BDNF, acting in the mesolimbic dopamine reward pathway, promotes susceptibility to stress; however, the mechanisms controlling its release remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF levels in nucleus accumbens (NAc) of socially stressed mice, but not stress-naïve mice. This stress gating of BDNF signaling is mediated by CRF acting in NAc. These results unravel a stress-context detecting function of the brain’s mesolimbic circuit.

Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity.

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