Transcript The Nervous System

Neuroglia
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Outnumber neurons by about
10 to 1 (Einstein had an inordinate
amount of them).
6 types of supporting cells
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1.
4 are found in the CNS:
Astrocytes
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Star-shaped, abundant, and
versatile
Guide the migration of
developing neurons
Act as K+ and NT buffers
Involved in the formation of the
blood brain barrier
Function in nutrient transfer
Neuroglia
2. Microglia
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Specialized immune cells that act
as the macrophages of the CNS
Why is it important for the CNS to
have its own army of immune
cells?
3. Ependymal Cells
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Low columnar epithelial-esque
cells that line the ventricles of the
brain and the central canal of the
spinal cord
Some are ciliated which
facilitates the movement of
cerebrospinal fluid
Neuroglia
4. Oligodendrocytes
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Produce the
myelin
sheath
which
provides the
electrical
insulation for
certain
neurons in
the CNS
Neuroglia
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2 types of glia in the
PNS
1. Satellite cells
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Surround clusters of
neuronal cell bodies in the
PNS
Unknown function
2. Schwann cells
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Form myelin sheaths
around the larger nerve
fibers in the PNS.
Vital to neuronal
regeneration
Neurons
• The functional and structural unit
of the nervous system
• Specialized to conduct information from one part of the
body to another
• There are many, many different types of neurons but most
have certain structural and functional characteristics in
common:
- Cell body (soma)
- One or more
specialized, slender
processes
(axons/dendrites)
- An input region
(dendrites/soma)
- A conducting
component (axon)
- A secretory (output)
region (axon terminal)
Soma
• Contains nucleus plus most
normal organelles.
• Biosynthetic center of the
neuron.
• Contains a very active and
developed rough endoplasmic
reticulum.
– The neuronal rough ER is
referred to as the Nissl body.
• Contains many bundles of
protein filaments (neurofibrils)
which help maintain the shape,
structure, and integrity of the
cell.
In the soma above, notice the small
black circle. It is the nucleolus, the site
of ribosome synthesis. The light
circular area around it is the nucleus.
The mottled dark areas found
throughout the cytoplasm are the Nissl
substance.
Somata
• Contain multiple
mitochondria.
• Acts as a receptive service for interaction
with other neurons.
• Most somata are found in the bony
environs of the CNS.
• Clusters of somata in the CNS are known
as nuclei. Clusters of somata in the PNS
are known as ganglia.
Neuronal Processes
• Armlike extensions emanating from every neuron.
• The CNS consists of both somata and processes whereas
the bulk of the PNS consists of processes.
• Tracts = Bundles of processes in the CNS (red arrow)
Nerves = Bundles of processes in the PNS
• 2 types of processes that differ in structure and function:
– Dendrites and Axons
• Dendrites are thin, branched processes whose main
function is to receive incoming signals.
• They effectively increase the surface area of a neuron to
increase its ability to communicate with other neurons.
• Small, mushroom-shaped dendritic spines further increase
the SA
• Convey info towards the soma thru the use of graded
potentials – which are somewhat similar to action potentials.
Notice the multiple
processes extending
from the neuron on the
right. Also notice the
multiple dark circular
dots in the slide. They’re
not neurons, so they
must be…
• Most neurons have a single
axon – a long (up to 1m)
process designed to convey
info away from the cell body.
• Originates from a special
region of the cell body called
the axon hillock.
• Transmit APs from the soma
toward the end of the axon
where they cause NT release.
• Often branch sparsely, forming
collaterals.
• Each collateral may split into
telodendria which end in a
synaptic knob, which contains
synaptic vesicles –
membranous bags of NTs.
Axons
• Axolemma = axon
plasma membrane.
• Surrounded by a myelin
sheath, a wrapping of lipid
which:
– Protects the axon and electrically isolates it
– Increases the rate of AP transmission
• The myelin sheath is made by Oligodendrocytes in the
CNS and by Schwann cells in the PNS.
• This wrapping is never complete. Interspersed along the
axon are gaps where there is no myelin – these are nodes
of Ranvier.
