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Neuroscience Institute Journal Club 2018 Articles How Oxytocin Signaling in CA2 Begets Behavior

How Oxytocin Signaling in CA2 Begets Behavior

Social interaction is an essential component of animal behavior. The neural substrates of social cognition have been intensely studied for decades, with a spate of recent work focusing on the hippocampal subregion CA2. Functionally implicated in social memory and aggression, neurons in CA2 prominently express the oxytocin receptor (OXTR). Broadly, oxytocin signaling has been recognized as a modulator of parental and affiliative behavior. Specifically in CA2, oxytocin signaling is required for social memory. Our study addresses how oxytocin signaling in CA2 begets behavior by first considering the cellular consequences of oxytocin signaling. 

To begin, we investigated which hippocampal cell-types express the OXTR. Using two recently developed tools, the first OXTR antibody and a novel transgenic mouse line that targets gene expression to cells that express the OXTR, we demonstrated that both excitatory and inhibitory cells in CA2 express the receptor. This result is somewhat surprising given that in a neighboring hippocampal subregion (CA1) and in the cortex OXTR expression is restricted to interneurons. 

We next considered the intracellular consequence of OXTR stimulation using whole-cell electrophysiological recordings in acute hippocampal slices. Pharmacological stimulation of the OXTR caused depolarization in CA2 pyramidal cells that was often accompanied by dramatic bursts of action potentials. Optogenetic stimulation of oxytocin release from endogenous stores produced the same effect. This burst firing mode represents a stark shift from the normally quiescent basal state of CA2 pyramids. Interneurons, specifically those that express parvalbumin (PV), were similarly excited by oxytocin stimulation. 

We next investigated the molecular mechanisms underlying burst firing in CA2 pyramidal cells. Our first clue was that the cell’s input resistance increased following OXTR stimulation, suggesting the inhibition of a hyperpolarizing conductance. We then considered inhibition of the potassium-conducting “M-current,” so named for its modulation by muscarinic receptors. Pharmacological evidence, including blockade and activation experiments, implicated M-current inhibition as the primary means of OXTR-mediated depolarization. Inhibition of the M-current alone, however, was not sufficient to mimic the burst firing observed after OXTR stimulation. Only by jointly inhibiting the M-current and activating, via protein kinase C (PKC), ion channels involved in action potential formation were we able to recapitulate the OXTR effect. Thus, activation of two divergent signaling branches, leading to modulation of different ion channels is required to induce burst firing. Further, interplay between CA2 pyramidal cells and inhibitory neurons combines with cell-autonomous mechanisms to yield the burst–pause–burst pattern in its full glory.

Our preliminary experiments suggest that CA2 activation by oxytocin ultimately excites CA2’s primary output region, CA1. Our ongoing and future work continues to put CA2 activation in a circuit context, considering hippocampal and extrahippocampal output regions. Further, we are actively investigating when oxytocin release occurs during social behavior and how long-lasting oxytocin’s effects are. 

—Katherine Eyring

Read the paper “Oxytocin transforms firing mode of CA2 hippocampal neurons” in Neuron, published October 4, 2018.