The Dorsal Raphe Regulates the Duration of Attack through the Medial Orbitofrontal Cortex and Medial Amygdala

Abstract

The dorsal raphe (DR) is an evolutionarily conserved brain structure that is involved in aggressive behavior. It projects onto numerous cortical and limbic areas underlying attack behavior. The specific neurocircuit through which the DR regulates aggression, however, is largely unclear. In this study we show that DR neurons expressing CaMKIIα are activated by attack behavior in mice. These neurons project to the medial aspect of the orbitofrontal cortex (OFC; MeOC) and the medial amygdala (MeA), two key regions within the neural circuit known to control aggressive behavior. Using an in vivo optogenetic approach, we show that attack bouts are shortened by inhibiting CaMKIIα⁺ neurons in the DR and their axons at the MeOC and prolonged by stimulating the DR-MeOC axons during an attack. By contrast, stimulating the axons of CaMKIIα⁺ DR neurons at the MeA shortens attack. Notably, neither the DR-MeOC or DR-MeA pathway initiates attack when stimulated. These results indicate that the DR-MeOC and DR-MeA pathways regulate the duration of attack behavior in opposite directions, revealing a circuit mechanism for the control of attack by the DR.

Significance Statement The dorsal raphe (DR) is a major node in the brain circuit regulating multiple attack behaviors. The underlying neurocircuitry through which the DR acts on aggression, however, remains elusive. Here, we show that the DR regulates the duration of attack through the medial orbitofrontal cortex (OFC; MeOC) and the medial amygdala (MeA), areas known to play a key role in aggression. While neither pathway is sufficient to initiate an attack, silencing the DR-MeOC pathway or activating the DR-MeA pathway shortens an attack, and stimulation of the DR-MeOC circuit prolongs an already occurring attack. These findings identify two DR-mediated neural circuits that regulate attack behavior.