CSB332 Lecture 14 Notes

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Cell and Systems Biology
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Francis Bambico

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CSB332 Lecture 14 Slide 2 - There are basic, fundamental forms of learning that is different in terms of mechanism with higher forms of learning. These types of learning have psychological realities. - The mechanisms of habituation have been demonstrated in a vertebrate model. Habituation results in an increase in the frequent of the stimulation of the presynaptic axon. This means that the organism is repeatedly exposed to a stimulus, which results in a decrease of the specific response. The response can be studied in the Aplysia californica as the gill withdrawal reflex or the siphon withdrawal reflex. - The mechanism of habituation has to do with the fact that if you apply high frequency stimulation in the presynaptic axon, then it will eventually result in the inactivation of all voltage-gated calcium channels. If you expose an organism to a specific stimulus several times, then it will result in high frequency stimulation of a presynaptic axon, and repeated stimulation of the presynaptic axon results in the inactivation of voltage-gated calcium channels. o If an action potential arrives at the presynaptic axon, then it will result in the opening of voltage-gated calcium channels because they are required for exocytosis or transmitter release. o If you do this several times (e.g., high frequency stimulation, high frequency action potential generation), then all of the activated voltage-gated calcium channels will eventually switch into an inactivated mode. You won’t be able to give the presynaptic axon calcium channels to recover from its inactivated mode. This results in a decrease in exocytosis. o After a while, the inactivated calcium channels revert back to its activatable state. This will recover the habituation response. This type of learning is called dishabituation. - Habituation is a form of non-Hebbian learning because the mechanism only occurs in the presynaptic axon. It does not involve the activity of the postsynaptic neuron. Slide 3 - LTP and LTD are associated with consolidation or depositing information from STM to LTM. - If new information has been retained in the brain, something has to change in the synaptic connectivities that mediate this information. One way to figure that out is whether there are changes in the synaptic function of that synapse. One way to examine synaptic function is to examine the EPSP or IPSP in response to a stimulus. Slide 4 - Hippocampal formation is the medial most part of the temporal lobe. When the temporal lobe forms during development, the inferior part of the temporal lobe folds onto itself in the medial afferent of the brain and it forms the hippocampal formation. The hippocampal formation is composed of several structures: dentate gyrus and hippocampus. o The hippocampus is composed of several sub fields: CA3, CA2, CA1. CA stands for Cornu Ammonis (e.g., ram’s horn). CA3 is the input area of the hippocampus. CA1 is the output area of the hippocampus. o The dentate gyrus receives axons that are formed by the perforant fiber pathway. These axons come from many parts brain. This is the input region of the hippocampal formation. It receives axons from many parts of the brain coming from the subiculum and entorhinal cortex. It can receive information from the amydgala, prefrontal cortex, basal ganglia, etc. Many parts of the brain can input into the hippocampus because the hippocampus is involved in memory. The perforant fiber pathway synapses onto granule cells of the dentate gyrus. The dentate gyrus contains granule cells. They are called granule cells because they have tiny cell bodies. o The granule cells send axons to the input region of the hippocampus proper. These neurons are pyramidal neurons. All of the synapses are glutamatergic or excitatory synapses. pyramidal neurons in the CA3 region receives afferents from the dentate gyrus granule cells. This is called the mossy fiber. o The pyramidal neurons in the CA3 region send many axonal collaterals. One set of collateral synapse with the pyramidal neurons in the CA1 region. There are also axons that extend laterally to the other hemisphere of the brain called the hippocampal commissure. Therefore, the bundles of axons are collectively called the Schaffer collateral commissural pathway. The CA1 pyramidal cells then send axons to many other parts of the brain outside of the hippocampus. Slide 5 - It looks like is an interlocking C shaped structure. - To examine whether synaptic changes occur in any synapse, you can lower a recording electrode to any cell body (e.g., dentate gyrus granule cells) and examine changes in postsynaptic potentials. Since these are mainly glutamatergic synapses, so the type postsynaptic potential that you record from the cell bodies of the dentate gyrus granule cells will be EPSPs resulting from activation of glutamatergic receptors in the cell bodies. - The dentate gyrus receives axons from the perforant fiber pathway. The perforant fiber pathway cell bodies normally generate action potentials that are in low frequencies. - The researchers wanted to the manipulate the action potentials generated in the perforant pathway arriving in the cell bodies of the dentate gyrus and see if this will influence the strength/magnitude of the EPSPs recorded from the dentate gyrus cell bodies. o The researchers lowered a stimulating electrode to manipulate the frequency of presynaptic action potential. First, they mimicked normal firing frequency of the axons of the perforant fiber pathway. There will be no change from normal conditions. o Then they apply high frequency stimulation. They will increase the number of action potentials at a given time. This type of high frequency stimulation is called tetanic stimulation or the conditioning training of stimulations.  