Cell and Molecular Neuro Flashcards
(156 cards)
1
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Neurophysiology
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Branch of physiology abd neuroscience concerned with function of the nervous system.
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Significance
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As chiropractors we affect the nervous system with each adjustment
3
Q
Where in the spine are sensory receptors?
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Everywhere including the outer 1/3 of the vertebral disc.
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Injured state resulting in sensitization of nociceptors
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Can result from major trauma or repetitive microtrauma. Results in sympathetic hypersensitivity
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During an adjustment what happens to mechanic receptors?
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Stimulate Joint mechanoreceptors, which can potentially decrease nociceptive activation
In other cases may contribute to sensitized state
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Classes of neurons
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Multipolar
Psuedouniploar
Bipolar
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Multipolar Neuron
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has a single axon and contains multiple dendrites extending from the soma
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Psuedounipolar/unipolar
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Contains a single process extending from the soma that can branch to form dendrites and axon terminals
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Bipolar neuron
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Contains two processes, One axon and one dendrite extending from the soma.
10
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CNS Terminology
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NUCLEI - refers to neuron cell bodies that are morphologically distinct
TRACTS - refer to multiple axonal processes that are morphologically distinct in a bundle
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PNS terminology
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GANGLIA - refers to multiple neuron cell bodies
NERVES - are multiple axons in a distinct bundle
12
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Reticular Theory
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Outdated Theory by Camillo Golgi
Neurons are connected to neighboring neurons through protoplasmic links
Neurons linked together forms continuous nerve cell network or “reticulum”
Information may flow in any direction within the network
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(Main Ideas of) Contact Theory
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Argued against Reticular Theory (By Santiago Ramon y Cajal)
Neurons are distinct cells
Neurons communicate with each other at distinct points of contact
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5 principles of Contact Theory
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1) Neuron is the elementary structural and signaling unit of the nervous system
2) Information is recieved at a receptive point of a neuron and travels in a unilateral direction along the axon to the terminal LAW OF DYNAMIC POLARIZATION (specialized areas for receiving and sending)
3) The axon terminal of one neuron is in close proximity with the receptive region of another neuron at a specialized junction called a synapse
4) An individual neuron will only communicate with synaptic contacts on specific portions of a neuron. Connection between neurons are not random, neuronal circuits pass information through specific pathways. Concept is CONNECTION SPECIFICITY
5) Connections between neurons can be modified by experience, either through strengthening or weakening of synapses. Makes brain function more efficient. SYNAPTIC/NEURAL PLASTICITY
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Electrophysiology
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Can provide a detailed picture of the events taking place at the individual cell level.
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Digital Cathode Ray Oscilloscope
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A lab instrument that provides accurate time and amplitude measurements of voltage signals over a wide range of frequencies
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CRO Macroelectrodes
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Measure the activity of a population of cells
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CRO Micro-electrodes
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Can be placed in or near a single cell to measure that cells electrical activity
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Population (Global) recording
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Utilizes macro-electrodes
Measures voltage
EEG (for the cortex)
EMG (muscles)
ERP (specific sensory pathway) activity of the brain in response to a stimulus
Whole nerve (Peripheral nerves)
Excellent temporal resolution, poor spatial resolution
Clinical assessment (provides us with knowledge of whether or not there is a problem)
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Q
Single Cell Recording
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Utilizes Micro-electrodes Measures Ion current and voltage Resting Membrane Potential IPSP, EPSP AP Intracellular (in Vito, in vitro) Extracellular (in vivo) Patch clamp (in vitro)
Experimental method
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Neural connection properties
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Electrical Unique to excitable cells Very fast Only the plasma membrane is involved ATP-dependent Signaling is directly and indirectly coupled to all cellular biochemical process by ion channels and numerous signal transduction pathways (STPs)
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Membrane voltages
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Graded (EPSPs, IPSPs) or All or None (AP)
Graded potentials occur at dendrites and the soma
AP are initiated at a region adjacent to the axon hillock and travel along the axon to the terminal button
Both rely on activity of ion channels located throughout the plasma membrane
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Q
ERP
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Measuring activity in a sensory pathway
Visual (Flash, Pattern)
Auditory (Click, Tone)
Sensory (Light touch, Pressure)
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Three techniques of Single Unit Electrophysiology
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Extracellular: Voltage measurement taken outside of the cell, which records all-or-none action potentials
Intracellular: Voltage measurement taken inside of the cell which records Resting Membrane Potential, graded potentials, and APs
Patch Clamp: Records ionic current (not voltage) of either a single or a group of ion channels
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Resting Membrane Potential
Allows the membrane to be in a “ready state”. All electrical activity results from a change to this potential.
