Cellular Physiology of the Nervous System

Title

Cellular Physiology of the Nervous System

Module 1

Title Your Instructors

Sister Lisa ZuccarelliOP. Ph.D.

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Dr. Zuccarelli received her BA degree in Biology and Chemistry from Albertus Magnus College and her MS and PhD in Biology from New York University. She did post-doctoral studies at Georgetown University School of Medicine and was a faculty member at Georgetown University School of Medicine and the School of Nursing and Health studies from 1993-2003.

She is currently the Chair of the Department of Biology and Biomedical Sciences at Salve Regina University. She is interested in the regeneration of the nervous system and in biofeedback.

Title Introduction and Objectives

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Objectives

■ Describe the different types of cells in the nervous system

■ Identify the various structures of the neuron

■ Differentiate the type and structures of neurons

■ Differentiate the types and structures of glial cells

■ Identify the mechanisms of neurotransmission of impulses

■ Describe the specific functions of the numerous neurotransmitters

■ Describe the embryonic development of the nervous system

■ Relate the structure of the blood–brain barrier (BBB) to its function

This chapter will discuss the cellular anatomy and physiology of the nervous system.

Title

Module 1: Cellular Physiology of the Nervous System Part 1

Title Cellular Physiology

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Types of Cells in the Nervous System

Neurons Neuroglia

Functional units of the nervous system, modulated by cellular activity

Supportive and protective cells of the nervous system with a variety of functions

Excitable, capable of conducting electrical impulses throughout their lengths and across membrane gaps and synapses

Not excitable

Conduct electrical stimulus More glial cells than neurons

Classified by length, structure and function

Classified by cell body length, process,function and myelin-producing capabilities


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Typical Structure of a Neuron

■ Cell membrane Phospholipid bilayer capable of creating a membrane potential between inside and outside of cell Acquires and uses membrane potential to complete electrical functions Semipermeable to ions and other fat-soluble substances such as gas (oxygen, carbon dioxide) and alcohol Contains specialized ion channels, and gates to modify ion exchange across the membrane Transports and molecules inside the cell when needed, and exports them when they become toxic

■ Cytoskeleton (aligns with cell membrane to create processes and projections) Changes shape to cause growth and elaboration of a neuron Growth cones are supported by filaments and proteins which elongate the cell body This creates foot processes for the growth cones

▫ This is important for developing and targeting structures such as muscles▫ Muscles then enhance the relationship between themselves and neurons

A typical structure of a neuron consists of several main parts: the cell membrane, the cytoskeleton, the cell body, and projections.


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Typical Structure of a NeuronCytoskeleton (continued):

Cytoskeleton consists of several types of proteins:

■ Actin filaments Extend from tip of elongating ends of

neurons to produce a moving growth cone Maintain the general shape of the mature

axon

■ Microtubules and microtubule-associated proteins (MAPS) Important for maintaining the shape of all

neuronal processes Integrated with the ability to create

anterograde (forward) and retrograde (backward) movement of materials along the length of the axon

Cell body Where much of the biochemistry of the cell

occurs Nucleus

▫ Porous, membrane-bound, large, round structure.

▫ Includes genetic components of the cell – DNA, RNA

Cytoplasm: gel composed primarily of water▫ Gel-filled compartment holding complex

organelles and membranes▫ Contains, absorbs, and secretes

dissolved solutes, gases, and ions


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ORGANELLES MITOCHONDRIA

• One of the most important organelles • Double-membrane structure capable of numerous biochemical reactions• Outer membrane capable of transporting small molecules and ions• Able to use respiratory enzymes, such as adenosine diphosphate (ADP) and adenosine

triphosphate (ATP) to create an energy molecule • Energy molecules have potential to convert ADP to ATP under anaerobic and aerobic

conditions• Neurons that use a lot of energy to metabolize substances like glucose have a higher levels of

mitochondria compared to other cells

Typical Structure of a Neuron


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Typical Structure of a Neuron ENDOPLASMIC RETICULUM (ER)

• Set of convoluted membranes that provide surface area for protein and steroid synthesis Smooth ER

• Missing a number of dense color structures that accompany ribosomes• Produces proteins • Participates in the production of steroid hormones, membranes appear smooth in electron

micrographs Rough ER

• Has membranes studded with RNA-rich ribosomes that appear rough, clumpy and dark in electron micrographs (formerly called Nissl bodies)

• Participates in protein translation and posttranslational modification of messenger RNA into proteins• Modifying new proteins to be used in specific areas within the body for a variety of functions


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Typical Structure of a NeuronOnce proteins are made, they are transported to Golgi Bodies.

GOLGI BODIES (GOLGI APPARATUS)• Have stacks of disk-like membranes• Process and package posttranslational products of protein synthesis for

transport in and out of the cell

LYSOSOMES• Membrane-enclosed vesicles capable of endocytosis• Contain proteolytic enzymes used to digest protein fragments and other

intracellular debris• Clean up debris: capable of engulfing protein fragments or foreign bodies out

of the cell


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Typical Structure of a NeuronNeuronal projections and processes■ Dendrites Receive sensory or incoming information from receptive field Short processes with multiple projections that come off the cell body Occasionally present as an extensive elaboration called a dendritic tree Can be small and short to interact with each other Can be large, tree-like structures to connect with neurons around them and with the rest of

the body Receives information externally and conducts it to inside the cell body The cell body is capable of integrating a great number of sensory inputs From this information, the cell body creates an action That action is translated from one place to the next via another type of neuronal projection

called an Axon


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Typical Structure of a NeuronAxons

■ Can be quite long processes extending from the cell body▫ Divide at their terminal ends into several branches▫ Provides a surface area to connect with other cells:

terminal boutons and swellings• Such as neurons, muscle cells, excitable cells, or

glands

■ Have a number of ion channels, neurofibrals & transporters

■ Can conduct electrical impulses away from cell body

■ Transports materials and neurotransmitters via microtubules and MAPs in both anterograde and retrograde manner throughout axoplasm

■ Filled with numerous membrane-bound vesicles filled with neurotransmitters or neurotransmitters co-localized with peptides

■ Capable of releasing neurotransmitters and peptides from the terminal boutons onto synapses or other glands


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Typical Structure of a NeuronAxons can be covered in a substance called myelin. Not all are.

