Harnessing the lateral habenula: Unlocking resilience against stress and related disorders

Stress is a major risk factor for chronic pain, mood disorders, and substance use. The lateral habenula (LHb), a glutamatergic brain region involved in aversion, nociception, and reward processing, has emerged as a potential therapeutic target for stress-related psychopathology. This study investigated how acute stress produces long-term behavioral and sensory changes, and whether LHb activity contributes to these outcomes. We first examined how the nature, controllability, and predictability of stress influence the development of stress-induced hyperalgesia (SIH), independent of neural manipulation. All stress paradigms led to persistent mechanical hypersensitivity, though predictable stress offered short-term protection. To test LHb involvement, we utilized chemogenetic inhibition of LHb glutamatergic neurons during stress exposure. This prevented SIH and reduced fentanyl intake but did not reverse stress-induced anhedonia or behavioral avoidance. We next tested whether chronic LHb inhibition after symptom onset could reverse hyperalgesia; however, this approach yielded only modest relief. Finally, we assessed abuse liability using a conditioned place preference paradigm and found that LHb inhibition was not reinforcing, even in previously stressed animals. Together, these findings identify the LHb as a key node linking stress to sensory and reward vulnerability and support its potential as a non-addictive, circuit-specific therapeutic target.