biostudies-literature00470Bortz DMNIMH NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Mental Health2186-2194https://www.ebi.ac.uk/biostudies/studies/S-EPMC6898642biostudies-literatureUnknown44(13)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.Neuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyThe medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.PMC68986421F32MH115550F32 MH115550MH057440-11Gazo KLGrace AABortz DM47falseThe medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.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.2019-01-01T00:00:00Z2019 Dec2024-11-07T13:16:07.062Z2021-02-20T02:11:07ZS-EPMC68986423126136810.1038/s41386-019-0453-1