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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS DISTINCT ROLES FOR DOPAMINE CLEARANCE MECHANISMS IN REGULATING BEHAVIORAL

FLEXIBILITY Article Open access 30 June 2021 THE EFFECT OF SELECTIVE NIGROSTRIATAL DOPAMINE EXCESS ON BEHAVIORS LINKED TO THE COGNITIVE AND NEGATIVE SYMPTOMS OF SCHIZOPHRENIA Article 15

November 2022 LASTING DYNAMIC EFFECTS OF THE PSYCHEDELIC 2,5-DIMETHOXY-4-IODOAMPHETAMINE ((±)-DOI) ON COGNITIVE FLEXIBILITY Article Open access 07 February 2024 DATA AVAILABILITY All data

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references 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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department of Psychiatry, University of Florida, Gainesville, FL, 32610, USA Mojdeh Faraji & Barry

Setlow Authors * Jena Delaney View author publications You can also search for this author inPubMed Google Scholar * Sanya Nathani View author publications You can also search for this

author inPubMed Google Scholar * Victor Tan View author publications You can also search for this author inPubMed Google Scholar * Carson Chavez View author publications You can also search

for this author inPubMed Google Scholar * Alexander Orr View author publications You can also search for this author inPubMed Google Scholar * Joon Paek View author publications You can also

search for this author inPubMed Google Scholar * Mojdeh Faraji View author publications You can also search for this author inPubMed Google Scholar * Barry Setlow View author publications

You can also search for this author inPubMed Google Scholar * Nikhil M. Urs View author publications You can also search for this author inPubMed Google Scholar 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 CORRESPONDING AUTHOR Correspondence to Nikhil M. Urs. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL

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