In brain, the over-activity of stress hormones and endogenous excitatory amino acids (EAA) causes shortening of dendrites in the CA3 region and suppresses neurogenesis in the dentate gyrus (DG). Yet, even these changes, although impairing some functions such as declarative memory, may not constitute """"""""damage"""""""" but rather a form of adaptive plasticity that is protective against permanent damage and also reversible and potentially treatable with antidepressants and mood stabilizers. We focus our studies on the DG-CA3 because it is where both neurogenesis and remodeling of dendrites occurs. The DG-CA3 is the critical entry point for information processing by the hippocampus and it is also vulnerable to damage because of its circuitry. Hence it is also a nexus for the remodeling effects of stress that involve glucocorticoids and excitatory amino acids and which cause impairment of hippocampal dependent memory. We believe that the remodeling of dendrites holds the key to whether the cumulative effects of stress may be ultimately irreversible. Our main hypothesis is that dendrite remodeling in DG-CA3 under stress is a reversible, adaptive process involving EAA and glucocorticoids that, like a fuse box, reduces the likelihood of permanent damage to this important and vulnerable system and affords some neuroprotection and the opportunity for reversibility. The DG-CA3 involves collaterals that excite other CA3 neurons and both feed-forward and feed-back effects that are delicately balanced and subserve memory processing; Chronic stress leads to activation of EAA release resulting in a chronic """"""""on"""""""" state that drives dendritic remodeling. This drives the reorganization of the microtubules and associated proteins which is dependent on extracellular modulators such as PSA-NCAM expressed in DG-CA3 that facilitates movement of cellular processes and modulates BDNF. We predict that removal of PSA from NCAM will prevent stress-induced remodeling and lead to permanent damage to CA3 pyramidal neurons. Translational studies have shown that hippocampal shrinkage occurs in major depression and bipolar disorder as well as Cushing's Disease, where it is partially reversible, lending hope to the ability to reverse hippocampal atrophy in psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Winsky, Lois M
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Rockefeller University
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New York
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