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All learning depends on memory. Memory formation seems to occur in two separate phases, firstshort-term memory. (e.g. people undergoing electroconvulsive therapy (to relieve depression) are unable to recall events that happened immediately before the procedure, but their memory of previous events remains unchanged), followed by formationlong-term memory. Damage to the temporal lobes of the brain can cause the loss of the ability to remember new learning for more than an hour. Two systems that have proven particularly useful for unraveling the cellular and molecular basis of memory formation are the sensitization of the sea snail Aplysia and the long-term potentiation (LTP) study.
Long-Term Enhancement (LTP)
Rats and mice can be taught to solve simple tasks. For example, if a mouse is placed in a pool of murky water, it will swim until it finds a hidden platform to climb on. With repetition, the mouse will soon learn to locate the platform faster. Presumably, it does this by visual cues placed around the perimeter of the pool, as it cannot see or smell the platform itself.
Rats or mice that had part of the brain calledhippocampusdamaged, he cannot learn this task, although he still solves it quickly if trained before his brain injury. This suggests that neurons in the hippocampus are needed for this type of learning. Unlike the rest of the brain, new neurons are formed in the hippocampus throughout life. They arise from a pool of stem cells in the brain. Integrating the newly formed neurons into existing hippocampal circuitry makes it easier to learn new memories (as well as forget old ones).
Demonstration of long-term potentiation
The behavior of some synapses in the "CA1" region of the rat (or mouse) hippocampus is consistent with them being essential for this form of long-term memory. Hippocampal slices can be removed and their CA1 neurons studied in vitro using recording electrodes. Rapid and intense stimulation of presynaptic neurons produces action potentials in the postsynaptic neuron. This is exactly what we would expect from the properties of synapses.
What is unusual about this system is that over time, the synapses become more and more sensitive, so that a constant level of presynaptic stimulation is converted into more postsynaptic power (graph to the right). This long-term enhancement can last for weeks. Treating a piece of the hippocampus with a drug called aminophosphonovaleric acid ("APV") blocks the formation of LTP. This is because APV blocks the action of NMDA receptors, a subgroup of postsynaptic receptors that normally respond to the excitatory neurotransmitter glutamate (Glu). NMDA receptors (synapse B above) differ from other Glu-activated receptors by being stimulated by the drug,N-methyl-D-asparaginian (NMDA).
NMDA receptors contain a transmembrane channel that allows facilitated diffusion of calcium ions (Ca2+) across the plasma membrane of the synapse. Glu (or NMDA) binding andD-serine released from the astrocyte near these receptors opens a channel allowing Ca2+flow if and only if the same postsynaptic cell was simultaneously depolarized by other synapses on it (synapse A above). (The picture is very simplistic: each CA1 neuron has tens of thousands of synapses on it.)
influx ca2+in the neuron, it activates an enzyme called calcium-calmodulin-dependent kinase II (CaMKII). Kinases attach phosphate groups to proteins and thus change their function. In this case, CaMKII phosphorylates a second type of Glu receptor, called the AMPA receptor, which makes them more permeable to sodium ions (Na+) thus reducing the resting potential of the cell and making it more sensitive to incoming impulses. In addition, there is evidence that CaMKII activity increases the number of AMPA receptors in the synapse.
The ability to create transgenic mice provided the tools to test this LTP model.
mutated rats
Mice homozygous for the mutated CaMKII transgene do not develop LTP. This has been shown (A. J. Silver et al., vScience 257:206, 1992) in two ways:
- measurement of the current in the postsynaptic cell of normal and mutant mice. The graph above (left) shows that mutant mice do not develop the increase in current flow that normal mice have (graph above).
- The same LTP failure occurs when mice are tested on a hidden platform (right graph).
transgenic mice
They show transgenic mice that produce very large amounts of NMDA receptorsImproved LTPas shown by
- increased postsynaptic currents in the hippocampus
- its better performance in the hidden platform test
- and better scores on other tests of learning and memory
These findings were reported in the September 2, 1999 issueNatureby Tang, Y-P et al. The experiments described above show that manipulations that affect the postsynaptic electrical response (EPSP) of electrically stimulated neurons also affect learned behavior. They don't show this learningevokesincrease in EPSP in hippocampal postsynaptic neurons. Now researchers at MIT have done just that.
They used mice that were implanted with a series of closely spaced recording electrodes in the CA1 region of the hippocampus. These rats were then placed in a training device where, in one test, they learned that going from a lighted chamber to a dark one could shock them.
In just 30 minutes, some, but never all, of the recording electrodes picked up increased EPSPs in CA1 neurons, and the number of AMPA receptors increased in CA1 cells. Thus, learning this conditioned response resulted in LTP electrical and synaptic changes, but only in certain areas of the hippocampus. Presumably, other types of learning would cause LTP in other parts of the CA1 region. (You can read a report on his work at Whitlock, J.R.,i inni,ScienceAugust 25, 2006.)
Initial LTP vs. Late LTP
LTP comes in two phases:
- early (around the first hour), which involves increased synaptic sensitivity without any new gene transcription or mRNA translation
- late, which requires transcription of new genes and mRNA translation and results in growthnumerAMPA receptors, accompanied by an increase in the size of the synaptic connection. These changes last for hours and even days. However, the increased formation of AMPA receptors appears to require constant stimulation because (at least in rats) interfering with this process removes late LTP (and memory) even a month later.
