Networks of emotions in sexually dimorphic stress sensitivity

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Emotional information processing is modulated by a complex interplay of internal and external signals. A central feature in affective disorders is the attentional bias towards stimuli of negative valence. Notably, there is an increased sensitivity to stress and increased prevalence of mood disorders in women compared to men. The etiology of affective disorders involves diverse networks, engaging both subcortical and cortical neural circuits, yet a comprehensive understanding of the heterogeneity and the distinct functional roles of these circuits in shaping emotional responses remains elusive.
A subcortical pathway with a key role in negative valence extends from the lateral hypothalamic area (LHA) to the lateral habenula (LHb), eliciting robust aversive responses and contributing to depression-like states. Our research classified neurons within the LHA–LHb pathway into six glutamatergic types, each conveying unique emotional information. Notably, estrogen-sensitive (Esr1+) LHA–LHb neurons induce aversion and a sex-specific sensitivity to stress, while neuropeptide Y-expressing (Npy+) LHA–LHb neurons prompt arousal and rearing behavior. The persistent aversive state induced by Esr1+ LHA–LHb neurons is encoded by the prelimbic region of the prefrontal cortex (PFC).
Beyond the PFC, the insular cortex (IC), often referred to as ‘the emotional cortex’, plays a pivotal role in emotional information processing. IC encodes interoception, fear, and anxiety state transitions both in mice and in humans. Performing rabies tracing of the Esr1+ LHA–LHb pathway, we identified a population of estrogen-sensitive pyramidal neurons in the insular cortex, defined their connectivity, and investigated their functional contributions to emotional behaviors and aversive states.
In summary, our work investigates the crucial role of hormone-sensitive networks in emotional information processing and sexually dimorphic stress sensitivity.