Abstract
Cognitive flexibility deficits are one of the most pervasive symptoms across psychiatric disorders, making continued investigation of the circuitry underlying this function a top priority. Medial septum (MS) lesions lead to perseverative, inflexible-type behavior; however, a role for this region in cognitive flexibility circuitry has never been examined. We activated the MS (DREADDs) and measured performance in a T-maze spatial reversal learning task in male Sprague-Dawley rats. Systemic activation of the MS (CNO) significantly decreased both trials to perform a reversal and entries into the previously baited arm. Intra-ventral subiculum CNO enhanced reversal learning in the same manner as systemic CNO and also significantly increased ventral tegmental area and decreased substantia nigra dopamine neuron population activity. Finally, co-injection of the D1 antagonist SCH23390 with CNO prevented the enhanced reversal learning performance seen in the previous two experiments. Taken together, these data suggest a key role for the MS in cognitive flexibility, and suggest that MS-mediated changes in midbrain dopamine neuron population activity could be one mechanism by which this occurs.