Basic elements: Neurons and Glia. Mary ET Boyle, Ph. D. Department of Cognitive Science, UCSD

Transcription

1 Basic elements: Neurons and Glia Mary ET Boyle, Ph. D. Department of Cognitive Science, UCSD

2 High level learning objectives Differentiate the basic classes of cells found in the central nervous system (CNS) Characterize the anatomy of a neuron Cell body, dendrites, axons and synapses Understand and describe the elements of the CNS

3 Continued: Describe the basic classes of cells found in the central nervous system (CNS) Describe the basic functions of the three types of glial cells found in the CNS Characterize the blood brain barrier.

4 Check your understanding? What is the neuron doctrine? Who had the insight? How?

5 ? What are the differences between a Golgi and Nissl stain? How does the information differ?

6 Check your understanding? What are the functions of each of the following structures: Nucleus, mitochondria, rough ER, synaptic vesicle, Golgi apparatus, MAP, neurofilament, microtubules, microfilament Which are specialized for neurons?

7 Check your understanding? Classify the following neuron based on: (a) Number of neurites (b) Dendritic spines (c) Connections (d) Axon length

8 Neurophilosophy mind/body Glia and Neurons?? Relationship between mind and brain Neuroglia (glia) Insulates, supports, and nourishes neurons Electrical and chemical functionality Neurons: Primary processors of neural information Sense environmental changes Communicate changes to other neurons Command body response

9 Nervous system components: Neurons Neuroglia Vascular endothelium Primary processors of neural signals Support the electrical and chemical functions of neurons Involved in the blood supply to brain tissue

10 Small size Difficult to study Neuron size range: mm Histology Microscopic study of tissue Cytoarchitecture important for understanding function and gross anatomy Tissue preparation Visualization levels light and electron Histochemistry Fiber tract tracing Identification of receptor types Mapping distribution of a particular gene

11 Named for German neurologist: Franz Nissl ( ) Methylene blue Cresyl violet Neutral red Toluidine blue (cationic dyes) Nissl bodies/substance = cytoplasmic granules in neuronal soma By 1950 s Nissl bodies are aggregations of rough ER Staining the high concentrations of rrna Good for distinguishing neurons from glia more rough ER in neurons Great to visualize the cytoarchitecture of neurons in different brain regions Under pathological conditions Nissl bodies dissolve or disappear (chromatolysis.) Nissl stain Image from Wikipedia (top) Nissl-stained horizontal section through the mouse hippocampus showing various classes of cells (neurons and glia).

12 Soak the brain in silver chomate solution only a small percentage of neurons become darkly colored in their entirety. The gain in brain is mainly in the stain!

13 Umemoria, H and Hortsch, M. (Eds.) 2009 In: The Sticky Synapse: Cell Adhesions Molecules and Their Role in Synapse Formation and Maintenance

14 Golgi v. Ramón y Cajal Reticular Theory Golgi Continuous syncytial network Nerve fibers, dendrites and neuronal cells directly connected to each other by cytoplasmic bridges Neuronal cell bodies provide nourishment. Ironically, Golgi stain led to demise of theory Neuron Doctrine Ramón y Cajal Neurons are not continuous Neurons communicate by contact, not continuity Golgi stain identification of subcellular units of the neuron Soma Axon Dendrite Circuitry Electron microscopy Synapse (not gap junctions) Neurons were not continuous Same data; different conclusion.

15 This drawing by Santiago Ramon y Cajal first appeared in volume two, part two of Cajal's Textura del Sistema Nervioso del Hombre y de los Vertebrados, published in Madrid in The image shows the six layers of the mouse neocortex, labeled A through F, in Cajal's hand. Cajal's drawings provided the foundation of modern neuroanatomy by showing that the nervous system is composed of individual nerve cells, as opposed to a web of continuous elements History of Neurosciene

16 Check your understanding? What is the neuron doctrine? Who had the insight? How?

17 ? What are the differences between a Golgi and Nissl stain? How does the information differ?

18 Fundamental functional unit dendrites Input zone cell body Metabolic machinery axon Conducting zone unique Morophology Bioelectric Intercellular communication axon terminal Output zone

19 Grey matter White matter Image from : Grey matter

20 Fundamental functional unit Cytosol: Watery fluid inside the cell The Soma Metabolic machinery Organelles: Membrane enclosed structures within the soma unique Morophology Bioelectric Intercellular communication Cytoplasm: Contents within a cell membrane (e.g., organelles, excluding the nucleus)

21 Neuron internal view Neuronal membrane Mitochondrion Rough ER Ribosomes Nucleus Polyribosomes Golgi apparatus Smooth ER Axon hillock Microtubules Axon

22 Within the soma: The nucleus Gene expression Transcription RNA processing

23 Rough endoplasmic reticulum Major site for protein synthesis

24 Protein synthesis also on free ribosomes; polyribosomes Protein destined to reside in the cytosol Protein likely to be inserted in membrane

25 Smooth ER and Golgi Apparatus Sites for preparing and sorting proteins for delivery to different cell regions (trafficking) and regulating substances

26 Lin, M. T. & Beal, M. F (2006)

27 Difference in gene expression Post genomic era Information about the genes expressed in our tissues can be used to diagnose and treat diseases. Biological basis for neurological and psychiatric disorders.

