K_ATP channel functional remodeling is associated with neuroinflammatory and dopaminergic alterations under metabolic...

Metabolic stress and neuroinflammation are associated with depression, but the mechanisms connecting peripheral metabolic dysfunction to reward-related circuit alterations remain incompletely understood. ATP-sensitive potassium (K_ATP) channels couple cellular energy state to neuronal excitability and may link metabolic and neuroimmune signaling. Here, we used female mice exposed to post-weaning isolation combined with a high-fat diet to model convergent psychosocial and metabolic stress. We tested whether K_ATP channel modulation is associated with behavioral, inflammatory, and dopaminergic-marker changes under this combined stress condition. Peripheral K_ATP channel modulation was achieved by interscapular brown adipose tissue infusion of glibenclamide, and dopaminergic neuron-specific Kir6.2 conditional knockout mice were used to assess the contribution of neuronal K_ATP channel signaling. Combined stress induced obesity, hyperglycemia, depression-like behavioral alterations, peripheral cytokine imbalance, increased inflammatory markers, and reduced dopaminergic activity markers in the mesolimbic pathway. Glibenclamide improved glucose tolerance, attenuated stress-associated behavioral and inflammatory-marker changes, and increased Fos expression under stress conditions, while enhancing SUR1 maturation and surface localization. Kir6.2 deletion attenuated stress-associated behavioral alterations and reduced nucleus accumbens Iba1-positive cell accumulation, whereas effects on ventral tegmental area tyrosine hydroxylase-positive cell density were more modest. Together, these findings support K_ATP channel functional state as a candidate link between metabolic stress, neuroimmune alterations, and dopaminergic circuit adaptations in female mice, and suggest K_{ATP c}hannel modulation as a potential therapeutic strategy for metabolic-associated depression.