Apply stimulation of 100 Hz for 5 seconds, for example  Examine the EPSP generated in the cell body in response to a test stimulus (e.g., one action potential)  Compare the magnitude of the EPSP in response to the test stimulus before and after the application of the tetanic stimulation Slide 6 - The blue dots are the magnitude of EPSPs without the application of the tetanic stimulation. - The red dots are the magnitude of the EPSPs after one bout of stimulation, after a second bout of stimulation, after a third bout of stimulation, and a fourth bout of tetanic stimulation. - They found that the presynaptic tetanic stimulation progressively increases the magnitude of EPSPs recorded from the granule cell bodies. - This illustrates LTP. The experience (e.g., high frequency stimulation) of the presynaptic axon results in a greater EPSP that is recorded from the postsynaptic cell. This is a function of how many times you apply the tetanic stimulation onto the presynaptic axon. - This suggests that the synaptic strength of the synapse is dramatically increased in response to an increase in the frequency of stimulation of the presynaptic axon. Slide 7 - Another way of examining the synaptic strength of the synapse in response to the presynaptic stimulation is to examine how long it takes for the enhanced EPSP to return to normal amplitude without further stimulating the presynaptic axon. - The temporal duration or decay of LTP induced by the tetanic stimulation is correlated with the number of times you tetanically stimulate the presynaptic axon. - This graph represents how long it takes for the EPSP to return back to normal. After tetanic stimulation, in all cases, the EPSP is increased 2.5 times the normal EPSP amplitude. They examined the changes in the strength of the EPSP. After one bout of tetatnic stimulation, the EPSP decays much faster than 4 or 8 bouts. After 8 bouts of tetanic stimulation, the EPSP amplitude initially drops, but then it will be retained for long periods of time, even for months. - What explains the difference in temporal decay of EPSP? o There are several phases of LTP. o The longer lasting form of LTP is explained by more stable changes. o The increase in EPSP amplitude suggests that there are changes going on in the synapse. The change is more stable if you apply greater number of tetanic stimulations to the presynaptic axon. o The shorter lasting LTP in response to one tetanic stimulation is called the early phase of LTP. The longer lasting LTP in response to four or eight tetanic stimulation is called the late phase of LTP. There are differences in terms of the amount of change that occurs in the synapse. The changes in the synapse are greater and more stable in the late phase of LTP in comparison to the early phase of LTP. Slide 8 - LTP1 is not long lasting, so the changes are non-genomic mechanisms. - LTP2 and LTP3 results in more stable, longer lasting LTP because it recruits genomic mechanisms in addition to non-genomic mechanisms. Slide 9 - A common feature in the mechanisms of LTP is changes in calcium. Calcium is an important intracellular secondary messenger that is associated with many forms of learning. Progressive changes of calcium inside the cell will result in the activation of so many proteins in the plasma membrane and in the cytosol of the neuron. - Calcium is important for the generation of early phase and late phase LTP. Slide 10 - How does calcium increase in the postsynaptic cell as a result of high frequency presynaptic axonal stimulation? - The glutamate receptor in the postsynaptic neuron that is involved in LTP is mainly composed of two types: AMPA receptor and NMDA receptor. AMPA and NMDA receptors are both ionotropic receptors that mediate the generation of EPSPs in the postsynaptic neuron. Only the NMDA receptor is permeable to calcium. AMPA receptors are not permeable to calcium. Embryonic forms of AMPA receptors do allow calcium to enter, but the adult form does not allow calcium to enter the cell. AMPA receptors are only permeable to sodium. - NMDA receptors are important for LTP and learning. NMDA receptors are permeable to both calcium and sodium. Under normal conditions, calcium is not able to enter the cell. You need an increase in calcium concentration or calcium entry before LTP can be generated. However, magnesium is plugged into the pore of the NMDA receptor, and does not allow calcium or any ions to enter into the neuron. How can you increase the entry of calcium into the neuron? o One has to depolarize the postsynaptic neuron to dislodge the magnesium. If you depolarize the interior of the plasma membrane, then the buildup of positive ions inside will dislodge magnesium and free the pore of the NMDA receptor to allow calcium to get into the glutamatergic postsynaptic neuron. o Further depolarization of the postsynaptic neuron will activate another channel, including voltage-gated calcium channels. This is another way by which calcium can enter into the neuron and increase the cytosolic concentration of calcium. For example, the L-type calcium channels. Slide 11 - Presynaptic axons are releasing glutamate in response to stimulation. AMPA receptors are not permeable to calcium, but only permeable to sodium. NMDA receptors are permeable to both sodium and calcium, but there is a magnesium plug under normal conditions or low level of stimulation. Many axons should activate many AMPA receptors to be able to depolarize the postsynaptic neuron. The buildup of positive concentration inside the neuron will result in depolarization and dislodge the magnesium within the pore of the NMDA receptor and allow calcium to enter the postsynaptic neuron. - The other way for calcium to get into the postsynaptic neuron is via voltage-gated calcium channels. Slide 12 - You don’t have to apply the tetanic stimulation one presynaptic input to generate an increase in the EPSP. You can apply the tetanic stimulation on another presynaptic axon, which will possibly increase the EPSP in the other synapse in response to a test pulse. - You can apply the tetanic stimulation on the presynaptic axon of synapse I/B, and you can generate LTP on the postsynaptic neuron in response to a test pulse applied on the presynaptic axon of syn
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