-70mV (between -40 and -90 mV dependent on size)
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Ionic basis of the Resting Membrane Potential
Neurons exist in an aqueous environment with + and - ions.
Ion species will attempt to achieve their own equilibriums.
The charge built up across the membrane at rest results from the differential distribution of the ion species.
More negative ions on the inside than on the outside.
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Ion distribution in a neuron at rest
More Na+ and Cl- ions are found on the outside of the neuron
More K+ and negatively charged ions are found on the inside of the neuron
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Homogenizing factors across the neural membrane
Random motion (concentration gradients)
Electrostatic pressure (like charges repel and opposite charges attract)
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Chemical synapses
Allow for cell to cell communication via the release of chemical agents (neurotransmitters) by presynaptic neuron.
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Neurotransmitter release
Released from synaptic vesicles from the Presynaptic axon terminal
Released synaptic cleft
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Three types of chemical synapses
Axodendritic - most common. Synapse on dendrite of postsynaptic neuron.
Axosomatic - synapse on the soma
Axoaxonic - synapse on the axon
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Properties of electrical synapse
3.5nm synaptic cleft with a 10-100 usec delay. Near instantaneous signaling.
Some synaptic plasticity but no amplification
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Properties of chemical synapse
20-40nm synaptic cleft. 1-5msec delay.
Provides temporally and spatially focused transmission. Provides alterations in synaptic core goth efficiency.
Synaptic plasticity and signal amplification.
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Chemical synapses divided by distance
Directed - neurotransmitter release site and reception site are in close proximity.
Non-directed - release site is at a distance from reception site.
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Neuromuscular junction
Chemical synapse between extramural and intramural muscle fibers of striated and skeletal muscle.
All NMJs utilize acetylcholine (ACh)
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Motor unit
One alpha neuron and all extramural muscle fibers innervated by its axon (branches at its terminal end.
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Nicotinic ACh receptor
Large protein consisting of 5 subunits. Alpha subunit contains an ACh-binding receptor.
Central pore functions as a passage for Na+ ions.
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CNS chemical synapses properties
Multiple transmitter ligands. Graded response consisting of EPSP and IPSP. Summation is necessary. Receptors may be ionotropic or metabotropic.
Presynaptic inhibition or facilitation.
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Properties of NMJ (PNS chemical synapses)
Single transmitter ligand. End Plate Potential (depolarization only). Only excites target. Only ionotropic receptors.
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How are postsynaptic potentials generated?
Binding of neurotransmitter on receptor causes the opening of ion channels and can induce depolarization or hyperpolarization.
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Depolarization
Bringing membrane potential closer to threshold of excitation (EPSP)
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Hyperpolariztion
Makes the membrane potential more negative. IPSP
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Properties of EPSPs/IPSPs
Graded potentials with varying amplitudes. Travel passively but rapidly from site of origin. Decrease in amplitude as they travel along the axon (decremental)
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Generation of AP
Sum of IPSPs and EPSPs must be sufficient to reach the threshold of excitation
-55mV to generate an AP
Generated in the region adjacent to the axon hillock
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Features of an AP
Momentary reversal of membrane potential from - to +
All or none response
Directly related to the concentration of Na inside and outside the cell
Voltage gated ion channels mediate the production and conduction of APs by altering the membrane potential.
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Two types of summation
Spatial - Multpile PSPs from different synapses are combined to form a a larger PSP
Temporal - Multiple PSP form the same synapse combine to form a larger PSP
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Phases of an action potential
```
Resting state
Threshold
Depolarization phase
Depolarization phase
Undershoot
Refractory Phase
Absolute refractory phase
Relative refractory phase
Return to Resting State
```
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Resting state
Voltage gated Na and K ion channels are closed and leak ion channels are open. Membrane potential is a RMP
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Threshold
One or more excitatory potentials (EPSPs) opensomevoltage-gated Na ion channels. When the threshold is reached, more Na+ ion channels will open and an action potential is triggered.
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Depolarization phase
With Na ion channels open, Na ions continue o rich into the cell, which alters the membrane potential.
K ion channels are still closed.
