Abstract
Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders.
Highlights
Chronic psychosocial stress in adulthood modulates brain structure and function, resulting in cognitive deficits and an increased risk for psychiatric disorders
We demonstrate that forebrain CRH receptor 1 (CRHR1) deficiency attenuates spatial memory deficits and prevents the dendritic regression of CA3 neurons and the loss of hippocampal nectin-3 expression induced by chronic social defeat stress
Our findings suggest that the forebrain Corticotropin-releasing hormone (CRH)-CRHR1 system plays critical roles in the modulation of memory function under chronic stress
Summary
Chronic psychosocial stress in adulthood modulates brain structure and function, resulting in cognitive deficits and an increased risk for psychiatric disorders (de Kloet et al, 2005; Lupien et al, 2009). Various forms of chronic stress lead to reversible but long-lasting spatial memory impairments in adult male rodents (Bisaz et al, 2011; Conrad et al, 1996; Wright and Conrad, 2005). These effects are associated with atrophy of apical dendrites of CA3 pyramidal neurons (Kole et al, 2004; Magariños and McEwen, 1995; McLaughlin et al, 2007; Watanabe et al, 1992), suppression of hippocampal synaptic plasticity (Joëls et al, 2004; Kole et al, 2004; Pavlides et al, 2002), and altered expression of synaptic cell adhesion molecules in the hippocampus (Bisaz et al, 2011; Sandi, 2004). Factors other than elevated glucocorticoids and CA3 dendritic retraction must be responsible for chronic stress-induced spatial memory impairments
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