Tobacco Use and Cessation Patterns Among Cancer Survivors: Results From Nine ECOG-ACRIN Cancer Research Group Trials.

Stress serves as an essential mediator of allostasis, a dynamic process enabling organisms to achieve stability through physiological or behavioral adjustments in response to threatening challenges. According to the allostasis theory, successful adaptation requires top–down regulation of neural circuits to meet anticipated demands, while excessive “allostatic load” from chronic stress may deplete adaptive capacities, leading to maladaptive states that ultimately compromise organismal survival. This framework explains the marked heterogeneity in chronic stress responses, which resilient individuals maintain circuit plasticity for homeostatic recalibration, whereas susceptible counterparts develop pathological hyperexcitability in valence-encoding circuits that disrupt emotional homeostasis, ultimately manifesting as depression. However, the precise neural mechanisms underlying this dichotomy remain unclear. Among key circuits governing stress responses, the lateral habenula (LHb) has emerged as a critical hub for integrating aversive valence signals and orchestrating stress-related behavioral adaptations. Substantial body of research indicates that LHb neurons is extensively activated by numerous stressors, with the degree of excitation correlating with negative affective states across species. Notably, chronic stress drives pathological LHb excitation, and its hyperactivity is consistently linked to depressive phenotypes in both clinical and preclinical studies. Importantly, a recent study further suggests that heightened LHb activity during stress appears to determine individual susceptibility, providing a mechanistic substrate for the valence-encoding circuit hyperexcitability that disrupts emotional homeostasis in vulnerable individuals. However, the specific neural circuit mechanisms mediating these effects remain to be elucidated. The LHb receives convergent inputs from multiple limbic and cortical regions. While prior studies have focused on aversive sensory signals transmitted through subcortical pathways mediating stress responses, the role of the medial prefrontal cortex (mPFC), a key hub for top–down regulation of stress adaptation and emotional homeostasis, in modulating LHb function under chronic stress remains poorly characterized. This highlights the importance of investigating this specific top–down regulatory axis in stress-induced maladaptation. Notably, our preliminary investigations in rodents indicate that neurons within a specific subregion of the mPFC, the dorsomedial prefrontal cortex (dmPFC), establish a functionally distinct projection to the LHb that encodes stress valence and its hyperactivity correlated with depressive phenotype. Nevertheless, how chronic stress disrupts this top–down pathway to drive pathological LHb hyperactivity during stress, as well as the molecular mediators underlying this dysregulation, remains a critical gap in understanding individual susceptibility trajectories.