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Fundamentals of Neuroscience; 4th Edition,
9/6/2019 8-9 am Fundamentals of Neuroscience (Chapters 3&4) - Cellular & Subcellular Components of Nervous Tissue
751 Neuro Conf rm 3717
9/13/2019 8-9 am Fundamentals of Neuroscience (Chapters 5&6) – Membrane Potential, AP, Neurotransmitters
751 Neuro Conf rm 3717
9/20/2019 8-9 am Fundamentals of Neuroscience (Chapters 7&8) -Neurotransmitter Release & Neurotransmitter Receptors
751 Neuro Conf rm 3717
9/27/2019 8-9 am Fundamentals of Neuroscience (Chapters 7&8) – Intracellular Signaling, Postsynaptic Potentials & Synaptic Integration
751 Neuro Confrm 3717
• Ernesto Solis, Jr.
• September 6, 2019
Neurons
Neuroglia (oligodendrocytes, astrocytes, microglia)
Other important cells (epithelial cells, VSMC, etc.)
Since late 1800s, Santiago Ramón y Cajal “founder of contemporary neuroscience” used Golgi stain to observe neuronal architecture.
Since late 1800s, Santiago Ramón y Cajal “founder of contemporary neuroscience” used Golgi stain to observe neuronal architecture.
Golgi’s “reticular view” (continuous cytoplasm/axons fuse).
Challenged with “neuron doctrine” that states that each neuron is an individual entity (the basic unit of neural circuitry).
Reticular Theory Neuron Doctrine
Which one is correct?
• Neurons – communicating cell (through synapses), form complex circuits with other neurons• Categorized based on size, shape, neurochemical characteristics, location, and connectivity
(important determinants of the functional role of the neuron in the brain)
• Circuits constitute the structural basis for brain function.
• Macrocircuit – involve a population of neurons projecting from one brain region to another region (example: Retina LGN Visual Cortex)
Macrocircuit
Cellullar components: NEURON
Cellullar components: NEURON
MicrocircuitMacrocircuit
• Neurons – communicating cell (through synapses), form complex circuits with other neurons• Categorized based on size, shape, neurochemical characteristics, location, and connectivity
(important determinants of the functional role of the neuron in the brain)
• Circuits constitute the structural basis for brain function.
• Macrocircuit – involve a population of neurons projecting from one brain region to another region (example: Retina LGN Visual Cortex)
• Microcircuit – reflect the local cell-cell interactions within a brain region (example: Cells in Retina)
Introduction to Psychology (Stangor & Walinga)
• Neurons – communicating cell (through synapses), form complex circuits with other neurons
• Studying the circuits can help to understand neuronal function and dysfunction in the diseased brain (example: corticospinal tract stroke, amygdala fear, hippocampus Alzheimer’s)
Cellullar components: NEURON
• Neurons – communicating cell (through synapses), form complex circuits with other neurons
• Studying the circuits can help to understand neuronal function and dysfunction in the diseased brain (example: corticospinal tract stroke, amygdala fear, hippocampus Alzheimer’s)
Cellullar components: NEURONCircuits underlie all behavior, including fear, anxiety, attention, appetite, etc.
Neural circuits engaged during fear conditioning
(Medina et al., Nature Rev Neuro, 2002)
Behavioral Autonomic Endocrine
Central Amyg.
Cellullar components: NEURON
• Cell body and dendrites receive input.
• One apical and 2 basal dendrites.
• Characteristic dendritic arbor shape defines receptive area.
• Neurons are highly polarized.
Cellullar components: NEURON
• Cell body and dendrites receive input.
• One apical and 2 basal dendrites.
• Characteristic dendritic arbor shape defines receptive area.
• Neurons are highly polarized.
• Preferential distribution of synaptic contacts on spines.
Cellullar components: NEURON
• Cell body and dendrites receive input.
• One apical and 2 basal dendrites.
• Characteristic dendritic arbor shape defines receptive area.
• Neurons are highly polarized.
• Preferential distribution of synaptic contacts on spines.
• Neocortical pyramidal neurons display varying cell size and dendritic arborization
• Some exhibit axon collaterals depending on neuron laminar localization (I-VI).
• Different types of pyramidal neurons with a precise laminar distribution project to different brain regions.
• Via corticospinal tract, Betz cells (gygantopyramidal neurons) in layer V of primary motor cortex project to spinal cord.
Cellullar components: NEURON
• Cell body and dendrites receive input.
• One apical and 2 basal dendrites.
• Characteristic dendritic arbor shape defines receptive area.
• Neurons are highly polarized.
• Preferential distribution of synaptic contacts on spines.
• Neocortical pyramidal neurons display varying cell size and dendritic arborization
• Some exhibit axon collaterals depending on neuron laminar localization (I-VI).
• Different types of pyramidal neurons with a precise laminar distribution project to different brain regions.
• Via corticospinal tract, Betz cells (gygantopyramidal neurons) in layer V of primary motor cortex project to spinal cord.
Where do they synapse on the spinal cord?
• Motor Neuron Diseases (UMN vs. LMN)• Amyotrophic lateral sclerosis (ALS)• Primary lateral sclerosis (PLS)• Progressive muscular atrophy• Progressive bulbar palsy• Pseudobulbar palsy• Spinal muscular atrophy (SMA)• Post-polio syndrome (PPS)
In ALS, are UMNs or LMNs affected?
