While chronic stress increases hyperpolarization-activated current (I_h) in dorsal hippocampal CA1 neurons, the underlying molecular mechanisms are entirely unknown. Following chronic social defeat stress (CSDS), susceptible mice displayed social avoidance and impaired spatial working memory, which were linked to decreased neuronal excitability, increased perisomatic hyperpolarization-activated cyclic nucleotide-gated (HCN) 1 protein expression, and elevated I_h in dorsal but not ventral CA1 neurons. In control mice, bath application of corticosterone reduced neuronal excitability, increased tetratricopeptide repeat–containing Rab8b-interacting protein (TRIP8b) and HCN1 protein expression, and elevated I_h in dorsal but not ventral CA1 region/neurons. Corticosterone-induced upregulation of functional I_h was mediated by the glucocorticoid receptor (GR), HCN channels, and the protein kinase A (PKA) but not the calcium/calmodulin-dependent protein kinase II (CaMKII) pathway. Three months after the end of CSDS, susceptible mice displayed persistent social avoidance when exposed to a novel aggressor. The sustained behavioral deficit was associated with lower neuronal excitability and higher functional I_h in dorsal CA1 neurons, both of which were unaffected by corticosterone treatment. Our findings show that corticosterone treatment mimics the pathophysiological effects of dorsal CA1 neurons/region found in susceptible mice. The aberrant expression of HCN1 protein along the somatodendritic axis of the dorsal hippocampal CA1 region might be the molecular mechanism driving susceptibility to social avoidance.

虽然慢性压力会增加背侧海马 CA1 神经元的超极化激活电流 ( I _{h )，但其潜在的分子机制完全未知。}在慢性社交失败压力 (CSDS) 之后，易感小鼠表现出社交回避和空间工作记忆受损，这与神经元兴奋性降低、perisomatic 超极化激活环核苷酸门控 (HCN) 1 蛋白表达增加以及背侧 I h升高_有关但不是腹侧 CA1 神经元。在对照小鼠中，沐浴皮质酮可降低神经元兴奋性，增加含有四肽重复序列的 Rab8b 相互作用蛋白 (TRIP8b) 和 HCN1 蛋白表达，并_升高Ih在背侧而不是腹侧 CA1 区域/神经元。皮质酮诱导的功能性I _h上调是由糖皮质激素受体 (GR)、HCN 通道和蛋白激酶 A (PKA) 介导的，但不是钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 通路介导的。CSDS 结束三个月后，易感小鼠在暴露于新的攻击者时表现出持续的社交回避。持续的行为缺陷与较低的神经元兴奋性和较高的功能性I _h有关在背侧 CA1 神经元中，两者都不受皮质酮治疗的影响。我们的研究结果表明，皮质酮治疗模拟了易感小鼠中发现的背侧 CA1 神经元/区域的病理生理学效应。HCN1 蛋白沿背侧海马 CA1 区体树突轴的异常表达可能是导致社会回避易感性的分子机制。