Project Summary (Project 3, Co-PIs: Tsien, Buzsaki, Froemke, Lin) Oxytocin is a neuropeptide that shapes vital behaviors such as pair bonding, parenting and social competition. There are many pressing questions about how such behaviors are steered by brain circuits. Understanding oxytocin’s actions in the brain is further motivated by possible disruption of oxytocin signaling in various neuropsychiatric disorders. Oxytocin is widely seen as affecting cellular excitability, synaptic transmission, and long-term plasticity in single neurons, but a mechanism-based understanding of behavior is still lacking. Project 3 and 4 have a suitable meeting ground for understanding modulatory mechanisms, examining circuits in hippocampus and lateral septum (LS) that successively relay input from neocortical areas and send output to other brain areas that control social behaviors. OXTRs are particularly enriched in the CA2 subregion of the hippocampus. Hippocampal CA2 harbors pyramidal neurons (PYRs) that directly receive input from lateral entorhinal cortex and are pivotal to generation of brain oscillations and establishment of social memory. The lateral septum, a largely GABAergic structure, includes neurons in its dorsal quadrant that receive inputs from CA2 and other neurons that connect to hypothalamic VMHvl to help control a range of behaviors including aggression and competition. Here we will study the cellular, synaptic and microcircuit signaling mechanisms of oxytocin, focusing on the CA2 subregion and the LS. Aim 1 builds on our recent discovery of how oxytocin alters excitability in CA2 PYRs: by diminishing inward rectifier potassium channels (IKir) (favoring membrane depolarization) and shutting off hyperpolarization-activated cyclic-nucleotide-gated channels (Ih) (providing a hyperpolarizing drive). The combined reduction in both IKir and Ih restrains membrane potential from quickly depolarizing from rest (thus enabling oxytocin to “signal slow”) but synergistically elevates membrane resistance, favoring dendritic integration. Indeed, we observe a new population of huge unitary synaptic currents. We will test whether these giant events arise from distal dendritic inputs, impinging on local GluR clusters several times bigger than at postsynaptic sites nearer the soma, potentially those arriving from entorhinal cortex. In Aim 2, we will pursue new data showing that fast-spiking interneurons (FSIs) display an unusual synergy between oxytocin and inhibitory transmission. A FSI driven to rapidly fire by OXTR stimulation can be persistently interrupted by brief GABAergic inhibition. We will test whether such combinatorial “signaling fast” supports sudden switching of circuits involved in social choice, as proposed by our Computational Modeling Core. In Aim 3, we will build on our surprising observation that oxytocin hyperpolarizes certain inhibitory LS neurons, causing them to cease their spontaneous firing (“signaling in reverse”), by heavily weighting...