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Repolarization phase
Voltage gated ion channels become INACTIVE while K ion channels begin to open.
K ions rush OUT OF the cell to change the membrane potential.
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Undershoot
Na ions channels are closed and K ion channels are closing but slowly K ions are still leaving the cell through the remaining open channels. Making the membrane potential more negative
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Refractory Period
in the wake of the AP, Na ion channels are deactivated for a brief time. Makes it difficult for the neuron to produce an AP.
Absolute Refractory Period - from initiation of AP to immediately after the peak. Cannot lead to another AP.
Relative Refractory Period - following absolute refractory period. Na channels begin to recover from inactivation. A stronger than normal stimulus is needed to elicit an action potential.
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Return to Resting State
The RMP of the neuron is restored as all K+ ion channels close and the Na/K pumps work to re-establish baseline concentration of these ion channels.
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Anti-Homogenizing factors across cell membrane
Neural membrane has different permeability to ions
passive property as it uses ion channels. K+ and C- can pass through the membrane. Na+ moves through with difficulty and (-) ions cannot move through at all.
Membrane bound transporters that consume energy.
Na-K pump that exchanges 3 intracellular Na+ ion for 2 extracellular K+ ions. MAJOR factor in maintaining the differential ion concentrations,
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Cl- ions in the neuron
Can readily diffuse across membrane. Negative internal potential drives Cl- ion s out of the neuron. As the ions accumulate outside the cell the concentration gradient pushes them into the neuron.
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Na+ ions
Has difficulty diffusing across the membrane. Tend to move into the cell due to their high extracellular pressure and negative charge of internal neuron. Na-K pump moves the Na out of he cell at the same slow rate that they enter the cell (maintains -70 mV)
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K ions in the neuron
neural membrane allows K+ ions to readily diffuse. Moves out of cell due to high internal concentration. Internal negative pressure moves ions back into the cell. Na-K pump maintains charge by moving K ions into the cell at the same rate that they leave.
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Two types of ion channels
Leak (non-gated) ion channels
| Gated ion channels
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Non-gated ion channels
open even in a resting state
selective for a single ion species
contributes to RMP
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gated ion channels
closed until opened by a stimulus
can be selective for one or multiple ion species.
Necessary for graded or all or none potentials and neurosecretions. (depolarizing and hyperpolarizing effects)
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Location of ion channels
Leak channels: cell body, dendrites, axon
Ligand gated channels: Cell body, dendrites
Voltage gated channels: Axon Hillock region, Axon, axon terminal
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Electrical synapses
Allow for direct cell to cell communication via the flow of electrical current through specialized membrane channels that connect the two cells
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Conduction of action potentials
APs are nondecremental and can travel in either direction though under normal physiological conditions they travel in one direction. Conducted slower than postsynaptic potentials.
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Conduction speed of AP is dependent upon...
Myelination - myelinated axons travel faster
| Diameter - large diameter axons conduct faster than smaller ones
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Defining criteria of Neurotransmitters
Presynaptic presence (enzymes and precursors may be used as evidence)
Must be released in response to presynaptic depolarization. release must be Ca dependent. Selective stimulation can be difficult and removal occurs quickly at the cleft.
Specific receptors must be present on the postsynaptic membrane
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Categories of NT
Large-molecule: Neuropeptides only
Small-molecule: 4 classes including amino acids, monogamies, actylcholine, and unconventional NT’s
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Small molecule NT
AA NT - Glutamate, Aspartate, Glycine, GABA
Monoamine - slightly larger than AA - Dopamine, Epinephrine, Norepinephrine, Serotonin
acetylcholine - add an acetyl group to a choline molecule. Main NT at NMJ. Also found in synapses of ANS and CNS
Unconventional NT - some are soluble gases - Nitric Oxide, Carbon Monoxide. Produced in neural cytoplasm and diffuse through the cell membrane to nearby cells then stimulate 2nd messenger cascades.
Endocannabinoids - similar to THC. Produced immediately before release. Affect presynaptic neurons through inhibition of synaptic transmission
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Large-molecule NT
Tend to modulate slower ongoing synaptic functions
Neuropeptides. Short proteins, and can act as hormones.
Pituitary peptides
Hypothalamic peptides
Brain-gut peptides
Opoid peptides
Misc. peptides
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Axonal Transport, Synthesis, Packaging of Small Molecule NT
Synthesized in the cytoplasm of the presynaptic terminal button. Enzymes needed for synthesis are produced in the cell body and are transported along microtubules to the axonal terminal via slow axonal transport.