This is further evidence that memories are acquired in two phases; early and late. Late LTP can involve not only the addition of AMPA receptors to existing synapses, but also the formation of entirely new synapses. Research conducted in Geneva, Switzerland, showed that the formation of LTP in rat brains coincides with the formation of additional synapses (at least one more) between the presynaptic axon terminal and the dendrite it synapses with. (Report by Toni, N. et al.,Nature, November 25, 99). Presumably, this also increases the efficiency of synaptic transmission.
summary
- Rapid and intense stimulation of CA1 neurons in the hippocampus depolarizes them.
- Glu and bindingD- cheese for youNMDA receptorsOpen them.
- ok2+Ions enter the cell through NMDA receptors and bind to themcalmodulin.
- This activates calcium and calmodulin-dependent kinase II (CaMKII).
- CaMKII phosphorylates AMPA receptors, making them more permeable to Na influx+ions and thus increases the sensitivity of the cell to depolarization.
- Over time, CaMKII also increases the number of AMPA receptors in the synapse.
- Increased gene expression (ie protein synthesis - possibly from AMPA receptors) also occurs during LTP development.
- During the formation of LTP, synaptic connections are widened and possibly additional synapses are formed.
LTP has also been demonstrated in cerebellar neurons.
Long-term depression (LTD)
Slow and weak electrical stimulation of CA1 neurons also causes long-term changes in synapses, in this case a decrease in their sensitivity. This is called prolonged depression or LTD. It reduces the number of AMPA receptors in the synapse. Long-term depression also occurs in isolated preparations of sea snail, Aplysia and mouse cerebellum neurons during conditioned response (CR) development
FAQs
What can increase LTP? ›
- Lifestyle, Dietary, And Other Factors That May Potentially Stimulate LTP.
- LACKING EVIDENCE: 1) Exercise. 2) Fasting. 3) Berberine. 4) Lipoic Acid. 5) Luteolin. 6) Ginseng. 7) Ashwagandha. 8) Fisetin. 9) Glycine. 10) Forskolin. 11) Taurine. 12) Ginkgo Biloba. 13) Curcumin. 14) Glucose. 15) Bacopa monnieri. 16) Erythropoietin.
Long-term potentiation (LTP) is a process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons. It is an important process in the context of synaptic plasticity. LTP recording is widely recognized as a cellular model for the study of memory.
Does exercise increase LTP? ›Exercise increased the neuronal excitability of granule cells at lower stimulus intensities (i.e., induced LTP at a lower intensity threshold). Exercise also increased EPSP to a higher degree after stimulation.
Can LTP be reversed? ›LTP could be nearly completely reversed by theta frequency stimulation when potentiation was induced by milder and more naturalistic stimulation patterns.
How is LTP activated? ›LTP and LTD are induced by activation of NMDARs at synapses between CA3 and CA1 pyramidal neurons (blue and red).
What triggers LTP in hippocampus? ›Rhythmic bursting activity is highly effective in inducing LTP and it is argued that the endogenous hippocampal theta rhythm plays a role in LTP induction in vivo.
What does LTP mean in the brain? ›In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons.
How long does late LTP last? ›Late LTP (L-LTP, lasting > ~2 h) requires protein synthesis (Stanton and Sarvey, 1984; Frey et al., 1998; Abraham and Williams, 2008) and can last at least a year (Abraham et al., 2002).
What is depression LTP? ›It can result from strong synaptic stimulation (as occurs in the cerebellar Purkinje cells) or from persistent weak synaptic stimulation (as in the hippocampus). Long-term potentiation (LTP) is the opposing process to LTD; it is the long-lasting increase of synaptic strength.
How long does exercise increase serotonin? ›The cortical changes lasted at least a week after discontinuing exercise, whereas serotonin activity in the brainstem is diminished by that time (Dey et al., 1992). The hypothalamus shows decreased serotonin metabolism one day after training, increasing again after a week's rest (Dey et al., 1992).
How much exercise increases serotonin? ›
Aerobic exercise — walking, running, biking and swimming — significantly increases serotonin production in the body. You need about 30 minutes to get the serotonin “high.” Other exercise like yoga, Pilates and weight-lifting increases serotonin, too, just not as much.
Does exercise spike serotonin? ›As reviewed by Jacobs and Fornal,61 motor activity increases the firing rates of serotonin neurons, and this results in increased release and synthesis of serotonin. In addition, there is an increase in the brain of the serotonin precursor tryptophan that persists after exercise.
What happens if long-term potentiation is damaged? ›Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss.
In which areas of the brain does long-term potentiation LTP occur? ›LTP has been most thoroughly studied in the mammalian hippocampus, an area of the brain that is especially important in the formation and/or retrieval of some forms of memory (see Chapter 31).
What is the opposite of LTP? ›Long-term depression (LTD) is the opposite of LTP, and is characterized by a decrease in postsynaptic strength. This happens by dephosphorylation of AMPA receptors and the facilitation of their movement away from the synaptic junction.
What does LTP depend on? ›LTP of the Schaffer collateral synapse exhibits several properties that make it an attractive neural mechanism for information storage. First, LTP is state-dependent: The degree of depolarization of the postsynaptic cell determines whether or not LTP occurs (Figure 25.7).
What is LTP dependent on? ›NMDA receptor-dependent LTP and LTD are triggered by standard high-frequency stimulations (e.g., one or more trains of 100 Hz stimulation)9,10 and low-frequency stimulations (LFS; e.g., 700–900 pulses at 1 Hz)11,12,13,14, respectively.
What impairs LTP? ›LTPGABA is impaired at 24 hours following morphine and cocaine injection, but not after nicotine.
What process does long-term potentiation LTP depend on? ›LTP shares many features with long-term memory that make it an attractive candidate for a cellular mechanism of learning. For example, LTP and long-term memory are rapidly induced, each depends upon the synthesis of new proteins, each has properties of associativity, and each can potentially last for many months.