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19. We will now turn to the application of several forms of repeated stress and illustrate what happens to neurogenesis and dendrite debranching within the hippocampus. We will also refer to new information as to how neurons in the amgydala respond to repeated stress.
20. One type of stress involves repeated restraint stress. We have restrained rats for 6h per day during their rest period, from 10AM to 4PM, and continued this treatment for up to 6 weeks. In spite of the fact that this appears to be a relatively innocuous and mild stress, rats react with a number of behavioral and structural changes.
For example, in recent work by Dr. Kara Pham, a single restraint stress session had no effect on dentate gyrus cell proliferation, using BrdU to label new cells, but 21d of repeated restraint stress suppresses cell proliferation. Dr. Pham then found that continuing daily restraint out to 6 wks results in decreased dentate gyrus neuron number and volume and reduction by half in the survival of cells born during the period of daily stress.
21. Besides suppressing neurogenesis, 21d of daily restraint stress reduces branching and total length of apical dendrites of CA3 neurons. Note that the basal dendritic tree is not altered by repeated restraint stress. Repeated stress has also been reported to decrease the length and branching of dentate gyrus granule neurons and CA1 pyramidal neurons. Dendritic remodeling is also produced by daily exposure to elevated corticosterone. Both stress- and glucocorticoid-induced remodeling are reversible.
Although glucocorticoids are able to mimic the effects of repeated stress on remodeling of dendrites, glucocorticoids are not acting alone. Excitatory amino acids play a major role in structural plasticity, and they may be responsible for suppressing neurogenesis in the dentate gyrus as well as participating in the remodeling of dendrites.
22. There are multiple, interacting mediators for dendritic remodeling in the CA3 region of the hippocampus. This has been shown by blocking the stress-induced remodeling with agents for different pathways.
Blocking glucocorticoids secretion, for example, each day during daily restraint stress prevents dendritic remodeling.. Likewise, blocking NMDA receptors also blocks remodeling. Excitatory amino acids are implicated by another drug. Using the anti-seizure medication, phenytoin, also prevents stress-induced remodeling, as well as remodeling caused by daily glucocorticoid treatment. Phenytoin produces its anti-seizure effects by blocking sodium and t-type calcium channels.
Another way of preventing both stress- and glucocorticoid-induced remodeling is by daily administration of a tricyclic antidepressant, tianeptine, which is supposed to enhance serotonin reuptake. Serotonin release is known to be increased by stress, and this may feed into the excitatory amino acid pathway by modulating NMDA receptor sensitivity.
Finally, enhancing inhibitory tone with a benzodiazepine prevents stress-induced dendritic remodeling.
23. Although other areas of the hippocampus are affected by repeated stress and glucocorticoids, the CA3 region seems to be among the most sensitive. This is because CA3 neurons excite each other when they are excited by mossy fiber input, as we have discussed earlier.. Moreover, they stimulate further excitatory input by sending collaterals back to mossy cells in the dentate gyrus. As a result of this feed-forward excitability, the CA3 is vulnerable to kainic acid induced seizures. Cell death ensues because the cells overexcite each other. Repeated stress may be activating the same mechanism, but in a more controlled manner. Here the outcome is retraction of dendrites, which may be a protective mechanism that reduces excitatory input and spares neurons from death.
24. Since there are many interacting pathways that appear to contribute to the remodeling of dendrites in CA3, there are also many points at which glucocorticoids interact to affect the various neurochemical systems that are involved. We have seen, for example, that adrenal secretions promote the stress-induced increase of extracellular glutamate levels. Glucocorticoids also increase expression of NMDA receptor subunits in hippocampus and increase certain types of calcium currents. They also facilitate serotonin turnover and in some brains areas increase expression of 5HT2A receptors, while down-regulating inhibitory 5HT1A receptors. Finally glucocorticoids modulate subunit composition of GABAa receptors in hippocampus and alter the efficacy of the GABAa receptors in different subfields of the hippocampus. Although the details of how these effects culminate to alter dendritic morphology are not clear, the nature of these effects is consistent with the hypothesis that glucocorticoids tip the balance towards excitation over inhibition within the hippocampus.
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