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.