Those that are Myelins: Can conduct electrical signals faster than unmyelinated cells Tends to be a fatty substance: lipid-rich, electrically neutral,

insulating substance covering axons Found in both the central nervous system (CNS) and the

peripheral nervous system (PNS) Produced by glial cells (wrap the myelin around the nearby

neurons) In the PNS: secreted by Schwann cells to create a sheath In the CNS: secreted by oligodendrocytes to surround axons White matter in the brain and spinal cord is covered with myelin In motor neurons, unmyelinated gaps, called nodes of Ranvier,

are instrumental in propagating the impulse


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Types and Structures of Neurons

Unipolar have a small, round cell body with a central nucleus

• Found only in mammals during development

• Have only one process leaving the cell body

Bipolar are found only in adults▫ Produce two processes, one conducting

impulses to the cell body (dendrite) and the other conducting impulses toward the cell body (axon)

▫ Have an elongated soma with a large central nucleus

▫ Are primarily sensory in function, found in cranial nerves of the special senses

• Olfactory (CN I)• Optic (CN II)• Acoustic (CN VIII)

There are a variety of different types of neurons: unipolar, bipolar, pseudo-unipolar and multipolar.


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Types and Structures of NeuronsPseudo-unipolar■ One axonal process and a dendritic tree, which emanates from the cell body

formed by the fusion of the proximal ends of two processes■ A large soma with a central nucleus■ Primarily sensory in function

• Found in all cranial nerves except I, II, and VIII• Dendritic receptors that conduct impulses from the periphery to the spinal

ganglia, where cell bodies reside, to the spinal cord via the axonal processMultipolar■ Function primarily as motor neurons■ Most common in the nervous system■ Large cell bodies projecting numerous dendrites or elaborations that take on

various forms■ Cell bodies located in the CNS within the brain and spinal cord■ Long axons that conduct impulses from the CNS to glands, muscles, and other

effector organs


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Types and Structures of Neurons

■ Golgi type I, also called projection neurons Have axons several feet long and form

long descending white tracts Often form collaterals leading to a number

of areas▫ Motor neurons from spinal cord to the

muscles▫ Cortical neurons connecting to the

brain stem and the spinal cord▫ Function primarily as motor neurons

■ Golgi type II, also called interneurons Have short dendrites and axons Have multiple synapses on one or

more neuron, and be synapsed upon Can be Axo-axonal, Axo-dendritic Are usually found in the CNS, in the

brain or spinal cord Excite or inhibit transmission Modulate and mediate communication

between groups of cells Populate the cerebral cortex, the site

of complex signal integration

Neurons are also characterized by the length of processes.


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Types and Structures of NeuronsNeurons are also characterized by their functions: ■ Sensory or afferent Conduct impulses from the periphery

into the nervous system Have a wide variety of receptor

endings to conduct various modalities: ▫ Light touch▫ Temperature ▫ Pressure

■ Motor or efferent Conduct impulses from the CNS to

effectors• Muscles• Glands• Organs

Have a variety of axon terminal designs to promote conduction effectively

■ Interneurons Connect motor and sensory neurons,

specifically in the spinal cord• Mediate impulses from a variety of

inputs • Modulate outputs • Create exact response demanded by

other neurons

E.g.,When an axon is in connection with a muscle, its terminal bouton buries itself deeply into the muscle. When a neurotransmitter (acetylcholine) is released, it gets deeply into the synapse in order to create a reaction in the muscle cell.


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Types and Structures of Glial Cells – Support CellsFour main types of support glial cells: astrocytes, oligodendrites, microglial cells and ependymal cells

1. Astrocytes: get their name because their cell bodies look like stars. From that cell body are numerous processes that radiate out They can wrap around structures

▫ Around the capillaries▫ Interact with the pia▫ Interact with the ependymal linings of ventricles

Astrocytes can produce glial fibrillary acidic protein, which adds structural support to neurons

Astrocytes have a biochemical function▫ They can move oxygen and nutrients around▫ They can remove and transfer ions▫ Secrete growth factors, clear out synapses of extra neurotransmitters

When in line with the capillaries, can form the blood brain barrier that protects the brain from bacteria, viruses, and other toxins

Glial cells, in particular, the astrocytes, when they proliferate during injury, can create what are known as glial scars, causing neuron growth to stunt


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Types and Structures of Glial Cells – Support Cells2. Oligodendrocytes

Have small cell bodies and they don't have very many processes, but the ones they have are very long

Line themselves along neurons and wrap processes spirally around several axons Capable of using their membrane layers that form a myelin sheath around the axon

3. Microglia: the defenders of the nervous system Small stellate cells found primarily in the gray matter Have numerous, lengthy processes Act like resting macrophages They start out life as a monocyte

▫ Migrate into the CNS as monocytes during late prenatal and early postnatal development

▫ Are normally quiet but CNS damage promotes their enlargement and movement▫ Their movement causes them to express major histocompatibility class I and II

antigens▫ Able to activate other glia such as astrocytes▫ Able to phagocytize debris that may result from neuronal damage▫ Microglia can sometimes cause a problem when there are too many of them,

creating toxic neurons


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Types and Structures of Glial Cells – Support Cells4. Ependymal cells Are epidermal cells, not derived from the

neuroectoderm Monolayer of cuboidal cells lined with villi line the

ventricles of the brain and the central canal of the spinal cord. Play a protective role in regulating the movement of

substances from the bloodstream to the brain Along with choroid tissue of the ventricles, form a

complex to secrete and reformulate the composition of CSF

Title

This Concludes Module 1 Part 1

Proceed to Part 2 of Module 1 to complete the course.

Title


Module 1

Title Your Instructor

Sister Lisa ZuccarelliOP. Ph.D.

