Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.

Summary Although the hippocampus is known to be important for declarative memory, how hippocampal output regulates motivated behaviors, such as social aggression, is less well understood. Here we report that hippocampal CA2 pyramidal neurons, which are important for social memory, promote social aggression. This action depends on CA2 output to the lateral septum that is selectively enhanced immediately prior to attack. Activation of lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventro-medial hypothalamus known to trigger attack. The social hormone arginine-vasopressin enhances social aggression by acting on arginine-vasopressin 1b receptors on CA2 presynaptic terminals in lateral septum to facilitate excitatory synaptic transmission. In this manner, release of vasopressin in lateral septum, driven by an animal’s internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter or proceeds to promote motivated social aggression.

Summary Input-timing dependent plasticity (ITDP) is a circuit-based synaptic learning rule whereby precisely timed, paired activation of direct entorhinal cortex (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 pyramidal neurons (PNs) produces a long-term enhancement of CA1 SC excitation, which has been linked to specificity of contextual memory. We report that paired activation of EC and SC inputs also increases SC excitation of CA2 PNs, which are important for social memory. However, whereas CA1 ITDP depends on endocannabinoid CB1 receptor-dependent long-term depression of feedforward inhibition (iLTD) mediated by cholecystokinin-positive interneurons, CA2 ITDP depends on δ-opioid receptor-dependent iLTD of parvalbumin-positive interneuron inhibition. Blockade of CA2 δ-opioid receptors blocked ITDP and impaired social memory whereas a social encounter with a novel animal decreased CA2 feedforward inhibition and occluded ITDP. Thus, ITDP may provide a more general synaptic learning rule for distinct forms of hippocampal-dependent memory through its recruitment by distinct hippocampal regions.