Neuronal activity in the hippocampus is critical for many types of memory acquisition and retrieval and influences an animal’s response to stress. Moreover, the molecularly distinct principal neurons of hippocampal area CA2 are required for social recognition memory and aggression in mice. To interrogate the effects of stress on CA2-dependent behaviors, we chemogenetically manipulated neuronal activity in vivo during an acute, socially derived stressor and tested whether memory for the defeat was influenced. One day after an acute social defeat (aSD), defeated mice spent significantly less time investigating another mouse when compared to non-defeated control mice. We found that this avoidant phenotype persisted for up to one month following a single defeat encounter. When CA2 pyramidal neuron activity was inhibited with Gi-DREADD receptors during the defeat, subject mice exhibited a significantly higher amount of social avoidance one day later when compared to defeated littermates not expressing DREADDs. Moreover, CA2 inhibition during defeat caused a reduction in submissive defense behaviors in response to aggression. In vitro electrophysiology and tracing experiments revealed a circuit wherein CA2 neurons connect to caudal CA1 projection neurons that, in turn, project to corticolimbic regions including the anterior cingulate cortex. Finally, socially avoidant, defeated mice exhibited significant reductions in cFos expression in caudal hippocampal and limbic brain areas during a social investigation task 24 h after aSD. Taken together, these results indicate that CA2 neuronal activity is required to support behavioral resilience following an acute social stressor and that submissive defensive behavior during the defeat (vs. fleeing) is a predictor of future resilience to social stress. Furthermore, CA2 preferentially targets a population of caudal CA1 projection neurons that contact cortical brain regions where activity is modulated by an acute social stressor.

海马体中的神经元活动对于许多类型的记忆获取和检索至关重要，并影响动物对压力的反应。此外，海马区 CA2 的分子不同的主要神经元是小鼠社会识别记忆和攻击性所必需的。为了询问压力对 CA2 依赖性行为的影响，我们在急性、社会衍生的压力源期间对体内神经元活动进行了化学ogenogen 操作，并测试了对失败的记忆是否受到影响。在急性社交失败 （aSD） 后一天，与未失败的对照小鼠相比，失败的小鼠研究另一只小鼠的时间明显更少。我们发现，这种回避表型在一次失败遭遇后持续长达一个月。当 CA2 锥体神经元活动在失败过程中被 Gi-DREADD 受体抑制时，与未表达 DREADD 的失败同窝小鼠相比，受试者小鼠在一天后表现出显着更高的社交回避量。此外，失败过程中的 CA2 抑制导致对攻击性的顺从防御行为减少。体外电生理学和示踪实验揭示了一个回路，其中 CA2 神经元连接到尾部 CA1 投射神经元，而 CA1 投射神经元又投射到皮质边缘区域，包括前扣带皮层。最后，在 aSD 后 24 小时的社会调查任务中，社交回避型、失败的小鼠在尾部海马和边缘大脑区域的 cFos 表达显着降低。综上所述，这些结果表明，需要 CA2 神经元活动来支持急性社交压力源后的行为弹性，以及失败期间的顺从防御行为（vs. 逃离）是未来对社会压力的适应能力的预测指标。此外，CA2 优先靶向接触皮质脑区域的尾部 CA1 投射神经元群，这些神经元的活动受到急性社会压力源的调节。