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.

Public Health Relevance

Stress is common in modern life, affects all of us, and can influence our ability to learn and remember. Memory processes involve changes in the structure of delicate protrusions of brain cells (dendritic spines). We will study a how a stress hormone released during short stress in a memory center of the brain, disturbs memory-related changes in dendritic spines. We will use the resulting information to design novel therapies that will prevent stress-induced memory problems.

National Institute of Health (NIH)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of California Irvine
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Ozkan, Emin D; Creson, Thomas K; Kramár, Enikö A et al. (2014) Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 82:1317-33
Lynch, Gary; Cox, Conor D; Gall, Christine M (2014) Pharmacological enhancement of memory or cognition in normal subjects. Front Syst Neurosci 8:90
Seese, Ronald R; Maske, Anna R; Lynch, Gary et al. (2014) Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism. Neuropsychopharmacology 39:1664-73
Wang, Yubin; Zhu, Guoqi; Briz, Victor et al. (2014) A molecular brake controls the magnitude of long-term potentiation. Nat Commun 5:3051
Regev, Limor; Baram, Tallie Z (2014) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol 35:171-9
Maras, P M; Molet, J; Chen, Y et al. (2014) Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress. Mol Psychiatry 19:811-22
Briz, Victor; Baudry, Michel (2014) Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms. Front Endocrinol (Lausanne) 5:22
Cox, Conor D; Rex, Christopher S; Palmer, Linda C et al. (2014) A map of LTP-related synaptic changes in dorsal hippocampus following unsupervised learning. J Neurosci 34:3033-41
Riazifar, Hamidreza; Jia, Yousheng; Chen, Jing et al. (2014) Chemically induced specification of retinal ganglion cells from human embryonic and induced pluripotent stem cells. Stem Cells Transl Med 3:424-32
Baudry, Michel; Bi, Xiaoning (2013) Learning and memory: an emergent property of cell motility. Neurobiol Learn Mem 104:64-72

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