(a-e) polecat, otter, raccoon, harp seal, fur seal
(f-j) wild dog, mongoose, caracal, leopard, lion
(k-o) tiger, marmoset, tamarin, tamarin, monkey
(p-t) monkey, monkey, baboon, baboon, gibbon
**Note the very large size of these pyramidal neurons in the representatives of the Genus Panthera (i–k)
(Jacobs et al., J Comp Neurol., 2017)
Cellullar components: NEURON
Betz cells (gygantopyramidal neurons) differ across species
*Giraffes, horses = similar size of cell body but much larger volume.*Large felines have much larger cell body size.
Cellullar components: NEURON
5 General Categories of Neurons1. Excitatory projection neurons – distant contacts
(e.g. pyramidal neurons in the cerebral cortex)
2. Inhibitory interneurons – local contacts (e.g. GABAergic interneurons in cerebral and cerebellar cortex and hippocampus)
3. Excitatory interneurons – local contacts (e.g. spiny stellate cells of the cerebral cortex)
(Zumla and Basu, Curr Opinion in Neurobiol., 2017)
Cortico-hippocampal circuit projections
5 General Categories of Neurons1. Excitatory projection neurons – distant contacts
(e.g. pyramidal neurons in the cerebral cortex)
2. Inhibitory interneurons – local contacts (e.g. GABAergic interneurons in cerebral and cerebellar cortex and hippocampus)
3. Excitatory interneurons – local contacts (e.g. spiny stellate cells of the cerebral cortex)
4. Inhibitory projection neurons – distant contacts (e.g. medium spiny neurons in the basal ganglia or Purkinje cells in of the cerebellar cortex.
5. Neuromodulatory neurons – influence neurotransmission
Cellullar components: NEURON
(Zumla and Basu, Curr Opinion in Neurobiol., 2017)
Cortico-hippocampal circuit projections
MSN in striatum
(Taverno et al., J Neuro., 2012)
(Rangel-Barajas and Rebec, J of HD., 2016)
5 General Categories of Neurons1. Excitatory projection neurons – distant contacts
(e.g. pyramidal neurons in the cerebral cortex)
2. Inhibitory interneurons – local contacts (e.g. GABAergic interneurons in cerebral and cerebellar cortex and hippocampus)
3. Excitatory interneurons – local contacts (e.g. spiny stellate cells of the cerebral cortex)
4. Inhibitory projection neurons – distant contacts (e.g. medium spiny neurons in the basal ganglia or Purkinje cells in of the cerebellar cortex.
5. Neuromodulatory neurons – influence neurotransmission
Cellullar components: NEURON
MSN in striatum
(Taverno et al., J Neuro., 2012)
(Rangel-Barajas and Rebec, J of HD., 2016)
(Zumla and Basu, Curr Opinion in Neurobiol., 2017)
Cortico-hippocampal circuit projections
What neurological condition is characterized by degeneration of MSNs?
5 General Categories of Neurons1. Excitatory projection neurons – distant contacts
(e.g. pyramidal neurons in the cerebral cortex)
2. Inhibitory interneurons – local contacts (e.g. GABAergic interneurons in cerebral and cerebellar cortex and hippocampus)
3. Excitatory interneurons – local contacts (e.g. spiny stellate cells of the cerebral cortex)
4. Inhibitory projection neurons – distant contacts (e.g. medium spiny neurons in the basal ganglia or Purkinje cells in of the cerebellar cortex.
5. Neuromodulatory neurons – influence neurotransmission
Cellullar components: NEURON
MSN in striatum
(Taverno et al., J Neuro., 2012)
(Rangel-Barajas and Rebec, J of HD., 2016)
(Zumla and Basu, Curr Opinion in Neurobiol., 2017)
Cortico-hippocampal circuit projections
What neurological condition is characterized by degeneration of MSNs?Answer: Huntington’s Disease
What neurological condition is characterized by loss of DAergic neurons?
5 General Categories of Neurons1. Excitatory projection neurons – distant contacts
(e.g. pyramidal neurons in the cerebral cortex)
2. Inhibitory interneurons – local contacts (e.g. GABAergic interneurons in cerebral and cerebellar cortex and hippocampus)
3. Excitatory interneurons – local contacts (e.g. spiny stellate cells of the cerebral cortex)
4. Inhibitory projection neurons – distant contacts (e.g. medium spiny neurons in the basal ganglia or Purkinje cells in of the cerebellar cortex.
5. Neuromodulatory neurons – influence neurotransmission
Cellullar components: NEURON
MSN in striatum
(Taverno et al., J Neuro., 2012)
(Rangel-Barajas and Rebec, J of HD., 2016)
(Zumla and Basu, Curr Opinion in Neurobiol., 2017)
Cortico-hippocampal circuit projections
What neurological condition is characterized by degeneration of MSNs?Answer: Huntington’s Disease
What neurological condition is characterized by loss of DAergic neurons?
Answer: Parkinson’s Disease
Small Basket
w/ arciform axon
Chandelier cell
Double Bouquet
Neurogliaform c.
Peptidergicneuron
GABAergic Interneurons of the CortexInterneuron Nomenclature Group categorized GABAergic cortical interneurons based on:
Anatomical classification – projections (3 major types): 1. Cells that target pyramidal cells2. Cells that do not show target specificity3. Cells that specifically target other interneurons
Molecular classification – expression of cellular biomarkers (5 major types):1. Parvalbumin2. Somatostatin3. Neuropeptide Y (NPY) in the absence of somatostatin4. Vasointestinal peptide (VIP)5. Cholecystokinin (CCK) in the absence of somatostatin
and vasointestinal peptide
Physiological classification – electrical activity (6 types): 1. Fast spiking neurons2. Nonadapting/nonfast spiking neurons3. Adapting neurons4. Accelerating cells 5. Irregular spiking neurons6. Intrinsic bursting neurons
Cellullar components: NEURON
Chandelier cell
Large Basket cellSpiny Stellate cell
GABAergic interneurons (blue)Spiny Stellate cell (local exc.)Excitatory neurons (black)
• 1897, Charles Sherrington postulated that neurons establish functional contact with one another and with other cells via a theoretical structure called the synapse (Greek synaptein, to fasten together).
• Electron microscopy helped demonstrate the structural evidence for the synapse ~50 years later.
• Asymmetric excitatory synapses exhibit round synaptic vesicles presynaptically and thick postsynaptic densities.
• Symmetric inhibitory synapses tend to be made on dendritic shaft, presynaptic ‘boutons’ contain ovoid vesicles.
• Spines emanate from dendritic shaft and contain filamentous material.
(Chen et al., Brain Struct. and Funct., 2012)
Normal Sensory Experience Sensory-deprived
Effect of sensory deprivation on pyramidal neurons of the rat barrel cortex
For sensory-deprived, whiskers are trimmed every day since birth for 1 month
*In pyramidal neuron, more than 40% of total surface area is made out of spines (~20,000)
*Spines are dynamic structures that regulate many neurochemical events related to synaptic transmission and modulate synaptic efficacy
Cellullar components: NEURON Golgi staining
Spines undergo pathologic alterations and reduced number in many developmental, neurologic, and psychiatric illnesses
• Dementing illnesses
• Chronic alcoholism
• Schizophrenia
• Trisomy 21 (Down syndrome)
• Trisomy 13 (Patau syndrome)
Cellullar components: NEURON
Trisomy 13-15(newborn)
Trisomy 21(18-month)
Normal gestation
(Kaufmann and Moser, Cerebral Cortex 2000)
5th gest. month 7th gest. month neonatal period 2nd postnatal month
8th postnatal month
• Neuroglia – “nerve glue” coined by Rudolph Virchow in 1859, non-neuronal cells in brain/SC
• Nonexcitable
• Supporting cells
• Previously thought 10x more glia than neurons (closer to 1:1)
• Make up 50% of the volume of the brain and SC
• Highly diverse functions
• CNS) Oligodendrocytes, Astrocytes (Radial Glia), Microglia, Ependymal Cells
• PNS) Schwann Cells, Satellite Glial Cells
1. Oligodendrocytes / Schwann cells• Myelinate axons
2. Astrocytes• Maintenance of neuronal physiology and extracellular environment
• Secrete trophic factors
• In development, guide neurons
• Help form BBB (structure interposed between the circulatory system and brain substance – serves as the molecular gateway to brain tissue)
• Regulate local vascular tone
3. Microglia• Reactive microglia
4. Ependymal Cells• Production/regulation of CSF
Cellullar components: GLIA
1
2
3
4
Neuron
Neuron
• Neuroglia – “nerve glue” coined by Rudolph Virchow in 1859, non-neuronal cells in brain/SC
• Nonexcitable
• Supporting cells
• Previously thought 10x more glia than neurons (closer to 1:1)
• Make up 50% of the volume of the brain and SC
• Highly diverse functions
• CNS) Oligodendrocytes, Astrocytes (Radial Glia), Microglia, Ependymal Cells
• PNS) Schwann Cells, Satellite Glial Cells
1. Oligodendrocytes / Schwann cells• Myelinate axons
2. Astrocytes• Maintenance of neuronal physiology and extracellular environment
• Secrete trophic factors
• In development, guide neurons
• Help form BBB (structure interposed between the circulatory system and brain substance – serves as the molecular gateway to brain tissue)
• Regulate local vascular tone
3. Microglia• Reactive microglia
4. Ependymal Cells• Production/regulation of CSF
Cellullar components: GLIA
1
2
3
4
Neuron
Neuron
Cellullar components: GLIA Oligodendrocyte (CNS)
Invertebrates have large axon (squid giant axon) Thickness allows fast conduction (10-20 m/s)
No extracellular space or EC matrix
Cellullar components: GLIA Oligodendrocyte (CNS)
Invertebrates have large axon (squid giant axon) Thickness allows fast conduction (10-20 m/s)
Myelin sheath
• Myelin is made up of PM of the oligodendrocyte.
• At the end of each myelin segment, there’s a bare portion of the axon (called node of Ranvier).
• Myelin segments are called internodes.
• The main function of myelin is to insulate the axon to be able to have fast conduction.
• Cytoplasm is removed between each turn of myelin to optimize space.
• Neuroglia – “nerve glue” coined by Rudolph Virchow in 1859, non-neuronal cells in brain/SC
• Nonexcitable
• Supporting cells
• Previously thought 10x more glia than neurons (closer to 1:1)
• Make up 50% of the volume of the brain and SC
• Highly diverse functions
• CNS) Oligodendrocytes, Astrocytes (Radial Glia), Microglia, Ependymal Cells
• PNS) Schwann Cells, Satellite Glial Cells
1. Oligodendrocytes / Schwann cells• Myelinate axons
2. Astrocytes• Maintenance of neuronal physiology and extracellular environment
• Secrete trophic factors
• In development, guide neurons
• Help form BBB (structure interposed between the circulatory system and brain substance – serves as the molecular gateway to brain tissue)
• Regulate local vascular tone
3. Microglia• Reactive microglia
4. Ependymal Cells• Production/regulation of CSF
Cellullar components: GLIA
1
2
3
4
Neuron
Neuron
Membrane (cytoplasm)Intermediate filaments
“stellate”
Neuron
Cellullar components: GLIA Astrocytes (CNS)
Astrocytes – described as “star-shaped”
• Constitute 20-50% of volume of most brain areas.
• Appear stellate when labeling intermediate filaments.
• Extensive, complex morphology when entire cytoplasm is visualized.
• Envelop neuropil elements (neurons and synapses).
Cellullar components: GLIA Astrocytes (CNS)
Protoplasmic astrocytes (gray matter)
Fibrous astrocytes (white matter)
Bergmann glial cells
Protoplasmic astrocytes (gray matter)• Processes pass between neuron cell bodies.• Processes are shorter, thicker, more branched.• Store glycogen, phagocytic function, conduit for
metabolites, produce trophic substances.
Fibrous astrocytes (white matter)• Processes pass between nerve fibers.• Each process is long, slender and smooth.• Provide supporting framework, are electrical
insulators, limit spread of NT, take up K+.
Astrocytes in human cerebellar cortex
• The two main forms, protoplasmic and fibrous astrocytes, predominate in gray and white matter, respectively. Most express glial fibrillary acidic protein (GFAP).
Cellullar components: GLIA Astrocytes (CNS)
Bergmann glial cells
Protoplasmic astrocytes (gray matter)
Fibrous astrocytes (white matter)
• The two main forms, protoplasmic and fibrous astrocytes, predominate in gray and white matter, respectively. Most express glial fibrillary acidic protein (GFAP).
• Embryonically, astrocytes develop from radial glial cells, which transversely compartmentalize the neural tube.
• Radial glial cells serve as scaffolding for the migration of neurons and play a critical role in defining the cytoarchitecture of the CNS.
• As the CNS matures, radial glia retract their processes and serve as progenitors of astrocytes.
• Some specialized astrocytes of a radial nature are still found in the adult cerebellum (Bergmann glial cells) and the retina (Müller cells).
Astrocytes in human cerebellar cortex
Protoplasmic astrocytes (gray matter)• Processes pass between neuron cell bodies.• Processes are shorter, thicker, more branched.• Store glycogen, phagocytic function, conduit for
metabolites, produce trophic substances.
Fibrous astrocytes (white matter)• Processes pass between nerve fibers.• Each process is long, slender and smooth.• Provide supporting framework, are electrical
insulators, limit spread of NT, take up K+.
More Common Cephalic Disorders:• Anencephaly• Colpocephaly• Holoprosencephaly• Ethmocephaly• Hydranencephaly• Iniencephaly• Lissencephaly• Megalencephaly• Microcephaly• Porencephaly• Schizencephaly
Can you rule out 3 or 4 of these disorders from the MRI scan?
Lissencephaly – from Greek lissos (“smooth”), affects 4 in 10 million
• Significant developmental delays, but these vary greatly from child to child depending on the degree of brain malformation and seizure control.
• Caused by defective neuronal migration during 12th-24th weeks of gestation (disrupted radial and tangential migration, neurons fail to reach cortical zone).
• Reduced development of gyri and sulci.
• Agyria (no gyri) and pachygyria (broad gyri) used to describe the brain.
• Treatment tailored towards individual symptoms, control seizures.
More Common Cephalic Disorders:• Anencephaly• Colpocephaly• Holoprosencephaly• Ethmocephaly• Hydranencephaly• Iniencephaly• Lissencephaly• Megalencephaly• Microcephaly• Porencephaly• Schizencephaly
Lissencephalic brain of human, lacking gyrification
Can you rule out 3 or 4 of these disorders from the MRI scan?
Cellullar components: GLIA Astrocytes (CNS)
Neuron
Processes spread from outer to inner surfaces of CNS, forming the outer and inner glial limiting membranes (beneath pia mater and ependyma, respectively).
• Astrocytes have in common unique cytological and immunological properties that make them easy to identify, including their star shape, the glial end feet on capillaries, and a unique population of large bundles of intermediate filaments that are composed of an astroglial-specific protein commonly referred to as glial fibrillary acidic protein (GFAP). S-100, a Ca2+-binding protein, and glutamine synthetase are also astrocyte markers.
• Astrocytes are connected to each other, and to oligodendrocytes, by gap junctions, forming a syncytium that allows ions and small molecules to diffuse across the brain parenchyma.
Astrocytes are involved in the neurovascular system.
• For a long time, astrocytes were thought to physically form the BBB, which prevents the entry of cells and diffusion of molecules into the CNS. In fact, astrocytes are indeed the BBB in lower species.
• However, in higher species, astrocytes are responsible for inducing and maintaining the tight junctions in endothelial cells that effectively form the barrier.
• Astrocytes also take part in angiogenesis, which may be important in the development and repair of the CNS. Their role in this important process is still poorly understood.
• Astrocyte astrocytic endfeet on blood vessels regulate vascular tone locally (increasing/decreasing CBF).
Astrocytes release EM proteins, adhesion molecules, growth factors and cytokines.
• Astrocytes are a major source of EM proteins and adhesion molecules in the CNS that participate in the migration of neurons, and in the formation of neuronal aggregates (nuclei), as well as networks.
• Astrocytes produce, in vivo and in vitro, a very large number of growth factors. These factors act singly or in combination to selectively regulate the morphology, proliferation, differentiation, and/or survival of distinct neuronal subpopulations.
