ENERGY-DEPENDENT MODULATION OF NUCLEUS ACCUMBENS OUTPUT VIA K-ATP CHANNEL ACTIVITY

Neuronal mitochondria are critical for meeting the high energy demands of synaptic signaling, yet how neurons rapidly adapt to fluctuations in energy supply—and how this shapes behavior—remains unclear. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, suggesting that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. Using mouse brain slices, we found that inhibition of mitochondrial complex I with rotenone reduced MSN intrinsic excitability, an effect reversed by intracellular ATP replenishment. Histology revealed that Kir6.2-containing ATP-sensitive potassium (K-ATP) channels are expressed in both D1- and D2-MSNs. K-ATP channel blockade prevented rotenone-induced decreases in excitability ex vivo and rescued the impaired effort-based performance in vivo. These results identify K-ATP channels in MSNs as rapid bioenergetic sensors that link energy state to neuronal output and motivated behavior.