Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.

Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-and how such adaptations shape behavior-remains poorly understood. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, which led us to hypothesize that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. To test this hypothesis, we examined how acute mitochondrial inhibition alters MSN function using mouse brain slices. Inhibition of mitochondrial complex I with the selective inhibitor rotenone reduced MSN intrinsic excitability, an effect that was counteracted by intracellular ATP replenishment. We next asked whether ATP-sensitive potassium (K-ATP) channels, canonical regulators of membrane excitability under metabolic stress, contribute to these responses. Histological analyses revealed specific expression of Kir6.2 subunits in both D1- and D2-MSNs, as compared to non-MSNs, and electrophysiological recordings showed that K-ATP channel activation blockade prevented rotenone-induced reductions in MSN excitability. In behavioral assays, complex I inhibition impaired effort-related performance, an effect that was rescued by K-ATP channel blockade. These findings identify K-ATP channels in MSNs as key mediators that sense acute changes in neuronal energy state and translate them into rapid adjustments in NAc excitability and behavior.