Regulation of social aggression through hippocampal CA2 inputs to lateral septum

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Heightened levels of social aggression, a motivated behavior, are often associated with neuropsychiatric disease. Although our understanding of the neural mechanisms regulating aggression is incomplete, both lateral septum (LS) and ventral hypothalamus are known to be important. Even though LS receives one of its strongest inputs from hippocampus, a region important for declarative memory, little is known about how hippocampus regulates aggression. Moreover, as hippocampus is implicated in several neuropsychiatric disorders associated with altered social behavior and aggression, a basic understanding of how hippocampus and its circuitry regulate aggression will likely yield important new insights into disease mechanisms. Here we focus on the role of the hippocampal CA2 region in social aggression. Relatively little is known about CA2, largely because of technical problems that limit its study with conventional lesioning approaches. We therefore developed a Cre mouse line that enables us to label and manipulate the activity of CA2 pyramidal neurons. Using a genetic silencing approach, we found that CA2 was critical during non-aggressive social exploration for the formation of social memory, the ability of an animal to recognize and remember another mouse (conspecific), but CA2 was not needed for other forms of hippocampal memory. Our recent results now show that CA2 also promotes social aggression, through an excitatory projection to LS that disinhibits a subnucleus in ventral medial hypothalamus important for aggression. Moreover, we find that the social neuropeptide arginine vasopressin promotes aggression by enhancing the CA2 to LS synapse. Here we ask: How does a single brain region, CA2, participate in social memory storage during non- aggressive social exploration and promote social aggression? Is there a single population of CA2 neurons that is activated during both social exploration and social aggression? Or are there specialist neurons for each behavior? Does CA2 actively encode distinct representations of social exploration and social aggression, or does CA2 encode a single social salience signal that does not in itself encode aggression but that is gated by the internal state of an animal to promote aggression through CA2 inputs to LS? We will test the hypothesis that vasopressin release in LS acts as such a permissive gate. As vasopressin also enhances social memory by acting within CA2, we will ask: How can a single neuromodulator produce two such distinct actions? Do distinct sources of vasopressin input to CA2 and LS promote, respectively, social memory and aggression? We will address these questions by characterizing CA2 circuits and neural activity during aggressive and non-aggressive social interactions using: 1. Activity-dependent genetic marking of active CA2 ensembles; 2. Electrophysiological characterization of CA2?LS circuits and their regulation by vasopressin in ex vivo brain slices; 3. Behavioral control of aggression using chemogenetics and optogenetics; and 4. In vivo optical and electrophysiological recordings of CA2 activity during non-aggressive and aggressive social interactions.