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Background The medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway may be the mechanism by which the MS regulates strategy switching and DA neuron population activity. Methods Male and female rats learned a complex discrimination strategy across two different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males-5.3 + 0.3 days, females-3.8 + 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat’s ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching). Results Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes, while inhibition of the pathway had little to no effect on strategy switching. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold. Activation, but not inhibiton, of the mPFC-MS pathway bidirectionally regulated DA activity in ventral tegmental area and substantia nigra pars compacta, similar to MS activation. Conclusions This study presents a top-down circuit from the prefrontal cortex to the midbrain, with the MS being a critical contributor, by which DA activity can be manipulated to promote flexible behavior.

Strategy switching is a form of cognitive flexibility that requires inhibiting a previously successful strategy and 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. We have 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 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. We chemogenetically activated the MS of male and female rats 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 training, but only in females. MS activation improved strategy switching in both sexes after 15 days of training. Infusion of bicuculline into the ventral subiculum (vSub) inhibited the MS-mediated decrease in SNc DA population activity and attenuated the improvement in strategy switching. Intra-vSub infusion of scopolamine inhibited the MS-mediated increase in VTA DA population activity but did not affect the improvement in strategy switching. Intra-vSub infusion of both bicuculline and scopolamine inhibited the MS-mediated effects on DA population activity in both the SNc and VTA and completely prevented the improvement in strategy switching. These data indicate that MS activation improves strategy switching once the original strategy has been sufficiently well-learned, and that this may occur via the MS's regulation of DA neuron responsivity.