Medial septum activation improves strategy switching once strategies are well learned via bidirectional regulation of dopamine neuron population activity

Abstract

Strategy switching is a form of cognitive flexibility that requires inhibiting a previously successful strategy and then switching to a new strategy of a different categorical modality. It is dependent on dopamine (DA) receptor activation and release in ventral striatum and prefrontal cortex, two primary targets of ventral tegmental area (VTA) DA projections. Although the circuitry that underlies strategy switching early in learning has been studied, few studies have examined it after extended discrimination training. This may be important as DA activity and release patterns change across learning, with several studies demonstrating a critical role for substantia nigra pars compacta (SNc) DA activity and release once behaviors are well learned. Our previous studies demonstrated that medial septum (MS) activation simultaneously increased VTA and decreased SNc DA population activity, as well as improved reversal learning via these actions on DA population activity. We hypothesized that MS activation would improve strategy switching both early in learning and after extended training through its ability to increase VTA DA population activity and decrease SNc DA population activity, respectively. To test this, we activated the MS of male and female rats with designer receptors exclusively activated by designer drugs and measured their performance on an operant-based strategy switching task, following 1, 10, or 15 days of discrimination training. Contrary to our hypothesis, MS activation did not affect strategy switching after 1 day of discrimination training. MS activation improved strategy switching after 10 days of discrimination training, but only in females. MS activation improved strategy switching in both sexes after 15 days of discrimination training. This improvement in strategy switching was attenuated by intra-ventral subiculum bicuculline infusion, which selectively inhibited the MS-mediated decrease in SNc DA population activity, and prevented by infusion of both bicuculline and scopolamine, which inhibited both the MS-mediated decrease in SNc and increase in VTA DA population activity. These data indicate that MS activation improves strategy switching, but only once the original strategy has been sufficiently well learned. They also suggest that the mechanism by which this occurs is likely via the MSs regulation of DA neuron responsivity, primarily via its ability to down-regulate DA population activity in the SNc.