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Title Introduction and Objectives

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Objectives

In Module 1 Part 2 we will:

■ Identify the mechanisms of neurotransmission of impulses

■ Describe the specific functions of the numerous neurotransmitters

■ Describe the embryonic development of the nervous system

■ Relate the structure of the blood–brain barrier (BBB) to its function

This chapter will discuss the cellular anatomy and physiology of the nervous system.Recall our objectives:

In Module 1 Part 1 we:

■ Described the different types of cells in the nervous system

■ Identified the various structures of the neuron

■ Differentiated the type and structures of neurons

■ Differentiated the types and structures of glial cells

Title

Module 1: Cellular Physiology of the Nervous System Part 2


Neurotransmission by Excitable Membranes■ The role of excitable membranes is to transmit electrical signals from one cell to the next■ In order to do so, the cell must be able to separate ions that carry electrical charge and then allow those ions

to move in and out of the cell in a regulated fashion■ By separating those ions and holding them at bay from each other, and then only allowing them to move at

certain times, creates a situation where the cell can do work■ Ion channels: “gatekeepers”

Like electrons moving in the wires in your house that light up your lightbulbs or run your toaster, these membrane-bound protein structures regulate the movement of ions by opening or closing their channels

Every ion channel is specific to a specific kind of ion Ions tend to move in relation to each other (together or far apart) Controlled by their responses to chemical, electrical, or mechanical signals

▫ Voltage-gated channels respond to changes in membrane potential▫ Ligand-gated channels respond to bound molecules to specific receptors▫ Mechanically gated channels respond to tension or stretch in the membrane, appearing in places that

do move, such as around vessels Can also be regulated by phosphorylation, competitive inhibitors, poisons and toxins, and drugs

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Neurotransmission■ Every cell has a resting membrane potential (Vm)

Different kinds of cells have different resting membrane potentials: a different condition in its resting state where positive charges are on the outside, usually, and negative charges are on the inside▫ Normally, in neurons and other cells, the outside of the cell has a very high sodium chloride

(NaCl) concentration▫ The inside of the cell, the cytoplasm, has a high potassium (K+) ion concentration▫ How the concentrations inside and outside of the cell are determined are by how the ion

channels for these different ions are working▫ There is a natural ion imbalance across the membrane▫ This is different for every cell but not different for every cell type

Typical body cell has a resting membrane potential of –70 mV▫ The difference between the inside of the cell and the outside of the cell can be measured to be a

difference of minus 70 millivolts


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Neurotransmission■ Changes in membrane potential

Created when ion channels open and ions flows across the membrane▫ When positive ions cross the membrane, the membrane becomes depolarized

• This reduces the difference in electrical charge between outside and inside of cell• Ions on the inside of the cell can also be removed to repolarize the cell

Membrane can be depolarized and repolarized by the movement of ions through specific channels Propagate the electrical signal—action potential Generated by ion flow through voltage-gated channels Varying properties of voltage-gated channels determine levels of excitability of a membrane


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NeurotransmissionThe special physiology of a neuron is the ability to create an action potential.■ Brief reversal of the membrane potential caused by fluxes of sodium and potassium across the

membrane■ Caused by sodium and potassium essentially switching places across the membrane■ Happens quickly – in a millisecond

Causes:

Sudden inward movement of Na+ ions: Na+ channels open fast Na+ follows its concentration gradient Na+ is attracted to negative inside membrane potential.

Subsequent outward movement of K+ ions K+ channels open more slowly K+ movement lags Na+ ions have dissipated the potential that once kept K+ in; now K+ is free to leave the cell. Repolarization begins to occur


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Neurotransmission■ The sodium and the potassium channels close and the sodium potassium pump kicks out any extra

sodium ions to bring back in the potassium ions■ The sodium potassium pump kicks out three sodium ions and brings in two potassium ions with each

switch■ An action potential usually happens in a very small patch of membrane

Initiated in one place on the neuron■ The quick depolarization and re-polarization creates and generates another action potential in the patch

of membrane that is adjacent to the original action potential■ The action potential spread out sequentially throughout the neuron and in particular, down the axon of

the neuron


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NeurotransmissionPhases of the action potential■ Resting phase

Membrane potential is at –60 mV inside Voltage-dependent Na+ and K+ channels are closed K+ channels leak to the outside of the cell more than Na+ channels The negative membrane potential helps keep K+ ions in the cell Depolarizations are small (less than 20 mV)

▫ Na+ comes in the few open channels▫ Incoming Na+ further reduces the membrane potential

• For example minus 60 millivolts it might be minus 55 millivolts▫ More Na+ channels open because of reduction of the membrane potential, leading to a chain

reaction▫ K+ leakage prevents the small depolarizations from summing into a full action potential

• This is called a resting phase


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Neurotransmission(action potential continued)■ The electrical response is “all or nothing” based on sufficient voltage change across the membrane to

initiate the opening of sodium channels When the threshold is reached, sodium ions open up and let sodium into the cell, creating a rush of

electrical change That creates a situation where these voltage-gated channels all open up so that all the sodium

channels will open up and a rush will occur

■ Refractory period prevents a second action potential from occurring too easily The absolute refractory period prevents the propagation of an action potential The relative refractory period allows an action potential to be propagated only after a supranormal

stimulus


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NeurotransmissionPhases of the action potential (continued)■ Depolarizing phase

Depolarizations greater than 20 mV cause many Na+ channels to open Na+ influx cannot be compensated for by leaking K+

Na+ influx leads to greater depolarization, leading to fully opened Na+ channels Na+ rushes in until [Na+]in = [Na+]out

Phase leads to the peak (+40 mV) of the action potential■ Repolarizing phase

Na+ channels close and become inactive until membrane potential becomes negative Negative membrane potential forces K+ channels open, and K+ rushes out As K+ rushes out, the membrane potential repolarizes back to –60 mV

Title

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NeurotransmissionPhases of the action potential (continued)After the repolarizing phase of the action potential, comes the hyperpolarizing phase.■ Hyperpolarizing phase

K+ channels are open, and the repolarization goes beyond the resting potential point Membrane potential sinks lower than -60 millivolts: -65 millivolts to -70 millivolts As the membrane potential reaches the resting potential, Na+ and K+ channels are closed The Na+/K+ pump make sure that sodium ends up on the outside The potassium ions that need to be balanced end up on the inside of the cell

■ Refractory phase follows the hyperpolarizing phase Allows an action potential to go through its entire phase without stimulating a second one in the

same region of the neuron membrane


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NeurotransmissionAfter the depolarization and re-polarization, it is time for the action potential to encourage other parts of the neuron to have their own action potentials.■ Propagation of the action potential to other parts of the neuron

Local currents are generated to hypopolarize adjacent sections of the axon membrane Threshold is reached, and the sodium and potassium channels respond accordingly Propagated action potential regenerates itself with no loss in the strength of the action potential

throughout the entire length of the axon Thus preserving the original signal that emanated from the cell body at the start


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NeurotransmissionThe action potential moves at a particular speed, called the conduction velocity (how fast the electrical signal gets from one end of the cell to the tip).Factors affecting conduction velocity of the action potential: 1. Diameter of the axon

Larger diameter axons conduct more quickly Smaller diameter axons conduct more slowly

2. Thickness of the myelin sheath Myelinated axons conduct the action potential at a faster rate, with velocities between 5 m/s to 120 m/s Unmyelinated neurons conduct the action potential at a slower rate, at velocities between .25 m/s to 5 m/s

3. Length of the axon Effects the time it takes for the action potential to travel from one side of the cell to the other

4. Distance between nodes of Ranvier in peripheral nerves The longer the distance between the nodes, the faster the conduction

5. Saltatory conduction Action potential leaps from one unmyelinated node of Ranvier to the next Ion channels at the nodes are more plentiful than those under the myelin sheath and are of different types


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NeurotransmissionOnce an axon has undergone its action potential, information has gone from the cell body down through the axon to the axon tip.

The axon tip is usually connected to something: ■ To another neuron or to a gland or to a muscle■ At the very end of the road there needs to be a way to get information to the next cell ■ That is called synaptic transmission


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NeurotransmissionSynaptic transmission: Electrical synapses and Chemical synapses (synapses = gap) ■ Electrical synapses are formed from close associations between adjacent joined cell membranes

Gap junctions between two cells promote high conductance of ions Ion currents flow directly from cell to cell to pass on the impulse Gap between cells is 3.5 nm There is almost no delay between cells The direction of the flow is bidirectional unless rectified by variations in cell membrane properties

■ Chemical synapses: one direction Are formed by associations between presynaptic terminals in association with postsynaptic

specialized surfaces Bigger gap between cells (approx. 10x as large) is 30–40 nm The presynaptic terminal releases neurotransmitter molecules into the gap Chemical transmitter traverses the gap to bind with specific receptors on the postsynaptic cell Depending on what kind of receptors are there, a modulation (conductance/inhibition) can occur

that either slows down the impulse or speeds it up


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NeurotransmissionSynaptic transmission■ Usually what happens is a postsynaptic cell (cell B) has many cells impinging on it■ It may be getting signals that say “this is excitatory, pass the information” or inhibitory signals that stall

the information■ All the information (very often coming from different places in the body) impinge on that second cell,

which then coordinates and integrates all that information and then the cell will either fire or it will not fire

■ It will either receive the information and take it in full or it will take information and have it in a modulated form


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NeurotransmissionMembrane relationships of synapses1. Axodendritic

Terminal bouton of the axon of the presynaptic cell aligned with dendrite of the postsynaptic cell Primarily excitatory influence

2. Axosomatic Terminal bouton of the axon of the presynaptic cell aligned with the cell body of the postsynaptic cell Primarily inhibitory influence

3. Axoaxonic Terminal bouton of the axon of the presynaptic cell aligned with the axon of the postsynaptic cell Either excitatory or inhibitory influence: modulating the information in the second cell


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NeurotransmissionCNS transmission■ Multiple inputs onto a single neuron from other neurons■ Up to 3,000 synapses on one neuron■ Each synapse induces small changes in membrane potentials caused by chemical transmission■ Each small change can either be excitatory or inhibitory

Excitatory postsynaptic potentials result from increasing graded depolarizations at multiple synapses

Inhibitory postsynaptic potentials result from increasing decay of the membrane potential to its resting level

■ The result is a combination of information coming to each of those cell bodies that are receiving the information, not unlike asking for advice from a number of people about a decision


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NeurotransmissionMuscle and nerve transmission:Many of our neurons go to our muscle cells.There is a different relationship between nerve cells and muscle cells than there are between nerve cells and other nerve cells.■ The relationship between the muscle and the nerve comes in the form of what is known as a

neuromuscular junction Intimate physical relationship exists between terminal boutons of axon and the coating or the

covering -- the plasma membrane (sarcolemma) of muscle cell The terminal bouton of an axon is embedded inside the sarcolemma of a muscle cell

▫ Each muscle fiber is innervated by one nerve endplate▫ Endplates are buried deep into postjunctional folds of the muscle plasma membrane

Gap of 30–40 nm exists between cells Edges of bouton correlate exactly with acetylcholine (ACh) receptor–coated areas in the invaginated

post-junctional folds


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NeurotransmissionPhysiology of nerve–muscle transmission: 11 steps1. Action potential is propagated down the presynaptic axon to the terminal bouton2. Voltage-dependent Ca++ channels are opened as the action potential passes down to the terminal3. Ca++ causes neurotransmitter vesicle migration and fusion with presynaptic membrane of the terminal4. ACh (as discrete quantal packets) is released from vesicles by exocytosis5. ACh diffuses across the synaptic cleft toward the postsynaptic membrane (sarcolemma of the muscle

cell)6. ACh binds to adjacent receptor sites clustered within the postsynaptic junctional folds7. Cell signaling opens ion channels8. Action potential is elicited in the postsynaptic muscle fiber9. ACh is hydrolyzed by acetylcholinesterase in the synaptic cleft

Resting potential is restored as ACh is removed from the cleft.1. Products of neurotransmitter hydrolysis are taken up by presynaptic end terminals


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NeurotransmittersCharacteristics and release mechanisms control the nature of the transmission

■ Proteins and peptides synthesized by the cell body■ Calcium-mediated release from presynaptic vesicles of neurons by the action potential

Action potential increases the permeability of the membrane-bound Ca++ vesicles Amount of neurotransmitter released is directly proportional to Ca++

■ Neurotransmitter is released into the synaptic cleft after vesicle fusion with the terminal bouton■ Neurotransmitter crosses the gap to bind to specific postsynaptic receptors■ Ligand–receptor interaction alters permeability of the postsynaptic cell membrane changing membrane

potential■ How is the neurotransmitter inactivated?

It would be a challenging situation if the neurotransmitters stayed bound on to the channels on the post synaptic (muscle) cell

That transmitter has to fall off and be gotten rid of That is done is by enzymes The new transmitter is synthesized often from the breakdown products of after an action has occurred


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NeurotransmittersCategories of neurotransmitters:■ Catecholamines

L-tyrosine and L-dopa, are precursors▫ Tyrosine hydroxylase converts tyrosine to L-dopa to initiate formation of catecholamines▫ DOPA carboxylase converts L-DOPA to dopamine▫ Dopamine beta-hydroxylase converts dopamine to norepinephrine▫ Phenylethanolamine N-methyltransferase converts norepinephrine to epinephrine


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NeurotransmittersCategories of neurotransmitters (con’t):■ Dopamine

Uses several D-receptor types Acts via cyclic adenosine monophosphate

(cAMP) second messenger system Located throughout CNS Opens K+ channels, closes Ca++ channels Regulates movement via action in basal

ganglia

Dopamine stimulates gut responses and growth responses that originate in the hypothalamus of the brain, and that regulate our metabolism throughout our body through the endocrine system to produce action on our bones, action on our tissues that causes growth, for example.

One of the neurotransmitters involved in Parkinson's disease

Cells that have lost their ability to make dopamine are no longer functioning

This causes many of the tremors and the slowed walking that one finds in Parkinson's patients

Dopamine is involved in mental functions It is found working in the corpus callosum and

in the cerebrum It is implicated in illnesses such as

schizophrenia


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Neurotransmitters: Categories■ Norepinephrine

Uses alpha- and beta-adrenergic receptors activating cAMP, inositol triphosphate, and G protein systems

Promotes both excitatory and inhibitory responses depending on tissues involved

Located diffusely throughout the CNS, concentrated in locus ceruleus, sympathetic nervous system

Released from adrenal medulla, it will increases blood pressure.

Action in hypothalamus promotes sympathetic vasodilation, resulting in muscle blood flow.

In the pons, projections from neuroendocrine cells promote the release of anterior pituitary hormones.

Is released at nerve endings at smooth muscle neuromuscular junctions

■ Epinephrine Uses multiple alpha- and beta-

adrenergic receptors Activates cAMP, inositol triphosphate

(IP3), and diacylglycerol (DAG) messenger systems

Located diffusely in the CNS Promotes both excitatory and inhibitory

responses depending on tissues involved

Epinephrine cells located in the medulla project to the hypothalamus to regulate autonomic response and blood pressure regulation.

Acts as vasodilator in cardiac system


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NeurotransmittersCategories of neurotransmitters (con’t)Acetylcholine■ Uses both muscarinic and nicotinic receptors■ Is widely distributed throughout the body

Concentrated in neuromuscular junction Active in the autonomic ganglia, cranial nerve,

parasympathetic neurons, and limbic systems Nicotinic receptor activation is excitatory,

directly opening Na+ channels to initiate changes in membrane potential

Muscarinic receptor activation can be inhibitory or excitatory indirectly, via cAMP, DAG, or IP3

second messenger systems by opening or closing Ca++ channels

Serotonin (5-hydroxytryptamine [5-HT])

■ Derived from an amino acid although it is not considered to be a catecholamine

■ Synthesized from the amino acid tryptophan■ Widely distributed throughout the body,

concentrated raphe magnus of the pons project widely in the brain: pons, pineal gland, midbrain, hypothalamus

■ Activates cAMP, IP3, and DAG messenger systems

■ Uses a great variety of 5-HT receptor subtypes, resulting in multiple actions throughout the body

■ The actions of serotonin are able to play themselves out in a wide variety of ways

■ Can be excitatory or inhibitory


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NeurotransmittersNot all transmitters are excitatory but certain ones are only inhibitory.Two of these are GABA-aminobutyric acid -- “GABA” -- and glycine.■ GABA

The major inhibitory neurotransmitter of the mammalian CNS, particularly in the spinal cord, cerebellum, and basal ganglia

It is colocalized with a number of other substances GABA-A and GABA-B receptors are used by GABA GABA-A receptors are colocalized with benzodiazepine binding sites, as well as barbiturate,

steroid, and picrotoxin binding sites A benzodiazepine that is applied to the body, and binds to a benzodiazepine binding site will

affect, for example, a GABA-A receptor GABA-A binding opens chloride channels GABA-B receptors bind few substances, but baclofen is a strong agonist These receptors are implicated in the action of K+ and Ca++ channels and work through a variety

of second messenger systems


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Neurotransmitters■ Glycine

It was formed originally from the amino acid serine Found particularly in the spinal cord (major inhibitory neurotransmitter in the vertebrate CNS) When glycine binds to the glycine receptor, it is considered to be inhibitory When bound to other receptors, it is excitatory Mostly, glycine binds to its glycine receptors It affects the opening of chloride channels which are negative ion channel passageways


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Neurotransmitters■ Excitatory amino acids—glutamate and aspartate

Amino acid neurotransmitters do not cross the BBB Use three inotropic receptors (i.e., kainic, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic

acid [AMPA], and N-methyl-D-aspartate [NMDA]) and one metabotropic receptor

Ca++ influx is the result of NMDA and receptor binding via direct or secondary messenger systems Excitatory: Part of the challenge with drugs that spur the release of excitatory amino acids is that

toxic levels of calcium ions can be released They may promote the release of toxic levels of Ca++ that lead to neuronal injury and death

We need the excitatory amino acids, glutamate and aspartate, but we do not need them or the result of them to be overabundant for the likelihood of killing a neuron by extra calcium ions being released from their normally sequestered state.


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Neurotransmitters■ Another category (a very large category) of neurotransmitter are known as neuropeptides■ Are colocalized with traditional neurotransmitters

Act to modulate action of the neurotransmitter▫ Attenuate activity▫ Increase activity▫ Act directly on neurons


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Neurotransmitters - NeuropeptidesPain-modulating neuropeptides:■ Endorphins

Use opiate receptors in the brain stem, thalamus, hypothalamus, pituitary, and spinal cord

Act in analgesia, sedation, emesis■ Enkephalins

Are closely related to the endorphins Regulate pain sensations at the spinal and supraspinal levels Act in response to stress-related antinociception

■ Substance P Acts as a neurotransmitter when exerting slow excitatory

response in sensory neurons In motor neurons, maintains the stretch response Increases spinal neuron excitability, facilitating flexor reflex Has numerous other physiological effects A molecule that has multiple, diverse actions

When adrenocorticotropic hormone (ACTH) is released in times of stress/strain/fear, a molecule of endorphin is simultaneously released.

The body seems to preparing itself for injury (or some other problem) with the ACTH and at the same time has an ability to blunt the injury/pain/suffering caused (as a response to fear of some thing) by dumping off a molecule of endorphin at the same time.


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Neurotransmitters - NeuropeptidesNeuromodulators: Hypothalamic hormonesCorticotropin, Gonadotropin, Luteinizing, Oxytocin, Thyrotropin, Somatostatin■ Hypothalamic hormones dictate a great deal to the anterior pituitary gland and indeed

produce two of their own: vasopressin and oxytocin■ Corticotropin-releasing hormone (CRH)—corticotropic-releasing factor

Integrates stress response Has excitatory effect on limbic system, hippocampus, cortex, and locus ceruleus

■ Gonadotropin-releasing hormone (Gn-RH)—gonadotropic-releasing factor Located in olfactory cells to modulate reproductive behavior Produces late, slow excitatory postsynaptic potential in the sympathetic system

■ Luteinizing hormone–releasing hormone (LH-RH)


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Neurotransmitters - Neuropeptides■ Oxytocin

Regulates autonomic functions via vagus nerve Modulates the release of norepinephrine and ACh in the brain Adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH) Neurotrophic activity involves behavior, attention, and learning Accelerates regeneration of injured neurons with their muscle targets in the PNS Accelerates the maturation of the developing neuromuscular system

We also know oxytocin as being that hormone (a neurotransmitter) it brings about feelings of warmth and affection in parents.We also know oxytocin as the substance delivered to a woman in labor, to promote labor and eventually the delivery of the child.


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Neurotransmitters - Neuropeptides■ Thyrotropin-releasing hormone (TRH)

Stimulates the anterior pituitary gland cells to produce thyroid-stimulating hormone This then stimulates the thyroid gland The thyroid gland is very active in metabolism Thyrotropin-releasing hormone causes excitation and potentiation of serotonin, and antagonizes the

effects for opiates It is also known to slow the rate of deterioration in ALS patients


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Neurotransmitters - Neuropeptides■ Somatostatin

Also produced in the hypothalamus Has inhibitory effects for the most part The neuropeptide that tells the body to stop growing Its action on ion channels is that it opens potassium channels and inhibits the calcium channels It regulates neuroblast proliferation: cells that will become mature neurons during brain development Decreased somatostatin has been linked to increased senile plaques, and neurofibrillary tangles

that have been associated with neurodegenerative diseases such as Alzheimer's disease


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Neurotransmitters - NeuropeptidesHypothalamic hormones as neuromodulators (continued)■ Oxytocin

Regulates autonomic functions via vagus nerve Modulates the release of norepinephrine and ACh in the brain

■ Adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH) Neurotrophic activity involves behavior, attention, and learning Accelerates regeneration of injured neurons with their muscle targets in the PNS Accelerates the maturation of the developing neuromuscular system

The neuropeptides operate in a wide variety of ways, as co-modulators and co-neurotransmitters.They are either released on their own via the endocrine system, or released via vesicles at the ends of axons in interactions between neurons and glands, and other neurons and muscles.


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Embryological Development of the Nervous SystemA properly functioning adult nervous system depends on a properly formed nervous system in the embryo.Begins during the third week of embryonic development.1. Neural plate

Initially is a single layer of cells from the dorsal ectoderm Invaginates longitudinally along the midline to form a neural groove

2. Neural groove Forms as a midsagittal cleft in the neural plate Defined folds emerge from the sides of the cleft

3. Neural folds The lateral folds extend dorsally until the cells from each side begin to touch each other The contacted folds fuse in a rostral–caudal direction to become the neural tube

4. Neural crest5. Neural tube Specialized cells


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Embryological Development of the Nervous SystemElementary Structures (continued)■ Neural crest

Specialized cells from the dorsolateral ectoderm within the neural fold form the neural crest Neural crest cells have the capacity to migrate widely and differentiate specifically into neurons and

other cells of the PNS Neural crest cells in the head migrate as a unit to become the following:

▫ Sensory roots/sheath cells of cranial nerves: Trigeminal (V), Facial (VII), Acoustic (VIII), Glossopharyngeal (IX), & Vagus ( X); affect the head/face

Juxtamural and intramural parasympathetic ganglia Branchial cartilages, dental papillae, and odontoblasts and head mesenchyme

■ Neural crest cells of the trunk disperse in two major directions: Superficial and dorsal direction: Pigment cells of epidermis and dermis Deep and ventral direction: Chromaffin cells of adrenal medulla; Gut parasympathetic ganglia


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Embryological Development of the Nervous SystemElementary Structures (continued)

■ Other migrating neural crest cells develop into the following:

Schwann cells

Cells of pia mater

Sclera and choroid layers of the eye

Receptor cells of carotid bodies


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Embryological Development of the Nervous SystemElementary Structures (continued)Neural tube ■ Begins as a hollow, closed tube formed by the walls of the fused neural folds■ Cells destined to become neuronal component of the nervous system and the central canal of the

spinal cord and ventricular system■ Differentiation of neural tube into three layers

1. Ventricular cell layer 2. Mantle3. Marginal


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Embryological Development of the Nervous SystemNeural tube differentiation of neural tube into three layers:

Ventricular cell layer retains capacity to divide throughout life. Cells are rapidly mitotic Cells differentiate into neuroblasts that migrate via radial glial cells through the thickness of the layer

Nonmigrating cells remain to line the ventricles & central canal of the CNS and participate in the production of CSF.

