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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS045260-09
Application #
8376697
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$213,699
Indirect Cost
$74,453
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Bi, Xiaoning; Sun, Jiandong; Ji, Angela X et al. (2016) Potential therapeutic approaches for Angelman syndrome. Expert Opin Ther Targets 20:601-13
Baudry, Michel; Bi, Xiaoning (2016) Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration. Trends Neurosci 39:235-45
Wang, Yubin; Lopez, Dulce; Davey, Pinakin Gunvant et al. (2016) Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury. Neurobiol Dis 93:121-8
Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C et al. (2016) Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses. J Neurosci 36:11295-11307
Wang, Yubin; Hersheson, Joshua; Lopez, Dulce et al. (2016) Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. Cell Rep 16:79-91
Lauterborn, Julie C; Palmer, Linda C; Jia, Yousheng et al. (2016) Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats. J Neurosci 36:1636-46
Sun, Jiandong; Liu, Yan; Tran, Jennifer et al. (2016) mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell Mol Life Sci 73:4303-4314
Liu, Yan; Wang, Yubin; Zhu, Guoqi et al. (2016) A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation. Neuropharmacology 105:471-7
Wang, Weisheng; Kantorovich, Svetlana; Babayan, Alex H et al. (2016) Estrogen's Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function. Neuropsychopharmacology 41:2723-32
Liu, Yan; Sun, Jiandong; Wang, Yubin et al. (2016) Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice. Learn Mem 23:399-404

Showing the most recent 10 out of 94 publications