• In the PNS, the exterior of the Schwann cell surrounding an
axon is the neurilemma
Myelination in the CNS
Myelination in the PNS
• A bundle of processes in the PNS is a nerve.
• Within a nerve, each axon is surrounded by an
endoneurium (too small to see on the photomicrograph) –
a layer of loose CT.
• Groups of fibers
are bound
together into
bundles
(fascicles) by a
perineurium (red
arrow).
• All the fascicles
of a nerve are
enclosed by a
epineurium
(black arrow).
Types of Nerve Fibers
1.
Group A
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2.
Axons of the somatic sensory neurons and motor neurons
serving the skin, skeletal muscles, and joints.
Large diameters and thick myelin sheaths.
Group B
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3.
Type B are lightly myelinated and of intermediate diameter.
Group C
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Type C are unmyelinated and have the smallest diameter.
Autonomic nervous system fibers serving the visceral organs,
visceral sensory fibers, and small somatic sensory fibers are
Type B and Type C fibers.
What is Blood Brain Barrier?
• The BBB is formed by the single layer of
endothelial cells that line the inner surfaces of
capillaries in the brain.
• It is a semi-permeable capillary membrane;
that is, it allows some materials to cross, but
prevents others from crossing. In most parts of
the body the capillaries, are lined with
endothelial cells. The endothelial tissue has
small spaces between each individual cell so
substances can move readily between the
inside and the outside of the vessel. However,
in the brain, the endothelial cells fit tightly
together and substances cannot pass out of the
bloodstream. (Some molecules, such as
glucose, are transported out of the blood by
special methods such as active transport.)
What is the Blood Brain Barrier?
• Structural and functional barrier which impedes
and regulates the influx of most compounds from
blood to brain
• Formed by brain microvascular endothelial cells
(BMEC), astrocyte end feet and pericytes
• Essential for normal function of CNS
• Regulates passage of molecules in and out of
brain to maintain neural environment.
• Responsible for metabolic activities such as the
metabolism of L-dopa to regulate its
concentration in the brain.
Structure of Blood Brain Barrier
Source: Bock et al
Differences between BMEC and normal
endothelial cells
• Structural differences:
– Absence of fenestrations
– More extensive tight junctions (TJ)
• Functional differences:
– Impermeable to most substances
– Sparse pinocytic vesicular transport
– Increased expression of transport and carrier
proteins: receptor mediated endocytosis
– No gap junctions, only tight junctions
– Limited paracellular and transcellular transport
Functions and Properties of the
BBB
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The BBB has several important functions:
1. Protects the brain from "foreign substances" in the blood
that may injure the brain.
2. Protects the brain from hormones and neurotransmitters
in the rest of the body.
3. Maintains a constant environment for the brain.
Functions and Properties of the
BBB
• General Properties of the BBB
1. Large molecules do not pass through the BBB easily.
2. Low lipid (fat) soluble molecules do not penetrate into the brain.
However, lipid soluble molecules rapidly cross the BBB into the brain.
3. Molecules that have a high electrical charge to them are slowed.
• Therefore:
– The BBB is selectively permeable to :Oxygen, Carbon dioxide and
glucose
– The BBB is not permeable to
hydrogen ions
Integrity of BBB
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Tight Junctions
Adherens Junctions
Pericytes
Astrocyte end feet
Tight Junctions between BMEC
Source: Ballabh et al
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Appear at sites of apparent fusion between outer leaflets of plasma
membrane of endothelial cells
Continuous
Anastomosing
Intramenbranous strands or fibrils on P face with complementary groove on
E face
Protein components:
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Claudin
Occludin
Junction Adhesion Molecules
Accessory proteins
Claudin
– 22kDa phosphoprotein
– 4 transmembrane domains
– localized in TJ strands
Source: Ballabh et al
Occludin
– 65kDa phosphoprotein,
– 1° structure very different from claudin
– Regulatory proteins: alters paracellular permeability.
Source: Ballabh et al
Barrier Function of Occludin and
Claudin
• Assemble into heteropolymers and form
intramembranous strands which contain
channels allowing selective diffusion of ions and
hydrophilic molecules.
