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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 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.

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Fig. 1: Viral injection, timeline, and testing strategy.
Fig. 2: MS activation has no effect on strategy switching after 1 day of discrimination training.
Fig. 3: MS activation improves strategy switching after 10 days of training in female rats.
Fig. 4: MS activation improves strategy switching in both sexes after 15 days of discrimination training.
Fig. 5: MS activation-induced improvement in strategy switching is inhibited by intra-vSub infusion of bicuculline and prevented by infusion of both bicuculline and scopolamine.

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Acknowledgements

We would like to thank Dr. Stan Floresco for his help in creating the strategy switching task, as well as his continued guidance and support.

Funding

This work was funded by NIMH grants 1F32MH115550 (DMB) and MH057440-11 (AAG).

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DMB and AAG planned all experiments. DMB, CMF, and CCP performed all experiments. All authors participated in manuscript writing and editing.

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Correspondence to David M. Bortz.

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AAG received funds from the following organizations: Lundbeck, Pfizer, Otsuka, Asubio, Autofony, Janssen, Alkermes, SynAgile, and Newron. DMB, CMF, and CCP declare no competing financial interests.

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Bortz, D.M., Feistritzer, C.M., Power, C.C. et al. Medial septum activation improves strategy switching once strategies are well-learned via bidirectional regulation of dopamine neuron population activity. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01387-1

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