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Enhanced cognitive flexibility and phasic striatal dopamine dynamics in a mouse model of low striatal tonic dopamine

Neuropsychopharmacology (2024)Cite this article

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Abstract

The catecholamine neuromodulators dopamine and norepinephrine are implicated in motor function, motivation, and cognition. Although roles for striatal dopamine in these aspects of behavior are well established, the specific roles for cortical catecholamines in regulating striatal dopamine dynamics and behavior are less clear. We recently showed that elevating cortical dopamine but not norepinephrine suppresses hyperactivity in dopamine transporter knockout (DAT-KO) mice, which have elevated striatal dopamine levels. In contrast, norepinephrine transporter knockout (NET-KO) mice have a phenotype distinct from DAT-KO mice, as they show elevated extracellular cortical catecholamines but reduced baseline striatal dopamine levels. Here we evaluated the consequences of altered catecholamine levels in NET-KO mice on cognitive flexibility and striatal dopamine dynamics. In a probabilistic reversal learning task, NET-KO mice showed enhanced reversal learning, which was consistent with larger phasic dopamine transients (dLight) in the dorsomedial striatum (DMS) during reward delivery and reward omission, compared to WT controls. Selective depletion of dorsal medial prefrontal cortex (mPFC) norepinephrine in WT mice did not alter performance on the reversal learning task but reduced nestlet shredding. Surprisingly, NET-KO mice did not show altered breakpoints in a progressive ratio task, suggesting intact food motivation. Collectively, these studies show novel roles of cortical catecholamines in the regulation of tonic and phasic striatal dopamine dynamics and cognitive flexibility, updating our current views on dopamine regulation and informing future therapeutic strategies to counter multiple psychiatric disorders.

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Fig. 1: NET-KO mice have enhanced reversal learning in a Probabilistic Reversal Learning (PRL) task.
Fig. 2: NET-KO mice have enhanced phasic dopamine transients in the Probabilistic Reversal Learning (PRL) task.
Fig. 3: Probabilistic Reversal Learning is intact in NE lesioned mice.
Fig. 4: Nestlet shredding and open-field activity in NET-KO mice.

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Acknowledgements

We would like to thank Dr. Marc Caron for providing us with monoamine transporter knockout mice. We would also like to thank Dr. Stan Floresco (U of British Columbia) for the Med-PC code for the reversal learning task and related advice.

Funding

This work was supported by a NIMH R21 (MH127377) and R01 (MH130778) grant (NMU) and NARSAD/BBRF Young Investigator grant (NMU).

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA

    Jena Delaney, Sanya Nathani, Victor Tan, Carson Chavez, Alexander Orr, Joon Paek & Nikhil M. Urs

  2. Department of Psychiatry, University of Florida, Gainesville, FL, 32610, USA

    Mojdeh Faraji & Barry Setlow

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Contributions

Jena Delaney –performed experiments, analyzed data. Sanya Nathani - performed experiments. Victor Tan - performed experiments. Alex Orr - performed experiments. Carson Chavez - performed experiments. Joon Paek – Analyzed data. Mojdeh Faraji – analyzed data. Barry Setlow - conceptualized experiments, wrote manuscript. Nikhil Urs - conceptualized experiments, performed experiments, analyzed data, wrote manuscript

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Correspondence to Nikhil M. Urs.

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Delaney, J., Nathani, S., Tan, V. et al. Enhanced cognitive flexibility and phasic striatal dopamine dynamics in a mouse model of low striatal tonic dopamine. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01868-5

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  • DOI: https://doi.org/10.1038/s41386-024-01868-5

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