28 December 11, 2007 vol. 104 no. 50

29 accessexcellence.org Transcriptome analysis of the brain and liver after sleep deprivation in three inbred mouse strains indicates that Homer 1a is specifically upregulated in the brain. Maret S et al. PNAS 2007;104:

30 Mitochondrion Site of cellular respiration (inhale and exhale) Pyruvic acid (inhale) 17 ATB (exhale) Krebs cycle ATP cell s energy source

31 Many lines of evidence suggest that mitochondria have a central role in ageingrelated neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.

32 Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as neurochemical diseases, it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. NATURE REVIEWS NEUROSCIENCE VOLUME 13 MAY 2012

33 The Neuronal Membrane Barrier that encloses cytoplasm ~5 nm thick Protein composition in membrane varies Structure of discrete membrane regions influences neuronal function The Cytoskeleton Not static Internal scaffolding of neuronal membrane Three bones Microtubules Microfilaments Neurofilaments

34 Big and run longitudinally along neurite Composed of strands of tubulin Microtubule associated proteins regulate microtubule assembly and function MAPs serve as anchors. Dissociated tau proteins are seen in neurodegenerative diseases.

35 AKA Intermediate filaments in other cells. Structurally resembles bones and ligaments Mechanically very strong structure.

36 Microfilament Braids of two thin strands of actin Important role in cell shape also anchored to the membrane run longitudinally down the core of a neurite

37 Check your understanding? What are the functions of each of the following structures: Nucleus, mitochondria, rough ER, synaptic vesicle, Golgi apparatus, MAP, neurofilament, microtubules, microfilament Which are specialized for neurons?

38 In the case of neurodegenerative tauopathies a group of disorders that includes Alzheimer s disease (AD) and the frontotemporal dementias (FTDs) neurofibrillary tangles (NFTs) twisted ribbons or other conformations of aberrantly phosphorylated forms of the microtubule associated protein (MAP) tau are the diagnostic hallmark lesions in the CNS. Moreover, added complexity may come from the fact that, aside from its well-established role in promoting the stabilization of microtubules (MTs), tau may have additional functions as a result of its interactions with other structures and enzymes Ballatore, C., et al (2007) nature reviews neuroscience volume 8

39 Figure 1 Direct and indirect pathological events that can contribute to tau-mediated neurodegeneration. Pathological events that can contribute to tau-hyperphosphorylation and detachment from microtubules are shown in the box on the left. The middle box shows the mechanisms that underlie the loss of normal function and toxic gain-of-function of tau, which ultimately result in impaired axonal transport and lead to synaptic dysfunction and neurodegeneration (right hand box). Aβ, amyloid-β; MT, microtubule; NFT, neurofibrillary tangle. Ballatore, C., et al (2007)

40 The Axon Axon hillock (beginning) Axon proper (middle) Axon terminal (end) Differences between axon and soma ER does not extend into axon Protein composition: Unique Structural differences = functional differences No protein synthesis import all proteins down the axon.

41 Differences between the cytoplasm of axon terminal and axon No microtubules in terminal Presence of synaptic vesicles Abundance of membrane proteins Large number of mitochondria

42 The Synapse Synaptic transmission Electrical to chemical toelectrical transformation Synaptic transmission dysfunction Mental disorders

43 Transportation The Axon Axoplasmic transport Anterograde (soma to terminal) Retrograde (terminal to soma)

44 Dendrites are the Antennae of neurons Dendritic tree Synapse receptors Dendritic spines Postsynaptic Structurally different Sensitive to synaptic activity Image from Wikipedia

45 Cortical pyramidal neuron Pyramidal cell Local axon collateral (local circuitry) Stellate cell Dendrites Descending axon (output) Example of a projection neuron

46 Knee Jerk Reflex

47 Cortical pyramidal neuron projection neuron

48 Classifying Neurons Classification Based on the Number of Neurites Single neurite Unipolar Two or more neurites Bipolar two Multipolar more than two

49 Classification Based on Dendritic and Somatic Morphologies Stellate cells (starshaped) and pyramidal cells (pyramid shaped) Spiny or aspinous

50 Further Classification By connections within the CNS Primary sensory neurons, motor neurons, interneurons Based on axonal length Golgi Type I projection neurons (from one part of the brain to the other) Golgi Type II local circuit neurons Based on neurotransmitter type e.g., Cholinergic = Acetylcholine at synapses

51 Count the many functions of Glia Support neuronal functions chemical Support neuronal metabolic function Participate in the inflammatory response in injured neural tissue, including phagocytosis of cellular debris Contribute to the formation of scar tissue in damaged brain and spinal cord. Make myelin insulating the axon to make neuronal signaling more efficient. Participate in neuron circuit formation and synaptic plasticity Blood brain barrier

52 Found primarily in gray matter Closely associated with neuronal cell bodies, dendrites and synapses Help maintain ionic balance of extracellular fluids Take up and process neurotransmitters from synaptic clefts Astrocytes Assist in the formation of new synapses and circuits Contribute to the formation of the blood brain barrier and brain ependymal (ventricular) barrier Contribute to the formation of scars following injury.

53 Astrocytes Most numerous glia in the brain Fill spaces between neurons Influence neurite growth Regulate chemical content of extracellular space

54 A Specialist among glia found in white matter because it is the white matter! Peripheral nervous system myelin: Schwann cells Myelin aids in the propagation of neural signals along myelinated axons Pro: Present antigens that influence the outgrowth of axons in developing and recovering brain to regenerate lost connections Con: present antigens that can attack CNS Multiple sclerosis. Myelinating glial cell in CNS: oligodendrocyte

55 Glia Myelinating Glia Oligodendroglia (in CNS) Schwann cells (in PNS) Insulate axons

56 Insulate axons by generating layers of membrane that wrap around axon segments Myelin makes the passive flow of current along the axon more efficient. Having gaps between myelin segments enables the neuron to conserve its resources by having ion channels and pumps concentrated in and around the myelin gap. Node of Ranvier Oligodendrocyte Ion channels and pumps are concentrated at nodes Myelin sheath

57 Oligodendro glial cells Node of Ranvier Region where the axonal membrane is exposed Other Non-Neuronal Cells Microglia as phagocytes (immune

58 Special type of mononuclear phagocyte in CNS Migrate to brain during embryonic development Two forms dormant and active Ramified is dormant lying in wait for injury or inflammation Amoeboid is active mobile and ready to phagocytize debris and release cytokines that modulate local inflammatory responses Injury or inflammation

59 Existing neurons New neurons Glial stem cell Blood vessel True stem cells give rise to more stem cells, astrocytes, oligodendrocytes and neurons! Subset of astrocytes located near vessels adjacent to the ventricles Proliferate Key properties of somatic stem cells self renewal Potential to make all the cells of a given tissue (e.g. CNS)

60 Oligodendrocyte precursor Differentiates into oligos, astrocytes, neurons Myelinating oligodendrocyte Oligodendroglial precursors are located in and around white matter Mostly give rise to oligos but can generate neurons and astrocytes

61 capillary astrocyte foot process nucleus brain capillary endothelial cell tight junction Blood brain barrier Specialized permeability barrier between the capillary endothelium and the extracellular space in neural tissue.

62 Check your understanding? Classify the following neuron based on: (a) Number of neurites (b) Dendritic spines (c) Connections (d) Axon length

63 Structure Correlates with Function NEURONS Soma Axons Dendrites Synapse Structural characteristics of a neuron tell us about its function e.g., Dense Nissl stain = protein; suggests specialization Elaborate structure of dendritic tree = receiver

64 Check your understanding? How does information flow through a neuron? a. Dendrite synapse cell body axon dendrite b. Synapse dendrite axon cell body synapse c. Synapse dendrite cell body axon synapse d. Axon dendrite synapse cell body axon e. None of the above

65 Check your understanding? Which set of microanatomical structures would be in white matter? (Typical scenario.) a. synapses, vascular endothelium, neuronal cell bodies, axons b. Vascular endothelium, axons c. synapses, vascular endothelium, neuronal cell bodies d. Vascular endothelium, neuronal cell bodies, axons e. None of the above

66 Check your understanding? Consider a patient that has suffered a stroke consequently it caused damage to a region in the brain. Which of the following glial cell activities occurred first? a. Microglia were stimulated to convert from ramified to amoeboid states. b. Astrocytes formed scar tissue to fill in space vacated by damaged tissue. c. Microglia phagocytosed cellular debris. d. Glial stem cells repopulated region of damage neural tissue. e. None of the above what was it?