Precursor molecules are taken into the terminal by transporter
Packaged into small, clear core synaptic vesicles by the Golgi complex within the terminal button.
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Axonal Transport, Synthesis, Packaging of Large Molecule NT
Synthesized in the cytoplasm of the cell body on ribosomes
Packaged into large, dense core synaptic vesicles by the Golgi complex in the cell body
These vesicles are transported along microtubules to the presynaptic terminal button via fast axonal transport
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Co-existence of NT
Many neurons synthesize and release two or more different neurotransmitters. Low frequency stimulation will release small molecule NT and high frequency stimulation is required for the release of neuropeptides.
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Release and recycling of NT molecules
There are mechanisms for releasing and recycling NT most of which are dependent upon Ca. Exocytosis and endocytosis follow each other in a rapid and constant fashion. Continuous release of NT if necessary.
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Synaptic Vesicle Cycle
NT molecules are packaged into synaptic vesicles at the presynaptic terminal.
Vesicles congregate near docking sites of the presynaptic membrane called “active zones”. Vesicles are anchored in place near the active zones by synapsins.
During an AP, the membrane is depolarizer, causing these ion channels to open allowing an influx of Ca+ into the terminal
This Ca+ influx leads to the phosphorylation of the synapsin proteins
Phosphorylation of synapsins readies vesicles of exocytosis by allowing them to dock at the presynaptic membrane facing the synaptic cleft, fuse with it, and release their transmitters into the synaptic cleft
Synaptic vesicles and/or membrane components are then rapidly retrieved (endocytosis)
Vesicles are recycled and re-filled with NT and are readied for re-release
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Vesicle release is directly related
Related to the level of the Ca within the terminal
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Ca level and Small NT
Small molecules are often released in a pulse each time an AP triggers a Ca+ ion influx.
Low frequency stimulation often only increases the Ca concentration near the membrane which favors the release of small molecule NT
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Neuropeptides and Ca level
Neuropeptides are released gradually as teh level of intracellular Ca ions
High frequency stimulation leads to a more general increase in Ca which will release both small molecule NT and neuropeptides
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Importance of voltage gated Ca molecules
Amount of NT released is very sensitive to the exact amount of Ca that enters
Blockage of voltage-dependent ca channels results in elimination of NT release as well as a postsynaptic response
Micro-injection of Ca into the presynaptic terminals can trigger NT release in absence of an AP
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small molecule NT Binding Patterns
Activate either ionotropic or metabotropic receptors
| Function to transmit rapid or brief excitatory or inhibitory signals
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Large Molecule NT
Almost all Biden to metabotropic receptors that act via 2nd messengers
Function to transmit slow and long lasting signals
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Activation of receptors by NT molecules
Basic properties - transmembrane protein with extracellular binding sites. Ligand specific.
Receptor subtypes - Different types of receptors to which a particular NT can bind to are called subtypes. Tend to be located in different brain types. Often respond differently to the same NT
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Classes of Postsynaptic receptors
Ionotropic - Receptors associated with ligand or voltage activated ion channels
Metabotropic - receptors associated with G-protein coupled receptors
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Ionotropic receptors
Often activated by small molecule NT
Binding of a NT to an ionotropic receptor causes a conformational change opening the ion channel.
Post-synaptic potential will be rapidly produced if Na channel is opened and EPSP will be produced. If a K channel of CL channel is opened an IPSP will be produced.
Direct action leads to a fast activation. Faster than metabotropic.
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Metabotropic receptors
More prevalent than ionotropic receptors. Can be activated by small NT or neuropeptides.
Results in activation of G-protein. Indirect action leads to slower activation. Longer lasting effects than ionotropic receptors.
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Autoreceptors
Metabotropic receptors located on the presynaptic membrane with a special function. Bind to their own neuron’s NT.
Thought as a homeostatic feedback system that can modulate the function of a presynaptic neuron.
Monster and regulate the amount of NT. Synthesized or released, or firing rate of the neuron.
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Ligand agonists and antagonists
Agonists bind to the receptor and create the same effect.
Competitive antagonists bind to the same receptor and prevents activation.
Non-competitive antagonists binds to a different site as the natural ligand and either fully or partially prevents activation.
