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Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity

Neuropsychopharmacology volume 48, pages 1821–1831 (2023)Cite this article

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Abstract

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained them in adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

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Fig. 1: Delay discounting is stable across development.
Fig. 2: Histological verification of Gi-DREADD expression.
Fig. 3: Systemic DREADD inhibition of mPFC neurons does not affect impulsive choice, however, inhibition of mPFC-NAc projections increases impulsive choice.
Fig. 4: Whole-cell patch-clamp recordings from nucleus accumbens medium spiny neurons (MSNs) verify hM4Di function.

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Acknowledgements

The authors are grateful for the support and technical expertise of Iness Gildish, Autumn Bows, and Brian Donnellan.

Funding

This work supported by National Institute on Drug Abuse grants R01 DA022340 and R01 DA042595 (JFC), F32 DA039690 (JMW), F32 DA043967 and K99 DA047419 (NEZ), and National Institute on Alcohol Abuse and Alcoholism grant F31 AA024683A (MHP).

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Author notes

  1. Jennifer M. Wenzel

    Present address: Department of Psychological Sciences, University of San Diego, San Diego, CA, 92110, USA

  2. Natalie E. Zlebnik

    Present address: Division of Biomedical Sciences, University of California, Riverside School of Medicine, Riverside, CA, 92521, USA

  3. Mary H. Patton

    Present address: St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

  4. Brian N. Mathur

    Present address: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

  5. These authors contributed equally: Jennifer M. Wenzel, Natalie E. Zlebnik.

Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Jennifer M. Wenzel, Natalie E. Zlebnik, Victoria M. Ayvazian, Hannah M. Dantrassy, Lan-Yuan Zhang & Joseph F. Cheer

  2. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Mary H. Patton

  3. Hennepin Healthcare Research Institute, Minneapolis, MN, 55404, USA

    John R. Smethells

  4. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Brian N. Mathur & Joseph F. Cheer

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Contributions

JMW, NEZ, and JFC conceived of and designed the study; JMW, NEZ, VMA, HMD, and MHP carried out the experiments; JRS, LYZ, BNM, and JFC provided essential intellectual input on study design, analysis, and data interpretation; JMW, NEZ, and JRS analyzed the data; JMW and NEZ wrote the initial draft of the manuscript; all authors contributed to, edited, and approved of the final manuscript.

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Correspondence to Jennifer M. Wenzel or Natalie E. Zlebnik.

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Wenzel, J.M., Zlebnik, N.E., Patton, M.H. et al. Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity. Neuropsychopharmacol. 48, 1821–1831 (2023). https://doi.org/10.1038/s41386-023-01604-5

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