The overall goal of this proposal is to determine the role of the stress-neuromodulator corticotropin releasing hormone (CRH) in early-life neuroplasticity that contributes to neurological disease. Studies during previous funding periods have demonstrated that central administration of synthetic CRH to infant rats led to long-term deficits of hippocampus mediated cognitive function, similar to those described after severe early-life stress in human infants. We have also demonstrated the presence of the 'cellular machinery' for endogenous CRH in immature hippocampus, i.e., substantial populations of CRH-expressing interneurons and abundant CRH receptors on hippocampal pyramidal cells innervated by these interneurons. Therefore, the current proposal aims to definitively test the hypothesis that enduring upregulation and excessive release of endogenous hippocampal CRH contribute crucially to the impaired functional integrity of the hippocampus following early-life adverse events such as chronic psychological stress or recurrent seizures. The driving hypothesis of this research is that certain stresses occurring during a period of heightened hippocampal plasticity elevate the 'set-point' of hippocampal CRH expression, increasing the peptide's levels in hippocampus longterm. Therefore, subsequent, acute stress at any point in life will evoke 'excessive' release of CRH from hippocampal interneurons. Pathological levels of CRH provoke acute and long-term hippocampal neuronal dysfunction, associated with synaptic reorganization. This research proposal focuses on understanding this process at the synaptic, cellular and system levels, defining the means for interrupting the deleterious actions of excessive endogenous CRH on hippocampal function and integrity. Therefore, the proposal aims to: (1) Investigate the effects of early-life (P2-P9) chronic 'psychological1 stress on hippocampal CRH expression long-term. (2) Delineate the unique synaptic machinery by which CRH (an excitatory neuropeptide), is stored in inhibitory interneurons, define the site of the postsynaptic elements mediating the peptide's actions, and determine whether stress activates post-synaptic hippocampal pyramidal cells via the release of endogenous CRH. (3) Characterize the functional, electrophysiological and structural hippocampal changes induced by early-life chronic psychological stress in a novel model. (4) Determine whether these effects of early-life stress are abrogated by blocking the actions of endogenous, stress-released CRH; in other words, whether the endogenous peptide is a required, crucial mediator of the enduring, life-long adverse effects of early-life stress on hippocampal functional integrity. These studies address the impact of early-life chronic psychological stress, such as child abuse and neglect (and perhaps recurrent seizures), on critical learning & memory functions. By defining the role of the stress-activated neuropeptide, CRH, in the mechanisms of the established adverse effects of these early-life events, these studies will provide truly innovative and exciting targets for prevention of a tremendous loss of human potential. ? ?
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