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How to terminate synaptic messages
Enzymatic degradation of NT in the synapse - breakdown products are brought back into the terminal button to be recycled
Reuptake - via specific transporter protein in the presynaptic plasma protein
Passive diffusion - may be taken up by glial cells
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Intercellular chemical synaptic transmission
Signal = NT
Transduction receptor = NT receptor on postsynaptic membrane
Target molecule = ion channel
Response caused by ion channel = electrical response of postsynaptic cell
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Intracellular Transmission
Signal = NT or hormone
Transducing receptor = G-protein coupled receptor
Target molecule = 2nd messengers (Ca and cAMP) and effector enzymes
Response = physiological response and gene expression
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Signal Amplification
An advantage of intracellular signal transduction is signal amplification.
A single reaction creates a greater response by generating a large number of molecular products
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Control of cell behavior
Complex signal transduction pathways allow for precise control of cell behavior over a wide range of time
Concentration of signaling molecules must be tightly regulated. Every molecules concentration must return to baseline before the next stimulus arrives in order to ensure rapid responses.
Keeping the intermediates in a signaling pathway activated is critical for sustained responses
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Classes of 3 signaling molecules
Cell-impermeant molecules: Bind to extracellular receptors on the target cell membrane, short-lived due to rapid metabolism and/or endocytosis
Cell-permeant molecules: cross the plasma membrane and bind to intracellular receptors in the cytoplasm or nucleus. Tend to be insoluble and are often transported in the blood or other extracellular fluid by binding to specific carrier proteins. Unlike cell-inpermeable molecules these may persist in the bloodstream for hours or days
Cell-associated molecules: Bound to extracellular surface of the plasma membrane of the signaling cell, bind to extracellular receptors on target cells that they come into contact with.
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Cell-impermeable molecule receptors STP
Proteins that span entire membrane. Extracellular binding portion and intracellular signaling portion.
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Cell-permeant molecule STP
Intracellular proteins found in cytoplasm or nucleus.
Often bound to an inhibitory complex. Once activated the complex is removed and a DNA-binding domain is exposed.
Often activating signaling cascades that produce new mRNA and proteins within the target cell.
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General classes of GTP_binding proteins
Both G-protein linked receptors and enzyme-linked receptors can activate biochemical reaction cascades that modify the function of target proteins. G-binding proteins are responsible for actions in these
Heteotrimeric G-proteins: made of hop to 3 distinct subunits
Monomeric G-proteins: Made up of a single subunit (tend to be growth factors)
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Activation of a G-protein Coupled receptor
Regulate the gating of ion channels and alter the function of downstream molecules. Many produce 2nd messengers.
May also directly bind to and activate ion channels.
Cardiac muscle cells have G-protein-coupled receptors that bind ACh. Activation of these receptors will open K+ ion channels, decreasing contraction rate of the muscle cells, thereby decreasing HR
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Regulation of Ca concentration
Concentration is ordinarily much higher outside the cell than inside. Maintained by a Na/Ca exchanger and a calcium pump. Calcium is also pumped into ER and mitochondria for later use
Ca ions enter the cytoplasm via voltage gated or ligand gated channels in the plasma membrane. Other channels allow Ca ions to be released form the ER into the cytoplasm in response to intracellular signals.
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Role of Ca as a 2nd messenger
Mechanisms for raising and lowering concentration of Ca allows For precise control of timing and location of Ca signaling within the neuron.
Allows Ca to control different signaling events. (Rapid rise of calcium in the terminal axon results in rapid exocytosis of synaptic vesicles)
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Phosphorylation and dephosphorylation caused by 2nd messengers
Rapidly and reversible changes teh function of a protein.
| Phosphorylation uses protein kinases and protein phosphatases.
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Nuclear signaling
2nd messengers can elicit prolonged effects by acting on proteins that promote the synthesis of new RNA and proteins.
Regulate gene expression by converting transcriptional activator proteins from inactive state to an active state.
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Neuroplasticity
The ability of synapses to alter their strength. Depends on frequency and previous activity.
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Establishing basic brain connections
Formation of distinct brain regions
Neurogenesis
Axogenesis: formation of axon tract
Synaptogenesis: synapse formation
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Mechanism of Neuroplasticity
STPs are often the mechanism by which these changes occur
| Modification of intracellular Ca levels leading to gene expression (effect of 2nd messengers)
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Periods during which experience may be more pronounced
CRITICAL PERIODS: Time windows in which the activity mediated (environmentally) influences are essential for development
Become less effective with age.
