function Sensory (afferent) neurons Carry impulses from the sensory receptors -Cutaneous sense organs -Proprioceptors detect stretch or tension Motor (efferent) neurons -Carry impulses from the central nervous system Interneurons (association neurons) -Found in neural pathways only in the central nervous system -Connect sensory and motor neurons

38 Neuron Classification

39 Classification of neurons based on their function Types of neurons: Sensory or afferent Interneurons Motor or efferent Sensory/afferent nerves: messages from periphery to CNS Motor/efferent nerves: messages from CNS to peripheral tissues.

40 Classification of neurons based on the type of information transmitted Direction of information flow: Afferent (sensory): neurons that transmit information into the CNS from sensory cells or sensory receptors outside the nervous system (dorsal root ganglion cell and neurons in the sensory nucleus of the fifth cranial nerve). Interneurons: relay or association neurons Efferent (motor): neurons that transmit information out of the CNS to muscles or secretory cells (spinal motor neurons and motor neurons in the ANS). Anatomical distribution of the information flow: Visceral: neurons that transmit information to or from internal organs or regions that arise embryologically from the branchial arch (e.g., chemoreceptors of the carotid body). Somatic: neurons that transmit information to or from all non-visceral parts of the body, including skin and muscle. Embryological origin of the structure being innervated: Special: neurons that transmit information to or from a "special" subset of visceral or somatic structures - special visceral neurons: information travels to or from structures derived from the branchial arch region of the embryo (e.g., pharyngeal muscles) - special somatic neurons, which handle only sensory information: the neurons arise from the organs of special sense (e.g. retina, taste receptors, cochlea).

41 Characteristics of Neurons 1) excitable - respond to stimuli - produce & conduct electrical impulses - release chemical regulators 2) amitotic- cannot divide by mitosis! 3) long-lived 4) high metabolic rate

42 neuroglia support & protect & nourish & signal smaller & numerous types: astrocytes microglia Schwann cells * oligodendrocytes * ependymal cells Non-neuronal Cells

43 Non-neuronal cells: Schwann cells and oligodendrocytes (PNS) (CNS)

44 Myelin -Layers of lipid membrane of oligodendrocytes (CNS) or Schwann cells (PNS) -The signal that causes these glial cells to myelinate the axons is an epidermal GF-like ligand (neuregulin), which derives from the axon and whose potency is dependent of axonal size (usually axons > 1 micrometer in diameter are myelinated ) - voltage-gated Na+ channels are highly concentrated in the nodes of Ranvier, and in low density beneath the sheath of myelin AP jump from one Ranvier to the next one saltatory conduction increased conduction velocity: m/sec in myelinated axons comparing to m/sec in unmyelinated axons

45 Myelin, Oligodendrocyts and network of intercellular channels between astrocytes (A) and oligodendrocytes (O) Orthmann-Murphy, J. L. et al. J. Neurosci. 2007;27:

46 Neuro-vascular unit

47 Neuron astroglia connections

48 Who are we? Cortical neurons in culture, Dr. AM Zagrean, Neuronal Cell Culture Lab