Estrogen signaling in the ventromedial hypothalamus is required for the development of aggression circuitry in male mice

Abstract

Aggression in male mice depends on developmental estrogen exposure, yet the neural mechanisms underlying this phenomenon remain poorly understood. Although estrogen receptor α (Esr1) has served as a genetic marker to identify aggression-regulating neurons in the ventrolateral division of ventromedial hypothalamus (VMHvl), its functional role in organizing male-aggression circuits remains poorly understood. Here, we developed a genetic strategy to knock out Esr1 in VMHvl neurons while simultaneous tracing and manipulating Esr1-deleted cells. Developmental Esr1 knockout selectively altered synaptic inputs from aggression-regulating regions onto VMHvl neurons, with a stronger effect observed in males, revealing the posterior intralaminar thalamic nucleus (PIL) as a critical upstream region involved in male aggression. Additionally, VMHvl Esr1+ neurons in knockout males showed reduced excitability and failed to initiate attacks upon chemogenetic activation. These findings underscore the essential role of Esr1 in establishing male-specific aggression circuits, providing new insights into male-specific neural circuit development and function.

Keywords: Esr1; VMHvl; aggression circuit; developmental critical period; estrogen; hypothalamus; neural circuit formation; neuronal excitability; sex differences; the posterior intralaminar thalamic nucleus.