• Breakdown of BBB in tissue surrounding brain
tumors occurs with concomitant loss of 55kDa
occludin expression
Junction Adhesion Molecules:
• 40kDa
• Integral membrane protein, single
transmembrane region
• Belongs to immunoglobulin superfamily
• Localizes at tight junctions
• Involved in cell-to-cell adhesion and monocyte
transmigration through BBB
• Regulates paracellular permeability and
leukocyte migration
• Also found on circulating leukocytes, platelets
and lymphoid organs.
BMEC intercellular space
Source: Ballabh et al
Barrier function of JAM
• Homotypic binding between JAM molecules on
adjacent endothelial cells acts as a barrier for
circulating leukocytes
• Heterotypic binding of endothelial JAM to
leukocyte JAM might guide transmigration of
leukocytes across interendothelial junctions
• So factors that decrease leukocyte migration
must either strengthen homotypic interactions or
weaken heterotypic interactions.
Cytoplasmic accessory proteins
• (ZO-1, ZO-2, ZO-3, cingulin etc)
– These link membrane proteins to actin
– maintenance of structural and functional
integrity of endothelium
– crosslink transmembrane proteins.
• Membrane associated guanylate kinaselike proteins (MAGUKS)
– subunits function as protein binding molecules
– role in organization the plasma membrane
Adherens Junction
• Complex between membrane protein cadherin
and intermediary proteins called catenins
• Cadherin-catenin complex joins to actin
cytoskeleton
• Form adhesive contacts between cells.
• Assemble via homophilic interactions between
extracellular domains of calcium ion dependent
cadherins on surface of adjacent cells
Pericytes:
• Cells of microvessels including capillaries, venules, and
arterioles that wrap around endothelial cells.
• Provide structural support and vasodynamic capacity to
microvasculature.
• Role in structural stability of vessel wall
• Endothelial cells associated with pericytes are more
resistance to apoptosis than isolated endothelial cells
– Indicates role of PC in structural integrity and genesis of the BBB
• Phagocytic activity
Astrocyte end feet
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Star shaped glial cells
Provides biochemical support for BMEC
Influence of morphogenesis and organization of vessel
wall
Factors released by astrocytes involved in postnatal
maturation of BBB
Direct contact between endothelial cells and astrocytes
necessary to generate BBB (Rubin et al, 1991)
Co-regulate function by the secretion of soluble
cytokines such as (LIF, leukemia inhibiting factor), Ca2+
dependent signals by intracellular IP-3 and gap
junction dependent pathways, and second messenger
pathways involving extracellular diffusion of purinergic
messenger.
Regions of brain not enclosed by BBB
• Circumventricular organs
– area postrema,
– median eminence,
– neurohypophysis,
– pineal gland,
– subfornical organ and
– lamina terminalis
These are regions which need to respond to
factors present in systemic circulation
Transport at the BBB
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There are five basic mechanisms by which solute
molecules move across membranes:
1.
2.
3.
4.
5.
simple diffusion
facilitated diffusion
simple diffusion through an aqueous channel
active transport through a protein carrier
Endocytosis
Transport mechanisms at the BBB. 1 = paracellular diffusion , 2 = transcellular diffusion , 3 = ion channel 4 = ion-symport
channel 5 = ion-antiport channel 6 = facilitated diffusion , 7 = active efflux pump 8 = active-antiport transport , 9 =
receptor mediated endocytosis
Diffusion
• Phospholipid bilayer
• Movement of substances down diffusion
gradient
• Transfer of lipophilic substances
– alcohol, nicotine, oxygen, carbon dioxide
Facilitated transport
• Carrier systems
– particular essential amino acids, glucose, these are
extremely specific
• transport D-glucose only,
• large neutral amino acids which act as precursors for
neurotransmitters,
• only which the brain cannot make,
• glycine: it can block the transmission of nerve signals, hence
special carrier which ensures that glycine can be removed
from brain
• Receptor mediated endocytosis
– Leptin, insulin, overlaps with carrier systems