• Most of the growth factors also act in a specific manner on the development and functions of astrocytes and oligodendrocytes. The production of growth factors and cytokines by astrocytes and their responsiveness to these factors is a major mechanism underlying the developmental function and regenerative capacity of the CNS.
Astrocytes Have a Wide Range of Functions
Cellullar components: GLIA Astrocytes (CNS)
Prevent excitotoxicity and clean up environment around neurons
• During neurotransmission, NTs and ions released at high concentrations in the synaptic cleft. The rapid removal of these substances is important so that they do not interfere with synaptic activity. The presence of astrocyte processes around synapses positions them well to regulate NT uptake and inactivation. GLU reuptake is performed mostly by astrocytes, which convert GLU into GLN and then release it into the extracellular space. GLN is taken up by neurons, which use it to generate GLU and GABA.
• Astrocytes contain ion channels for K+, Na+, Cl-, HCO3-, and Ca2+, as well as displaying a wide range of NT receptors.
• Astrocytic spatial buffering: K+ ions released from neurons during neurotransmission are soaked up by astrocytes and moved away from the area through astrocyte gap junctions.
• Astrocytes play a major role in detoxification of the CNS by sequestering metals and a variety of neuroactive substances of endogenous and xenobiotic origin.
Astrocytes: From passive glue to excitable cells
• Astrocytic Ca2+ are controversial. In response to stimuli, intracellular Ca2+ waves are generated in astrocytes. Propagation of the Ca2+ wave can be visually observed as it moves across the cell soma and from astrocyte to astrocyte. The generation of Ca2+ waves from cell to cell is thought to be mediated by second messengers, diffusing through gap junctions.
• In the adult brain, gap junctions are present in all astrocytes. Some gap junctions also have been detected between astrocytes and neurons. Thus, they may participate, along with astroglial NT receptors, in the coupling of astrocyte and neuron physiology.
Astrocytes are implicated in CNS conditions
• In neurotoxicity, viral infections, neurodegenerative disorders, HIV, AIDS, dementia, MS, inflammation, and trauma, astrocytes react by becoming hypertrophic and, in a few cases, hyperplastic.
• A rapid and huge upregulation of GFAP expression and filament formation is associated with astrogliosis. The formation of reactive astrocytes can spread very far from the site of origin. For instance, a localized trauma can recruit astrocytes from as far as the contralateral side, suggesting the existence of soluble factors in the mediation process. Tumor necrosis factor (TNF) and ciliary neurotrophic factors (CNTF) have been identified as key factors in astrogliosis.
Astrocytes Have a Wide Range of Functions (continued)
• Neuroglia – “nerve glue” coined by Rudolph Virchow in 1859, non-neuronal cells in brain/SC
• Nonexcitable
• Supporting cells
• Previously thought 10x more glia than neurons (closer to 1:1)
• Make up 50% of the volume of the brain and SC
• Highly diverse functions
• CNS) Oligodendrocytes, Astrocytes (Radial Glia), Microglia, Ependymal Cells
• PNS) Schwann Cells, Satellite Glial Cells
1. Oligodendrocytes / Schwann cells• Myelinate axons
2. Astrocytes• Maintenance of neuronal physiology and extracellular environment
• Secrete trophic factors
• In development, guide neurons
• Help form BBB (structure interposed between the circulatory system and brain substance – serves as the molecular gateway to brain tissue)
• Regulate local vascular tone
3. Microglia• Reactive microglia
4. Ependymal Cells• Production/regulation of CSF
Cellullar components: GLIA
1
2
3
4
Neuron
Neuron
Normal brainResting microglia
Diseased CortexActivated/Reactive microglia
Frank PathologyPhagocytic macrophages
Cellullar components: GLIA Microglia
Microglia – specialized macrophages, respond to inflammation, phagocytize necrotic tissue, and foreign substances that invade the CNS. • Microglia Become Activated in Pathological States. “Reactive” microglia can be distinguished from resting microglia by two criteria: (1) change in
morphology and (2) upregulation of monocyte–macrophage molecules. Although the two phenomena generally occur together, reactive responses of microglia can be diverse and restricted to subpopulations of cells within a microenvironment.
• Microglia not only respond to pathological conditions involving immune activation, but also become activated in neurodegenerative conditions that are not considered immunity-mediated. This latter response is indicative of the phagocytic role of microglia. Microglia change their morphology and antigen expression in response to almost any form of CNS injury.
Microglia Have Diverse Functions in Developing and Mature Nervous Tissue • Most ramified microglial cells are derived from bone marrow–derived monocytes, which enter the brain parenchyma during early stages of brain
development. These cells help break down degenerating cells that undergo programmed cell death as part of normal development. They retain the ability to divide and have the immunophenotypic properties of monocytes and macrophages.
• In addition to their role in remodeling the CNS during early development, microglia secrete cytokines and growth factors that are important in fiber tract development, gliogenesis, and angiogenesis.
• Neuroglia – “nerve glue” coined by Rudolph Virchow in 1859, non-neuronal cells in brain/SC
• Nonexcitable
• Supporting cells
• Previously thought 10x more glia than neurons (closer to 1:1)
• Make up 50% of the volume of the brain and SC
• Highly diverse functions
• CNS) Oligodendrocytes, Astrocytes (Radial Glia), Microglia, Ependymal Cells
• PNS) Schwann Cells, Satellite Glial Cells
1. Oligodendrocytes / Schwann cells• Myelinate axons
2. Astrocytes• Maintenance of neuronal physiology and extracellular environment
• Secrete trophic factors
• In development, guide neurons
• Help form BBB (structure interposed between the circulatory system and brain substance – serves as the molecular gateway to brain tissue)
• Regulate local vascular tone
3. Microglia• Reactive microglia
4. Ependymal Cells• Production/regulation of CSF
Cellullar components: GLIA
1
2
3
4
Neuron
Neuron
Ependymal cells (ependymocytes) are the thin neuroephithelial lining of ventricular system of the brain and the central canal of the spinal cord.
Specialized forms of ependymal cells make up the choroid plexus that produces and secretes CSF.
Cilia of ependymal cells help move CSF through the cavities of the brain.
These are nervous tissue cells with a ciliated simple columnar shape much like that of some mucosal epithelial cells. The basal membranes of these cells are characterized by tentacle-like extensions that attach to astrocytes.
Cellullar components: GLIA Ependymal Cells
Section of central canal of the spinal cord
Cellullar components: GLIA Schwann Cell (PNS)
How are Schwann cells different than Oligodendrocytes?
Schwann cells
• Produce a basal lamina “sleeve” that runs the entire length of the axon.
• Schwann cell and fibroblast-derived collagens prevent normal wear-and-tear compression damage.
• Respond vigorously to injury (like astrocytes, unlike OG).
• Exceptional regenerative capacity of PNS (due to growth factor secretion, debris removal after injury, basal lamina axonal guidance).
• Myelination provides trophic support that is essential for axon survival.
• Studies of primary demyelinating diseases, such as multiple sclerosis, and genetic dysmyelinating diseases (e.g., Charcot-Marie-Tooth diseases) indicate that axonal degeneration is the major cause of permanent disability.
“Unrolled” Schwann cell in the PNS in relation to the single axon segment that it myelinates
Compact myelin
Cytoplasmic channels
• Myelin in the PNS is generated by Schwann cells – principal glia of the PNS.
• Cytoplasmic channels remain open even after compact myelin has formed allowing exchange of materials among the myelin sheath, Schwann cell cytoplasm, and axon.
**Peripheral nerves pass between moving muscles and around major joints and are routinely exposed to physical trauma. A hard tackle, slipping on an icy sidewalk, or even just occupying the same uncomfortable seating posture for too long can painfully compress peripheral nerves and potentially damage them. Thus, evolutionary pressures shaping the PNS favor robustness and regeneration rather than conservation of space.
Cellullar components: GLIA Satellite Glial Cells (PNS)
Satellite glial cells (SGCs) are homologous to astrocytes in the CNS
• SGCs are glial cells that cover the surface of nerve cell bodies in sensory, sympathetic, and parasympathetic ganglia (like Schwann cells are derived from the neural crest of the embryo during development).
• SGCs have a significant role in controlling the microenvironment of sympathetic ganglia (based on the observation that SGCs almost completely envelop the neuron and can regulate the diffusion of molecules across the PM).
• Homologous role to astrocytes in the CNS; they share anatomical and physiological/electrical properties, presence of NT transporters (for GABA and GLU), and glutamine synthetase (GS), which catalyzes the conversion of GLU into GLN.
• Although SGCs express GFAP and different S-100 proteins, the most useful marker for SGC identification is GS. The levels of GS are relatively low at rest, but they greatly increase if the neuron undergoes axonal damage. Furthermore, SGCs also possess mechanisms to release cytokines, ATP, and other chemical messengers.
• Additionally, SGCs contain the glutamate related enzymes glutamate dehydrogenase and pyruvate carboxylase, and thus can supply the neurons with GLN, malate, and lactate.
• Gap junctions exist between SGCs in the sheaths of adjacent neurons as well as between SGCs in the same sheath (reflexive gap junctions). The degree to which SGCs are coupled to SGCs of another sheath or to SGCs of the same sheath is dependent on the pH of the cellular environment.
• SGCs 1) supply nutrients to the surrounding neurons, 2) have some structural function, 3) act as protective, cushioning cells, 4) express a variety of receptors (e.g. mAChR, ErythropoietinR) that allow for a range of interactions with neuroactive chemicals (i.e. Ach, GABA, GLU, ATP, NA, substance P, capsaicin), 5) speculation that in autonomic ganglia have a similar role to the BBB as a functional barrier to large molecules.
• Many of SGC receptors and ion channels have recently been implicated in health issues including chronic pain and herpes simplex.
• There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.
Wikipedia
Normal Brain Alzheimer’s DiseaseThe amyloid (Aβ ) cascade hypothesis
(Barage and Sonawane, Peptides, 2015)
Early role of vascular dysregulation on late-onset AD based on multifactorial data-driven analysis (Y. Iturria-Medina et al. & The Alzheimer’s Neuroimaging Initiative, Montreal, CA)
In cohort of 1,171 subjects (over 7,700 brain images) from the ADNI database, evaluated: 1. Aβ misfolded proteins (Florbetapir PET)
2. Glucose metabolism (Fluorodeoxyglucose)
3. Cerebral blood flow (Arterial Spin Labeling)
4. Functional activity (Resting MRI)
5. Structural tissue brain patterns (Structural MRI)
*(mapped in vivo using corresponding neuroimaging techniques)
Diagnosed as:
• healthy control (HC)
• early mild cognitive impairment (EMCI)
• late mild cognitive impairment (LMCI)
• probable Alzheimer’s disease patient (LOAD)
(Iturria-Medina et al., Nat Comm., 2016)
(Iturria-Medina et al., Nat Comm., 2016)
In cohort of 1,171 subjects (over 7,700 brain images) from the ADNI database, evaluated: 1. Aβ misfolded proteins (Florbetapir PET)
2. Glucose metabolism (Fluorodeoxyglucose)
3. Cerebral blood flow (Arterial Spin Labeling)
4. Functional activity (Resting MRI)
5. Structural tissue brain patterns (Structural MRI)
*(mapped in vivo using corresponding neuroimaging techniques)
Diagnosed as:
• healthy control (HC)
• early mild cognitive impairment (EMCI)
• late mild cognitive impairment (LMCI)
• probable Alzheimer’s disease patient (LOAD)
Early role of vascular dysregulation on late-onset AD based on multifactorial data-driven analysis (Y. Iturria-Medina et al. & The Alzheimer’s Neuroimaging Initiative, Montreal, CA)
Cellullar components: Vascular Cells
Cortical layers (I-VI)
Corpus Callosum
Microvasculature of adult mouse somatosensory barrel field cortex
Arrow points to area of increased vascular density in layer IV, where contralateral somatosensory inputs from the thalamus terminate.
• The cerebral vasculature delivers O2, glucose, and nutrients into the brain and removes CO2 and other metabolic wastes.
• Endothelial cells interact with neurons, astrocytes, microglia, and other perivascular cells, including smooth muscle cells and pericytes to form a neurovascular unit (NVU).
• Glucose is the main metabolic substrate of neurons, but it cannot cross the BBB. Glucose transporters on endothelial cells and glia supply glucose to brain.
Cellullar components: Vascular Cells
Different cell types of the neurovascular unit regulate cerebral blood flow (CBF) at different levels of the vascular tree
Penetrating artery – 2-3 layers of vascular smooth muscle cells (VSMCs) and astrocytes are innervated by neurons.
Arterioles – only 1 layer of VSMC. Contain transitional pericytes (a cell type between pericytes and VSMCs).
Capillaries – endothelial cells share common basement membrane with pericytes, both covered by astrocytic endfeet. Astrocytes and pericytesinnervated by local neurons.
Cellullar components: Vascular CellsUltrastructural analysis of PFC microvasculature of a
10-month-old wild-type mouse.
Morphological identification of pericytes
• Pericyte on a rat capillary• Label basement membrane with fluorescently-tagged isolectin B4• Soma exhibit classical “bump-on-a-log” appearance
Cellullar components: Vascular Cells Oligomeric Aβ acts on pericytes to constrict capillaries in human brain slices
Ultrastructural analysis of PFC microvasculature of a 10-month-old wild-type mouse.
Morphological identification of pericytes
• Pericyte on a rat capillary• Label basement membrane with fluorescently-tagged isolectin B4• Soma exhibit classical “bump-on-a-log” appearance
Slow axonal transport represents the delivery of cytoskeletal and cytoplasmic constituents to the periphery.
• Cytoplasmic proteins are synthesized on free polysomes and organized for transport as cytoskeletal elements or macromolecular complexes (1).
• Microtubules are formed by nucleation at the microtubule-organizing center near the centriolarcomplex (2) and then released for migration into the axon or dendrites.
• The molecular mechanisms are not as well understood as those for fast axonal transport, but slow transport appears to be unidirectional with no retrograde component.
• Studies suggest that motors like cytoplasmic dynein may interact with the axonal membrane cytoskeleton to move the microtubules with their plus ends leading (3).
• Neurofilaments may not be able to move on their own but may hitchhike on microtubules (4).
• Other cytoplasmic proteins may do the same or may be moved by other motors. Once cytoplasmic structures reach their destinations, they are degraded by local proteases (5) at a rate that allows either growth (in the case of growth cones) or maintenance of steady-state levels.
• The different composition and organization of the cytoplasmic elements in dendrites suggest that different pathways may be involved in the delivery of cytoskeletal and cytoplasmic materials to the dendrite (6). In addition, some mRNAs are transported into the dendrites, but not into axons.
Cytoskeleton – Cytoskeletal Proteins – give the cells their shape and provide mechanical resistance to deformation
Neuronal cytoskeletal changes are an early consequence of repetitive head injuryCase 1A professional boxer aged 23 at death who had started boxing at 11 years of age, and turned professional at the age of 19. He had approximately 80 fights at amateur level, and 20 fights (totaling 105 rounds) in his 4 years as a professional. He had no history of a severe head injury during his career, until his final fight, as a result of which he developed an acute subdural haematoma. He died 48 h after the contest, despite neurosurgical intervention.
Case 2A former boxer had a history of psychotic illness, and was 28 years old at death. He had been an amateur boxer since leaving school at 16, and had fought regularly at local club level, at the rate of one fight every 3 months for 4–5 years. He stopped boxing at the age of 21 as he had suffered from haematuria after contests. At the age of 20 he was admitted to a psychiatric hospital with a diagnosis of paranoid schizophrenia which responded to major tranquillisers. He was readmitted with an acute psychotic illness at the age of 25, this type more depressive in nature, and then again 2 years later. He died unexpectedly the following year during a grand mal seizure. He had no history of a serious head injury during his boxing career.
C A cortical vessel in the temporal lobe of case 1. D A vessel at the base of a sulcus in the insula in case 2.
