Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus

Abstract

Social behaviors, such as aggression or mating, proceed through a series of appetitive and consummatory phases1 that are associated with increasing levels of arousal2. How such escalation is encoded in the brain, and linked to behavioral action selection, remains an important unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell type-specific optogenetic activation of this region elicited attack behavior, but not mounting3. We have identified a subset of VMHvl neurons marked by the estrogen receptor 1 (Esr1), and investigated their role in male social behavior. Optogenetic manipulations indicated that Esr1+ (but not Esr1-) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behavior. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behavior, rather than attack, towards both males and females, as well as sniffing and close investigation (CI). Increasing photostimulation intensity could promote a transition from CI and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1+ neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1+ neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

Internal States and Behavioral Decision-Making: Toward an Integration of Emotion and Cognition

“…Together, these data suggest that optogenetic activation of VMHvl Esr1 þ neurons evokes different social behaviors in a scalable manner (Lee et al 2014): Low-intensity stimulation evokes appetitive and sexual behavior-social investigation and mounting-whereas higher intensities evoke attack (Figs. 6B, 7A).…”

“…First, the fraction of Esr1 þ neurons that are activated (c-fos þ ) following attack is approximately fiveto sixfold higher than after close investigation without attack ( Fig. 5H; Lee et al 2014). Second, electrophysiological recordings in VMHvl indicate that the average spiking rate ramps up quickly during the progression from CI to attack and that investigation is more likely to be followed by attack when the spiking rate is high ( Fig.…”

“…5D,E), whereas activation of Esr1 2 neurons was not (Lee et al 2014). Time-resolved optogenetic inhibition of Esr1 þ neurons interrupted ongoing attack (Fig.…”

“…6A, 7A; Lee et al 2014). Mounting was evoked toward normal and castrated males as well as females, with equal efficacy.…”

“…5A), 30% of which are activated during attack as determined by double-labeling for c-fos ( Fig. 5H; Lee et al 2014). To manipulate the function of these neurons, we generated gene-targeted mice expressing Cre recombinase in Esr1 þ neurons, allowing cell-type-specific expression of optogenetic effectors in VMHvl (Fig.…”