mPFC axons drive cognitive control enhancement during striatal stimulation

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) can alleviate symptoms of mental illness and may work in part by improving cognitive control, a feature of healthy decision making. The human VCVS DBS target and its mid-striatum analog in our preclinical rodent model contain both cortical axons and local striatal cell bodies. However, the specific neural components that stimulation acts on to mediate cognitive effects remain unclear. We addressed this by delivering high frequency optogenetic stimulation ("opto-DBS") to either medial prefrontal cortex (mPFC) axons or local mid-striatal (midSTR) neurons in a rodent Set-Shift task. Opto-DBS of mPFC axons reduced response times, effectively replicating the cognitive enhancement observed in a previous study that used electrical stimulation. Conversely, we observed cognitive impairment from sustained (>10 min) opto-DBS of midSTR neurons. In addition, the cognitive benefit from axonal opto-DBS exhibited time-dependent declines that were not observed with electrical stimulation. The improvement in response times declined within a session and was associated with attenuated magnitude of local midSTR evoked-response potentials. Across-testing days, we linked this decline to diminished mPFC responsiveness, evidenced by a reduction in the post-DBS functional strength of the circuit, suggesting a neuroplastic-like mechanism. These results demonstrate that mPFC-originating axons, rather than local neurons, are the primary drivers of cognitive control enhancements from electrical stimulation, providing insight into therapeutic mechanisms of VCVS DBS.