**It appears that repetitive head injury in young adults is initially associated with neocortical NFT formation in the absence of Aβ deposition.**
**immunostaining included β-amyloid precursor protein, amyloid β-protein (Aβ), tau and apolipoprotein E (apoE). Pathological findings in all cases were of neocortical neurofibrillary tangles (NFTs) and neuropil threads, with groups of tangles consistently situated around blood vessels in the worst affected regions. No Aβ immunoreactivity was detected.
(Geddes et al., Acta Neuropathol., 1999)
Pugilistica dementia
Questions?
Cytoskeleton – Cytoskeletal Proteins – give the cells their shape and provide mechanical resistance to deformation
Basic elements of neuronal subcellular organization. The neuron consists of a soma, or cell body, in which the nucleus, multiple cytoplasm-filled processes termed dendrites, and the (usually single) axon are placed. The neuron is highly extended in space; a neuron with a cell body of the size shown here could easily maintain an axon several miles in length! The unique shape of each neuron is the result of a cooperative interplay between plasma membrane components (the lipid matrix and associated proteins) and cytoskeletal elements. Most large neurons in vertebrates are myelinated by oligodendrocytes in the CNS and by Schwann cells in the in the PNS. The compact wraps of myelin encasing the axon distal to the initial segment permit the rapid conduction of the AP by a process termed “saltatory conduction”.
From Wikipedia
CNS) AstrocytesOligodendrocytes Microglia
PNS) Schwann cells
Fast axonal transport represents the transport of membrane-associated materials, having both anterograde and retrograde components.• For anterograde transport, most polypeptides are synthesized on membrane-bound polysomes, also
known as rough endoplasmic reticulum (1), and then transferred to the Golgi apparatus for processing and packaging into specific classes of membrane-bound organelles (2). Proteins following this pathway include both integral membrane proteins and secretory polypeptides in the lumen of vesicles. Cytoplasmic peripheral membrane proteins such as kinesins are synthesized on the cytoplasmic or free polysomes.
• Once vesicles have been assembled and the appropriate motors associate with them, they are moved down the axon at a rate of 100–400 mm per day (3).
• Different membrane structures are delivered to different compartments and may be regulated independently. For example, dense core vesicles and synaptic vesicles are both targeted for the presynaptic terminal (4), but the release of vesicle contents involves distinct pathways.
• After vesicles merge with the plasma membrane, their protein constituents are taken up by coated pits and vesicles via the receptor-mediated endocytic pathway and delivered to a sorting compartment (5).
• After proper sorting into appropriate compartments, membrane proteins are either committed to retrograde axonal transport or recycled (6).
• Retrograde moving organelles are morphologically and biochemically distinct from anterograde vesicles. These larger vesicles have an average velocity about half that of anterograde transport. The retrograde pathway is an important mechanism for the delivery of neurotrophic factors to the cell body. Material delivered by retrograde transport typically fuses with cell body compartments to form mature lysosomes (7), where most constituents are recycled. However, neurotrophic factors and neurotrophic viruses can act at the level of the cell body.
• Although evidence shows that vesicle transport also occurs into dendrites (8), less is known about this process. Dendritic vesicle transport is complicated by the fact that dendritic microtubules may have mixed polarity.
Axonal dynamics in a myelinated axon from the peripheral nervous system (PNS). Axons are in a constant flux with many concurrent dynamic processes. This diagram illustrates a few of the many dynamic events occurring at a node of Ranvier in a myelinated axon from the PNS. Axonal transport moves cytoskeletal structures, cytoplasmic proteins, and membrane-bound organelles from the cell body toward the periphery (from right to left). At the same time, other vesicles return to the cell body by retrograde transport (retrograde vesicle). Membrane-bound organelles are moved along microtubules by motor proteins such as the kinesins and cytoplasmic dyneins. Each class of organelles must be directed to the correct functional domain of the neuron. Synaptic vesicles must be delivered to a presynaptic terminal to maintain synaptic transmission. In contrast, organelles containing sodium channels must be targeted specifically to nodes of Ranvier for saltatory conduction to occur. Cytoskeletal transport is illustrated by microtubules (rods in the upper half of the axon) and neurofilaments (bundle of rope-like rods in the lower half of the axon) representing the cytoskeleton. They move in the anterograde direction as discrete elements and are degraded in the distal regions. Microtubules and neurofilaments interact with each other transiently during transport, but their distribution in axonal cross sections suggests that they are not stably cross-linked. In axonal segments without compact myelin, such as the node of Ranvier or following focal demyelination, a net dephosphorylation of neurofilament side arms allows the neurofilaments to pack more densely. Myelination is thought to alter the balance between kinase (K indicates an active kinase; k is an inactive kinase) and phosphatase (P indicates an active phophatase; p is an inactive phosphatase) activity in the axon. Most kinases and phosphatases have multiple substrates, suggesting a mechanism for targeting vesicle proteins to specific axonal domains. Local changes in the phosphoryation of axonal proteins may alter the binding properties of proteins. The action of synapsin I in squid axoplasm suggests that dephosphorylated synapsin cross-links synaptic vesicles to microfilaments. When a synaptic vesicle encounters the dephosphorylated synapsin and actin-rich matrix of a presynaptic terminal, the vesicle is trapped at the terminal by inhibition of further axonal transport, effectively targeting the synaptic vesicle to a presynaptic terminal. Similarly, a sodium channel-binding protein may be present at nodes of Ranvier in a high-affinity state (i.e., dephosphorylated). Transport vesicles for nodal sodium channels (Na channel vesicle) would be captured upon encountering this domain, effectively targeting sodium channels to the nodal membrane. Interactions between cells could in this manner establish the functional architecture of the neuron.