SENSITIVE PERIODS: Windows during which the environmental activity influences brain circuitry however, to a lesser degree than during the critical period.
Major of developmental effects occur during sensitive periods
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Evolutionary perspective of Neuroplasticity
Once formed neuronal circuits must be used. If not used they will not survive or function.
The advantage of slow development of human brains is that it allows for acquisition of experience.
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Sensory deprivation
Rats raised in darkness have fewer synapses and dendritic spines in their primary visual cortex. As adults they exhibited defects in pattern vision and depth perception
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Environmental enrichment
Rats raised in visual complex cages were found to hav ethicker corticies with more dendritic spines and synapses per neuron.
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Effect of nature of neurodevelopment
Neural pathways that receive the most input form stronger connections and can potentially take over cortical regions which would have been otherwise devoted to other functions (crossmodal plasticity)
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Monocular deprivation
Prolonged covering of one eye will limit the ability of that eye to activate the visual cortex. The ability of the other eye is increased.
A decrease in the branching of axons of LGN neurons was found on the covered side.
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Neuroplasticity in the sensory cortex
Changes in the sensory input experience will result in changes of the sensory cortex to match and adapt
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Early nervous system development
Before the NS is fully developed neurons fire spontaneously and interact with the environment. Allows for fine-tuning while developing.
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Effects of Musical Training on the Brain
Increase in the size of the region of the primary somatosensory cortex devoted to the fingers of the playing hand.
Higher volume of gray matter of the hippocampus, middle and superior frontal lobes, insula, and cingulate gyrus
Left anterior hippocampus region in musicians exhibited differential activation when sound variation was detected.
Different organization of the thalamocortical network and enhanced connectivity with auditory regions and precuneus
Age of onset of training is the strongest indicator of magnitude of change
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Neuroplasticity in adulthood
Increase, decreases, or modification of cortical synapses, terminal buttons, and or dendritic spines.
Activation of STPs leading to changes in gene expression is the most likely to elicit neuroplastic changes
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Neurogenesis
New neuronal growth
May occur in adults hippocampal and olfactory bulb regions.
Olfactory bulb neurons originate from adult neural stem cells that travel from the lateral ventricles
New hippocampal neurons are formed in the dentate gyrus of the nucleus
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Cortical Re-organization
Experience and stimulus can also affect the organization of the cortex of the brain.
Adults suffering tinnitus underwent a major reorganization of primary auditory cortex
Anesthetization of two fingers in adults reduced their representation in the contralateral somatosensory cortex
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Causes of neural injury
Brain tumors
Infections: caused by microorganisms, can result in infection
Contusions: a blow to the cranium that may penetrate the skull or not penetrate skull (closed) and damages the cerebral circulatory system, includes TBI and mTBI
Cerebrovascular events: A decreased perfusion of the brain resulting from either hemorrhage or occlusion of cerebral vessels
Most strokes are ischemic
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Ischemia induced Neural injury
Due to high metabolic demand of brain there is a high risk of ischemia. Limited oxygen and glucose supply. Prevents removal of metabolic waste products.
Evidence of damage is detected 1-2 days later. Damage does not occur equally (hippocampus is more susceptible)
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Ischemia Resulting in ionic imbalances
Deprivation of oxygen and glucose reduce energy (ATP) needed to maintain ion concentration gradients. Neuron membrane is depolarized due to change in ion concentration, voltage gated Ca ion channels open resulting in NT release.
Release is prolonged due to uncontrolled depolarization and hindered re-uptake mechanisms
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Ischemia resulting in Excitotoxicity
Prolonged exposure to excitatory NT (glutamate) causes activation of postsynaptic receptors at a level leading to cell death. Deterioration of cell structure and signaling capability.
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Glutamate in Ischemia-induced Cortical Damage
Ischemia may lead to excessive glutamate release from nearby neurons. Post-synaptic glutamate receptors are over-stimulated leading to excessive depolarization of the postsynaptic cell membrane
Na and Ca ions flood into the postsynaptic cell.
Overload of Ca can trigger activation of several signaling pathways
Free radicals, mitochondrial dysfunction, disruption of cell membrane, fragmentation of DNA
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Neuronal degeneration following an axonal transaction
Anterograde degeneration: degeneration of the distal portion of the axon between the cut and terminal button. Occurs rapidly (segment swells in a few hours and breaks in a few days)
Retrograde degeneration: degeneration of the proximal region between the cut and the body.