Mantle Mantle cells form the middle layer as migrating cells leave the ventricular zone Cells are organized in compact layers In the spinal cord, the mantle is considered gray matter

Marginal Outermost layer close to the pial surface Formed from migrating neuroblasts from the ventricular zone In the spinal cord, the marginal zone is considered white matter


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Embryological Development of the Nervous System

Basal plate Has a ventral division Contains primarily motor fibers Eventually becomes primary motor area of

the adult anterior horn of the spinal cord

Sulcus limitans forms in the fourth week of embryonic development. Medial longitudinal groove on inner surface of tube Divides the gray matter in half Extends throughout brain stem and spinal cord

Divisions created by sulcus limitans

Alar plate Has a dorsal division Contains primarily sensory fibers Eventually becomes primary sensory

area of the adult posterior horn of the spinal cord

Divisions of the neural tube into adult structures


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Neurulation: Vesicles of the neural tube give rise to the adult brain, ventricles, and cavities.1. Prosencephalon (forebrain)—Most rostral;

develops the following Telencephalon, which gives rise to the

following:▫ Cerebral hemispheres▫ Lateral ventricles

Diencephalon, which gives rise to the following:▫ Thalamus, hypothalamus▫ Third ventricle

2. Mesencephalon (midbrain)—Develops into the following: Midbrain only; is not subdivided Cerebral aqueduct

3. Rhombencephalon (hindbrain): Most caudal; develops into the following:

■ Metencephalon, which gives rise to the following: Pons and cerebellum Fourth ventricle

■ Myelencephalon, which gives rise to the following: Medulla Fourth ventricle and central canal

Divisions of the neural tube into adult structures (continued)


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system Once the embryo begins to put into place the variety of structures that will become part of the adult system, it's important for the embryological nervous system to make contacts with targets.The way of doing this is by creating growth cones; ability for the tips of neuron axons to find their targets.■ The general pattern is that the brain forms numerous embryonic interconnections■ It tries to align itself with elements of receptors■ It will dump eventually its neuro transmitters ■ It makes many, many connections and promotes the growth of these connections ■ Over time, the nervous system prunes the number of cells that have connections in order to strengthen

those connections that are the most efficient■ This is a safety mechanism in many ways■ All the structures of the body get neurons


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system ■ The neurons are enervating the entire body ■ Only those that eventually make strong connections are retained ■ The target tissues provide information to the neurons that are trying to travel toward them

Using chemotactic and chemotropic signals Chemotactic signals tell the neurons where they should go, and chemotropic signals help the

neurons grow toward their eventual targets■ These signals direct the movement of these growth cones by laying down surface molecules, lattices,

other pathways■ They tell the neurons to not go in one place but rather travel into another place■ Eventually, the tips of the neurons and the targets become regular communicators with each other

forming strong and efficient bonds


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system (continued)Maintenance of mature neuronal connections■ Neuronal survival is target dependent

Survival of neurons depends on constant contact with target tissue Axon health is determined by connectivity with target tissue Growth or pruning of the dendritic tree depends on contact at the synapse Neuronal survival is also activity dependent

■ Loss of connectivity decreases conduction of impulses Lack of electrical activity leads to the following:

▫ Dystrophic anatomic changes in the target▫ Upregulation or downregulation of receptors on target▫ Alterations in the release of neurotransmitters at axon terminals▫ Pruning of dendrites and remodeling of dendritic tree▫ Degeneration of the axon


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system (continued)■ Remodeling is a normal developmental process.

Establishes best connection by promoting competition at the target Ensures “safety factor” by ensuring that target tissues are innervated Provides for efficient use of neurotransmitters and other molecules Allows subsequent alterations in anatomy as functions change with time



■ Neuronal survival is target dependent Survival of neurons depends on

constant contact with target tissue Axon health is determined by

connectivity with target tissue Growth or pruning of the dendritic tree

depends on contact at the synapse Neuronal survival is also activity

dependent

■ Loss of connectivity decreases conduction of impulses Lack of electrical activity leads to the following:

▫ Dystrophic anatomic changes in the target▫ Upregulation or downregulation of receptors on target▫ Alterations in the release of neurotransmitters at axon

terminals▫ Pruning of dendrites and remodeling of dendritic tree▫ Degeneration of the axon

■ Remodeling is a normal developmental process Establishes best connection by promoting competition at the

target Ensures “safety factor” by ensuring that target tissues are

innervated Provides for efficient use of neurotransmitters and other

molecules Allows subsequent alterations in anatomy as functions change

with time

The maintenance of these mature neuronal connections is necessary throughout the life of the organism.

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Embryological Development of the Nervous SystemThere are both trophic and tropic molecules that are maintaining the connections between a neuron and its target.■ Trophic molecules promoting neuronal survival or nerve regeneration (growth)

In development they are very, very high in concentration Support the ongoing health of neurons Provide stimuli for elongation of growth cones, elaboration of dendrites, and formation of collateral

processes■ Tropic molecules, are ones that direct traffic and tell the growth cones where to travel■ Neurotrophins, which support cell growth and neuron survival, are numerous

Nerve growth factor—Supports growth of neurites during development Brain-derived neurotrophic factor—Active in remodeling the adult brain Neurotrophin 3—Has a role in both supporting neurite outgrowth and protecting neurons after injury Neurotrophin 4/5—Induces cell differentiation and supports cell survival Mesencephalic astrocyte-derived neurotrophic factor (MANF)—Restorative effects in animal models

of Parkinson-like diseases


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Embryological Development of the Nervous SystemTrophic molecules, Tropic molecules, and Neurotrophins.■ Some work at different times■ Nerve growth factor supports the growth of the neurites during development■ Brain-derived neurotrophic factor is active in remodeling the adult brain■ Neurotrophin three has a dual role:

Help the developing neurites Protect neurons after they've been injured

■ Neurotrophin four and five helps neural cells differentiate into their various types■ MANF are restorative as we’ve discovered in animal models of Parkinson’s-like diseases


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system (continued)■ Topographic interactions with chemospecific properties determine route of tract formation (tropism)■ Target tissues direct axons during development and regeneration■ Guidance molecules secreted from the target tissues are cues for direction

1. Integrins are the main signaling molecules in the extracellular matrix▫ Different forms present on all cells of the body▫ Variety provides opportunity for fine-tuning direction▫ Mediate cell–extracellular matrix and cell–cell adhesion

2. Cadherin are calcium-dependent molecules expressed through cell membranes▫ Allow other membranes to adhere and therefore cling as the leading edge of the growth cone advances▫ Involved in tissue morphogenesis, axonal migration, and regeneration

3. Netrins/SLIT family are chemotactic glycoproteins produced from floor plate cells▫ Direct neurons to a specific point by creating a concentration gradient▫ Guide in both dorsal and ventral directions by using attraction and repulsion

4. Ephrins and semaphorins are transmembrane proteins▫ Are inhibitory molecules that direct neurons by repelling them from certain surfaces▫ Support specific topographic arrangement of neurons▫ Collapse growth cones to suppress extension

The extracellular matrix like a ground.Think of it as a pavement upon which various cells can travel.

“Sticky parts”


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Embryological Development of the Nervous SystemDeterminants of growth in the nervous system (continued)

■ Neurotrophins help with growth

■ Tropic or the neurotropic molecules help with the direction

They work hand in hand in development and in the adult mature system to keep the neurons and their connections (their targets such as muscles and glands) in a healthy relationship.


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Embryological Development of the Nervous SystemHow do the tropic and the neurotrophic molecules know what they should do?They're controlled by gene expression. All proteins are directed by genes. They are regulated by what are known as “promoter molecules”.■ Promoters turn genes on and off at critical stages of development

Gene promoters are controlled by great numbers of chemical factors, particularly peptides Specific genes produce important peptides for gene expression in the developing nervous system

■ Certain peptides are paramount for proper formation of the basic organization of the nervous system. Bone morphogenetic proteins (BMPs) determine specifications of the neural plate, differentiation of

the dorsal columns Peptide from the gene sonic hedgehog (Shh) establishes the location of motor neurons in the spinal

cord Peptide from the gene wingless (wnt) determines neural induction, neural differentiation, and

neural crest formation


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Embryological Development of the Nervous SystemTropic and trophic molecules are controlled by precise gene expression ■ Anomalies of neural induction and differentiation are now known to be caused by improper regulation of

gene expression Folic acid, found readily in food, is well known to prevent spina bifida, promoting proper cellular

biochemistry of the aforementioned regulator molecules Shh, wnt, and BMP Shh is implicated in a number of diseases such as holoprosencephaly, medullablastomas, and basal

cell carcinoma■ Sequential gene expression controls the development of the embryo into regions■ The homeobox genes called Hox family and the PAX family of genes are expressed sequentially to form

the anterior–posterior plane of the nervous system


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Embryological Development of the Nervous SystemTropic and trophic molecules are controlled by precise gene expression. Errors in gene expression:■ Inadequate or inappropriate expression of specific Hox genes prevents the normal development of

organs at different levels of the body, such as the ears or eyes■ Rarer diseases, such as Waardenburg syndrome and autism, have been tied to genes similar to those

recently found in Drosophila Migration and differentiation of neuronal cells are dependent on gene expression of trophic and

tropic factors expressed by specific and novel genes■ Patients with lissencephaly (i.e., smooth brain) and other brain malformations were found to have genetic

defects in the reelin gene and the doublecortin gene Treatment or cure of many developmental anomalies in the future will concentrate on gene

therapeutics targeted to resolve errors of gene expression rather than traditional medicines


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Blood–Brain Barrier (BBB)Characteristics

Provides structural and bioelectrical protection of the brain from bloodborne substances Maintains a stable environment for neural tissue in the brain Excludes toxins, pathogens, and circulating neurotransmitters Incomplete around the circumventricular organs

▫ Allows the hypothalamus to “taste” the blood▫ Lets the body and brain know about its composition▫ Rest of brain is not exposed to the blood other than its own cerebral circulation


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Blood–Brain Barrier (BBB): AnatomySpecialized properties of the endothelium of capillaries, few fenestrations (open spaces) in the endothelium■ Allow passage of only small ions and molecules prevent viruses and bacteria from entering neural tissues■ High-resistance electrical tight junctions between endothelial cells prevents (K+) from entering the brain■ Few pinocytotic (fluid-endocytotic) structures minimized uptake of fluids■ Specialized transport receptors allow only certain molecules into the tissue

Specialized properties of astrocytes■ Extensions of the foot processes of astrocytes are intimately aligned with the capillary■ Multiple astrocytes contribute foot processes■ Almost no gaps exist between membranes of the foot processes

Properties of pericytes■ Small, flat cells inserted between the capillary endothelium and the foot processes■ Provide more barrier to the transport of materials■ Demonstrate ability to contract


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Blood–Brain Barrier (BBB)Summary of the physiology of the BBB:Selectivity of the BBB:

Allows passage of lipid-soluble substances—O2 and CO2

Impermeable to charged molecules and those with low lipid solubility▫ Controlled entry of drugs due to size and charge

Specialized receptor-mediated transport▫ Hexose transporters for glucose▫ Amino acid carrier systems▫ Multiple drug resistance (MDR) transporters

Specific ion channels and exchangers▫ K+–Na+ adenosine triphosphate (ATPase)▫ Na+/H+ and Cl–/HCO3

– exchangers

This makes it more challenging for pharmaceutical interventions in the brain.

The brain doesn't want to receive pathogens but it does want some larger substances such as glucose or amino acids, so it has transporters for those particular molecules.

All of these different parts of the blood brain barrier contribute to the fine tuning of what our brain cells see and what they're able to use, and in general, form a defense for our brain.

Title

Conclusion

Thank You

Ischemic Stroke


Module 1

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Cellular Physiology of the Nervous System