OPTOGENETIC DISSECTION OF PREFRONTAL–LATERAL HYPOTHALAMUS CIRCUIT IN STRESS-RELATED BEHAVIOURS

Stress recruits specific neuronal populations in the medial prefrontal cortex (mPFC), but the projection targets and functional roles of these stress-responsive neurons remain unclear. The lateral hypothalamus (LH) regulates innate behaviours like feeding and social interaction, which are influenced by stress. While mPFC–LH projections modulate these behaviours, their involvement in stress and anxiety is poorly understood. It is also unknown whether reactivation of stress-responsive mPFC neurons affects stress-related behaviours. To date, stress-activated mPFC ensembles and their functional contribution to mPFC–LH circuit dynamics have not been directly tested.
Three complementary approaches were employed: (1) optogenetic stimulation of mPFC–LH projections, (2) reactivation of stress-responsive mPFC–LH projecting neurons, and (3) reactivation of stress-responsive mPFC neurons independent of projection target. For 2-3, Cre dependent opsin (ChR2) construct was injected into mPFC of TRAP2 mice, optic fibers were implanted in mPFC and LH. Mice were subsequently injected with 4-hydroxytamoxifene during restraint. Behavioural consequences of optogenetic stimulation were assessed across paradigms probing anxiety-like, social, and motivational behaviours under metabolic, physical, and social stress conditions.
Activation of mPFC inputs to LH promoted behaviours that alleviated stress, such as food seeking following fasting or seeking out conspecifics following restraint. Thus, mPFC input to LH can promote adaptation in response to stress. We then identified stress-responsive mPFC–LH projecting neurons, and found that distinct neuronal ensembles were activated in stressful conditions compared to homecage. Reactivation of these neurons influenced behavioural responses. We gratefully acknowledge support by the ERC consolidator grant HypFeedNet, DFG CRC1451, EXC2030-CECAD.