Max Planck Institute of Psychiatry, Kraepelinstr 2-10, 80804 Munich, Germany.
Neurobiol Dis. 2011 Jun;42(3):300-10. doi: 10.1016/j.nbd.2011.01.020. Epub 2011 Feb 3.
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.
慢性应激会引起海马体的深刻结构和分子变化，这可能是空间记忆缺陷的基础。促肾上腺皮质激素释放激素 (CRH) 和 CRH 受体 1 (CRHR1) 介导了应激对树突棘形态的一些快速影响，并调节学习和记忆，从而为反复应激暴露导致的突触可塑性和空间记忆受损提供了潜在的分子基础。使用在前脑区域中条件性失活 CRHR1 的成年雄性小鼠，我们研究了 CRH-CRHR1 信号在慢性社交挫败应激对空间记忆、海马 CA3 锥体神经元树突形态以及突触细胞粘附分子 nectin-3 的海马表达的影响，nectin-3 在突触重塑中很重要。在慢性应激的野生型小鼠中，空间记忆受损，CA3 神经元的树突复杂性降低。相比之下，在前脑 CRHR1 缺乏的应激小鼠中，CA3 神经元的树突形态正常，空间记忆轻度受损。此外，我们表明，CA3 区 nectin-3 的表达受 CRHR1 依赖性慢性应激调节，并与空间记忆和树突复杂性相关。此外，前脑 CRHR1 缺乏可防止慢性应激引起的海马糖皮质激素受体表达下调，但在持续应激暴露期间诱导体重增加。这些发现强调了前脑 CRH-CRHR1 信号在调节慢性应激诱导的认知、结构和分子适应中的重要作用，这与应激相关的精神障碍有关。
