Independent inhibitory control mechanisms for aggressive motivation and action

Abstract

Social behaviors, like other motivated behaviors, frequently consist of a flexible motivatedseeking or approach phase followed by social action. Dysregulated social behavior may arise from changes to motivation, wherein individuals fail to enter a motivated seeking state, or may be in the execution of the social action itself. However, it is unclear how the brain generates and gates this flexible motivation-to-action sequence, and whether aggressive motivation and action are controlled by separate circuit mechanisms. Here, we record populations of neurons in the ventromedial hypothalamus ventrolateral area (VMHvl) of male mice at cellular resolution during "free" aggression and also during an aggression operant task, where the behaviors that precede attack are stereotyped. We find that this population encodes the temporal sequence of aggressive motivation to action and that the temporal selectivity of neurons is invariant to differences in motivated behavior. To test whether motivation and action could be independently regulated, we focused on two key inhibitory inputs to the VMHvl: a source of local . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made inhibition (VMHvl shell) and the primary source of long-range inhibition (the medial preoptic area, MPO). While we find that the VMHvl receives broad monosynaptic inhibitory input from both inputs, optogenetic perturbation of these inputs during recording reveals temporal selectivity during aggressive motivation and action, suggesting specificity of function. Encoding models applied to population calcium recordings of these inhibitory inputs during naturalistic social interactions and during the social operant task further reveal that these inputs have different temporal dynamics during aggression: VMHvl shell vgat+ activity peaks at the start of aggressive interactions, while MPO-VMHvl vgat+ activity peaks at behaviorally aligned endpoints of aggressive interactions. Finally, using closed-loop optogenetic stimulation timed to specific phases of the aggression-operant task, we find a double-dissociation of the effects on aggressive motivation and action: activation of MPO-VMHvl vgat+ , even briefly and temporally distant from the initiation of aggression, produces long-lasting motivational deficits, delaying the initiation of aggression and generating behaviors consistent with an unmotivated state. In contrast, activation of VMHvl shell vgat+ produces acute action-related deficits, causing an exit from an attack state. Fitting a Hidden Markov Model (HMM) to behavior further corroborates these findings by showing that MPO-VMHvl vgat+ stimulation prolongs a low motivation state and VMHvl shell vgat+ promotes exit from an attack state. Together, these data demonstrate how separable inhibitory circuits in the hypothalamus can independently gate the motivational and action phases of aggression through a single locus of c...

Medial preoptic circuits governing instinctive social behaviors

“…Optogenetic stimulation of ERα-positive GABAergic MPOA neurons in male mice converted male-directed attack to mounting with ultrasonic vocalizations characteristic of female mounting. Indeed, long-range MPOA projections reach the VMHvl, 82 specifically, ERα-positive GABAergic MPOA neurons project to the VMHvl ( Figure 5 ), and optogenetic stimulation of their terminals in VMHvl strongly inhibited aggression. 37 Chemogenetic inhibition of ERα-positive cMPOA neurons resulted in repeated attacks toward female intruders, while their chemogenetic stimulation was consistent with optogenetic data as it nearly abolished intermale aggression.…”