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Degenerative changes in a neuron suggest that
The neuron will die due to apoptosis, necrosis, or both.
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Regenerative changes in neurons suggest that
The cell is in the process of mass producing proteins to replace the damaged axon.
Increase in size
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Transneuronal degeration
Degeneration can spread to non-damaged neurons through synaptic contacts with neurons that are injured.
ANTEROGRADE - spread of degeneration from a damaged neuron to a neuron that it synapses on
RETROGRADE - reverse of anterograde
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Regeneration of axons in CNS
Rarely occurs
| Failure to regrow often leads to permanent dysfunction
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Regeneration of PNS axons
Regenerate more readily than CNS (several cm)
Axons may re-establish previous synaptic contacts with peripheral targets
Re-growth an establishment of synaptic contacts may lead to functional recovery.
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Conditions for axonal regenration
Appropriate gene expression - injured neuron must initiate a sequence of events that leads to the activation of genetic factors that support elongation of the axon leading to a *growth cone*
A supportive environment
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CNS environment after an axon lesion
Unfavorable for re-growth. Reactive microglia, astrocytes and other cells produce inhibitory signals near the injury site that contribute to this impediment. A protein called Nogo has been found to block an axon elongation by interacting with the growth cone.
Macrophages do not promptly arrive to remove axon and myelin fragments.
Inflammatory response occurs with the release of cytokines.
CNS neurons rarely reactivate the expression of axonal regeneration-associated genes (RAG)
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CNS environment after an axon lesion
Severed axons undergo Wallerian degeneration
A favorable environment is created for regrowth.
Macrophages will travel to the area of damage and remove degenerating axon and myelin fragments
RAGs are often reactivated
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Neural regeneration in the PNS
Proximal end of a damaged nerve will begin to grow within 2-3 days.
Three events may occur
If myelin sheaths are intact the regenerating axon can grow through then to reach the original target
If the nerve is severed and the ends are seperated by a few millimeters the regrowing axon often grows into the incorrect sheath and guided to the incorrect target
If seperated by a large distance it will regrow into a mass and die
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Wallerian Degeneration and Repair
Degenrative process of the distal axon following axonal injury in the PNS.
1) Distal portion of the axon swells and disintegrates
2) Mononuclear leukocytes extravasated through blood vessel walls, differentiate into macrophages, accumulate near the Schwann cells and remove remaining cellular debris
4) Neuron cell body induces the activation of RAGS
5) Schwann cells secrete growth factors and proliferate
6) Schwann cells line up and act as “guidance tubes” for the new axon sprouts
7) Regenerating axon regenerates from the portion proximal to the lesion and creates sprout known as “growth cone”
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Degeneration of CNS axons
Different from Wallerian degeneration in the PNS. May take several months to clear fragments following injury.
Infiltration of reactive microglial cells in the area of inquiry may persist for years. Inadequate growth factors.
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Treatment for CNS injuries
Methods for improving QOL in those afflicted include:
Blocking inhibitory molecules
Enhancing axon regeneration
Providing tropic support to surviving neurons
It is possible to graft peripheral nerves as bridges to aid recovery and growth of CNS
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Cross-Modal plasticity
Without visual input to the cortex the auditory and somatosensory corticosteroids expand.
Gain an increase in the functional ability of these senses.
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Mechanisms of neural reorganization
Strengthening of existing connections
Establishment of new connections by collateral sprouting
Support for these mechanisms respectively comes from observations that reorganization occurs too quickly to be attributed solely to neurogenesis
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Recovery of function after brain damage
Most likely to occur when damage is limited and victim is young.
