Hippocampal corticotropin-releasing hormone neurons support recognition memory and modulate hippocampal excitability

Corticotropin-releasing hormone (CRH) signaling in the hippocampus has been established to be important for mediating the effects of stress on learning and memory. Given our laboratory’s recent characterization of a subset of hippocampal CRH neurons as a novel class of GABAergic interneurons, we hypothesized that these local GABAergic hippocampal CRH neurons may influence hippocampal function. Here we applied an array of molecular tools to selectively label and manipulate hippocampal CRH neurons in mice, in order to assess this interneuron population’s impact on hippocampus-dependent behaviors and hippocampal network excitability. Genetically-targeted ablation of hippocampal CRH neurons in vivo impaired object recognition memory and substantially enhanced the severity of kainic acid-induced seizures. Conversely, selective activation of CRH neurons in vitro suppressed the excitability of the mossy fiber-CA3 pathway. Additional experiments are needed to reconcile the functions of GABA and CRH signaling of hippocampal CRH neurons on hippocampal function. However, our results indicate that this interneuron population plays an important role in maintaining adaptive network excitability, and provide a specific circuit-level mechanism for this role.海马体内的促肾上腺皮质激素释放激素（Corticotropin-releasing hormone, CRH）信号通路，已被证实可介导应激对学习与记忆的调控效应。本实验室近期将一部分海马体CRH神经元鉴定为一类新型γ-氨基丁酸能中间神经元（GABAergic interneurons），基于此我们提出假说：这类局部存在的海马体CRH中间神经元可对海马体功能产生调控作用。本研究通过一系列分子工具，在小鼠体内选择性标记并操控海马体CRH神经元，以评估该中间神经元群对海马依赖性行为及海马网络兴奋性的影响。在活体小鼠体内通过基因靶向手段敲除海马体CRH神经元，会损伤物体识别记忆，并显著加重红藻氨酸（kainic acid）诱导的癫痫发作程度。反之，在体外选择性激活CRH神经元，则会抑制苔藓纤维-CA3通路（mossy fiber-CA3 pathway）的兴奋性。目前仍需开展额外实验，以厘清海马体CRH神经元所介导的γ-氨基丁酸（GABA）信号与CRH信号在调控海马体功能时的具体关联。但本研究结果表明，该中间神经元群在维持适应性网络兴奋性中发挥重要作用，并为该作用提供了特异性的环路层面调控机制。