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Involvement of cortical input to the rostromedial tegmental nucleus in aversion to foot shock

Neuropsychopharmacology volume 48, pages 1455–1464 (2023)Cite this article

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Abstract

The rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. Previous research has focused on regulation of RMTg activity by the lateral habenula despite studies revealing RMTg afferents from other regions including the frontal cortex. The current study provides a detailed anatomical and functional analysis of cortical input to the RMTg of male rats. Retrograde tracing uncovered dense cortical input to the RMTg spanning the medial prefrontal cortex, the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area that is also implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V, are glutamatergic, and collateralize to select brain regions. In-situ mRNA hybridization revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Consistent with cFos induction in this neural circuit during exposure to foot shock and shock-predictive cues, optogenetic stimulation of dmPFC terminals in the RMTg drove avoidance. Lastly, acute slice electrophysiology and morphological studies revealed that exposure to repeated foot shock resulted in significant physiological and structural changes consistent with a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding to aversive stimuli such as foot shock and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over reward and aversion.

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Fig. 1: Anatomical characterization of cortical inputs to the RMTg.
Fig. 2: RMTg-projecting dmPFC neurons express glutamatergic markers and are positive for D1 and D2 receptor mRNA.
Fig. 3: Optogenetic stimulation of RMTg-projecting dmPFC terminals drives avoidance.
Fig. 4: cFos induction in RMTg-projecting dmPFC neurons following exposure to aversive stimuli.
Fig. 5: Physiological and structural neuroadaptations in RMTg-projecting dmPFC neurons following exposure to foot shock.

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  • 13 July 2023

    The author L. Judson Chandler was tagged incorrectly in the HTML version of the original article.

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Acknowledgements

The authors thank Joseph Pitock for technical support and Joroen Verharen for sharing the ImageJ cell density analysis protocol. We are also grateful to Patrick Mulholland for methodological assistance with dendritic spine imaging and analysis and Sam Centanni for providing a detailed protocol for the analysis of the RNAScope data using Imaris Software.

Funding

This work was supported by NIH grants AA022836 (EJG), AA024208 (EJG), AA022701 (LJC), AA019967 (LJC), AA027706 (LJC), DA013951 (JJW), DA042518 (WNW) and USA ED HSI-STEM grant P031C160237 (AG). EJG is also supported by NIH grants AA029130 and AA022538.

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Authors and Affiliations

  1. Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Elizabeth J. Glover, E. Margaret Starr, Andres Gascon, Kacey Clayton-Stiglbauer & Christen L. Amegashie

  2. Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA

    Alyson H. Selchick, Dylan T. Vaughan, Wesley N. Wayman, John J. Woodward & L. Judson Chandler

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Contributions

EJG and LJC conceived of and designed experiments. EJG and EMS collected and analyzed data for in-vivo optogenetics experiments. EJG, EMS, and AG collected and analyzed data for tract tracing experiments. EJG, EMS, and CLA collected and analyzed data for collaterals experiment. EJG, EMS, and KCS collected and analyzed data for dendritic spine analysis. EJG, AHS, DTV, and LJC collected and analyzed data for in-situ hybridization experiments. EJG, WNW, JJW collected and analyzed data for ex-vivo slice electrophysiology experiments. EJG, JJW, and LJC contributed to interpretation of findings. EJG and LJC drafted the manuscript with WNW and JJW providing critical revisions. All authors reviewed manuscript content and approved of the final version prior to publication.

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Correspondence to Elizabeth J. Glover.

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Glover, E.J., Margaret Starr, E., Gascon, A. et al. Involvement of cortical input to the rostromedial tegmental nucleus in aversion to foot shock. Neuropsychopharmacol. 48, 1455–1464 (2023). https://doi.org/10.1038/s41386-023-01612-5

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