Short-Term Stress Disrupts Spine Integrity and Plasticity

University Of California-Irvine, Irvine CA

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Abstract

The cognitive defects provoked by short-term stress are now emerging as a major clinical problem. The impact of severe, hours-long stresses-such as incurred on a battlefield or during emotional or physical trauma--is profound, because these stresses are frequent and unavoidable in modern life. Remarkably, relatively little is known about the underlying mechanisms. In a novel rodent model of a physical / psychological short-term stress, we observed major memory impairments associated with selective disturbances of hippocampal LTP and loss of dendritic spines. Thus, disturbances to synaptic plasticity and spine integrity, both involving dynamic actin organization, are shared among stress and several disorders discussed elsewhere in this application, and may share common mechanisms. Stress involves steroid, monoamine and peptide mediators;we have shown that the neuropeptide CRH (corticotropin releasing hormone) is released in hippocampus during stress and can impair dendritic spines in domains that are impaired after stress, suggesting involvement of CRH in stress-induced defects of spine integrity and synapse function. Therefore, this project will test the hypothesis that acting via CRH-CRH receptor (CRFR{1}) signaling, stress leads to disturbances of dendritic spine actin organization: (1) Stress Interferes with basal actin assembly resulting In spine loss;(2) In common with other disorders discussed in this program, stress deranges activity-driven assembly and stabilization of the spine actin-skeleton. Four Specific Aim are (1) To test if short stress reduces the number and actin-assembly of mature spines, and if this takes place via mechanisms involving endogenous CRH-CRFR{1} signaling;(2) To test if short stress disrupts activity-induced spine actin assembly and stabilization by mechanisms involving CRH-CRFR{1} signaling;(3) To examine the mechanisms downstream of CRFR{1}, specifically if the actin-regulating GTPase RhoA is involved in CRH-provoked spine loss, and if this spine loss is prevented by BDNF;and (4) To translate the results of the above In vitro studies into potential therapies, by testing if stress-induced deficits of spines, LTP and memory are abrogated by blocking CRFR{1}, augmenting BDNF, or combining the two approaches. Collectively, these studies will transform our understanding of how stress provokes memory deficits. Stress is the most common complaint of individuals in the modern world, and its effects on human function are inestimable. Uncovering the mechanisms by which stress impairs cognitive function and deriving targeted therapies based on these mechanisms will therefore have a profound impact.