Difficult to discern from true recovery and compensatory changes
Improvement after brain damage has also been attributed to cognitive reserve = intelligence and education
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Treatment of NS Damage
Blocking Neurodegeneration - reduce neural damage (apoptosis inhibiting factors, estrogens)
Promoting Regeneration - peripheral nerve transplantation. Regeneration from myelin sheath
Neurotransplantation - transplanting fetal tissue into damaged area (substantia nigra into Parkinson’s patients); Transplanting stem cells (cells migrated to damaged area, maturation, regained motor control yet uncoordinated)
Rehabilitative training -
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Short term plasticity
Changes in synaptic strength that last from seconds to minutes
Allows for types of short-term memory
Manifests as an activity-dependent change in amplitude of a post-synaptic potential
May result in either facilitation or depression
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Short-term facilitation
Transient increase in synaptic strength
APs arrive closer together
Ca ion removal systems are overloaded
Elevated concentration of Ca ions in presynaptic terminal
Increased # of NT release following an AP
Increased amplitude of EPSPs (if successive)
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Signal Transduction Pathway and facilitation
Often occurs as a stepwise process in which facilitation occurs first, followed by a slow increase in efficacy known as augmentation and finally with prolonged high-frequency stimulation, a third phase of increased PSP amplitude called potentiation occurs and can last for several minutes
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Short0term depression
APs arrive seperated in time or low frequency stimulation
results in decreased numbers of synaptic vesicles released
Subsequent decrease in amplitude of PSPs
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Proposed mechanisms of short-term depression
Depletion of synaptic vesicles in the readily releasable pool
Inhibitory feedback from presynaptic autoreceptors
Ca ion channel inactivation
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Long term Potentiation
Best described form of plasticity. Originally demonstrated in hippocampal neurons through experiments with high frequency electrical stimulation. Neurons then demonstrated increased response to next stimulus.
Requires proximity between pre and postsynaptic neuron.
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Long term potentiation results in
Learning and formation of long term memory
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Structural changes in synapse with Long-term potentiation
Addition of AMPA receptors on the postsynaptic neuronal membrane.
Recruits “silent” synapses.
Increase in size and or density of dendritic spines
Increased arborization of dendritic trees
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Long-term plasticity
Changes in synapse strength that last from hours to years
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3 phases of LTP
Induction: Process by which high-frequency stimulation signals to the synapse to change efficacy
Expression: Actual presynaptic and/or postsynaptic changes that determine changes in synaptic efficacy
Maintenance: Mechanisms underlying the persistence of the structural changes associated with synaptic plasticity
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Activation of NMDA receptors
Glutamatergic receptors that are both ligand gated and voltage sensitive
Contain ion channels that move the obstructing Mg ion to allow Ca and Na ions to flow into cell.
Glutamate must be bound to receptor and there must be a depolarization (Small depolarizations may allow for passage of Na ions but not the larger Ca ions)
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AMPA receptors
Found on the postsynaptic membrane at excitatory gluatmatergic synapses
When bound to glutamate AMPA receptors allow Na ions into the cell thereby depolarizing the membrane
If stimulus from presynaptic neuron is high frequency then depolarization will dislodge Mg ions from NMDA receptor
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Induction of LTP
Following activation of NMDA receptors, Ca ions flow into the postsynaptic neuron. Influx of Ca triggers LTP in postsynaptic neuron
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Expression and maintenance of LTP
After Ca flux of induction
High frequency stimulation at one synapse affects changes on only that synapse while other synapses on the same postsynaptic neuron are unchanged
Protein kinases activated by ca in postsynaptic cell lead to LTP
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Structural changes with LTP
Additional AMPA receptors at silent synapses or synapses already containing AMPA
(Increase sensitivity to glutamate)
Increases in the size and or density of dendritic spines as well as branching of dendrites
Increased likelihood of Vesicle release from presynaptic neuron may also occur. (NO is formed in the postsynaptic neuron to diffuse back to presynaptic neuron and increase Vesicle secretion)
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Role of LTP in Learning and Memory
committing a piece of information to memory requires the creation of a
new neural network of synaptic connections
When an individual recalls this memory, it causes activation of the neurons of this
network to fire again
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Long-term depression
Synaptic efficacy is decreased by very low level stimulation or uncoordinated stimulation
Low amplitude rise in Ca in postsynaptic neuron occurs
EPSPs decrease in amplitude
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Mechanism of LTD
Activation of protein phosphotases (1 and 2b)
Phosphatases dephosphorylate target proteins which can result in the internalization of postsynaptic AMPA receptors through clathrin-dependent mechanisms (reduces sensitivity to glutamate)
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LTP vs. LTD
Both LTP and LTD require activation of NMDA receptors and entry of Ca2+ into the
postsynaptic cell
Small influxes in Ca2+ lead to depression
Large influxes lead to potentiation
LTP relies on the activities of protein kinases whereas LTD relies on protein
phosphatases
It has been proposed that the enzymes associated with LTP and LTD phosphorylate and dephosphorylate the same set of regulatory proteins
