Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Chronic social stress is a significant risk factor for the development of anxiety and major depressive disorder (MDD). While the lateral hypothalamus (LHA) and the lateral habenula (LHb) are known to be involved in stress and motivation, the specific role of the circuit connecting these two regions—specifically the projections from LHA orexinergic neurons to the LHb—in managing the aftermath of social defeat remains largely unknown. This study aimed to characterize how this circuit functions in socially defeated mice and whether manipulating it could alter behavioral symptoms.

Researchers used a multidisciplinary approach involving mice subjected to a 10-day chronic social defeat stress (CSDS) protocol. Key methods included:

• FosTRAP Strategy: To genetically label and identify neurons activated by social stress.
• Fiber Photometry: To observe real-time calcium activity in specific neuronal populations during social interactions.
• Optogenetics: To selectively activate LHA orexinergic neurons or their terminals in the LHb.
• Neuropharmacology: To test the behavioral impact of directly manipulating orexin signaling in the LHb using orexin A and an orexin receptor 2 (OxR2) antagonist.

Social defeat stress strongly activated LHA orexinergic neurons and LHb glutamatergic neurons. The researchers discovered that:

• Increasing orexin signaling in the LHb successfully alleviated social avoidance and depression-like behaviors following CSDS.
• Blocking OxR2 in the LHb exacerbated depressive-like phenotypes, suggesting this receptor plays a critical role in the antidepressant effects of the circuit.
• Optical activation of LHA orexinergic cell bodies or their projections to the LHb significantly reduced anxiety-like behaviors in tests such as the elevated plus maze and open field test.