Medial Prefrontal Cortex to Medial Septum Pathway Activation Improves Cognitive Flexibility in Rats

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, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) 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 2 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. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation. Conclusions This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility.