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Research Articles, Systems/Circuits

Ventral tegmental area dopamine neural activity switches simultaneously with rule representations in the medial prefrontal cortex and hippocampus

Mingxin Ding, Porter L. Tomsick, Ryan A. Young and Shantanu P. Jadhav
Journal of Neuroscience 17 March 2025, e1670242025; https://doi.org/10.1523/JNEUROSCI.1670-24.2025
Mingxin Ding
1Graduate Program in Neuroscience, Brandeis University, Waltham, MA 02453, USA
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Porter L. Tomsick
2Undergraduate Program in Neuroscience, Brandeis University, Waltham, MA 02453, USA
3Department of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
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Ryan A. Young
4Department of Psychology, Brandeis University, Waltham, MA, 02453, USA
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Shantanu P. Jadhav
1Graduate Program in Neuroscience, Brandeis University, Waltham, MA 02453, USA
4Department of Psychology, Brandeis University, Waltham, MA, 02453, USA
5Volen National Center for Complex Systems, Brandeis University, Waltham, MA, 02453, USA
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Abstract

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and medial prefrontal cortex (mPFC) is known to represent spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key in reward seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals must adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching, and rule representation changes in mPFC and CA1? We addressed these questions using simultaneous recording of neuronal population activity from the hippocampal area CA1, mPFC and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and mPFC ensembles showed rule-specific activity both during maze running and at reward locations, with mPFC rule coding more consistent across animals compared to CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule-switching in coordination with transitions in mPFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in mPFC/CA1, the dopamine reward signal and behavioral strategy.

Significance Statement This study examines neural activity in mammalian brain networks that support the ability to respond flexibly to changing contexts. We use a rule-switching spatial task to examine whether the key reward-responsive and predictive dopamine (DA) activity changes in coordination with changes in rule representations in key cognitive regions, the medial prefrontal cortex (mPFC) and hippocampus. We first established distinct rule representations in mPFC and hippocampus, and predictive coding of reward outcomes by DA neuronal activity. We show that the rule-specific DA reward prediction after a rule switch develops in temporal coordination with changes in rule representations in mPFC, eventually leading to behavioral changes. These results thus provide an integrated understanding of reward prediction, cognitive representations of rules and behavioral adaptation.

Footnotes

  • This work was supported by the National Institutes of Health (R01MH112661) to S.P.J. and a T90 training grant (R90DA033463). We would like to thank Dr. Naoshige Uchida, Dr. Joshua Berke and Dr. Ali Mohebi for the protocol of the opto-tagging experiment, Dr. John Bladon and Audrey Hooker for piloting the W-track rule switching task, Dr. Justin Shin in assisting in implant surgeries, Dr. Wenbo Tang, Dr. Jacob Olson, Dr. Blake Porter and other lab members in providing feedback on the research project.

  • Authors report no conflict of interest.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Ventral tegmental area dopamine neural activity switches simultaneously with rule representations in the medial prefrontal cortex and hippocampus
Mingxin Ding, Porter L. Tomsick, Ryan A. Young, Shantanu P. Jadhav
Journal of Neuroscience 17 March 2025, e1670242025; DOI: 10.1523/JNEUROSCI.1670-24.2025

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Ventral tegmental area dopamine neural activity switches simultaneously with rule representations in the medial prefrontal cortex and hippocampus
Mingxin Ding, Porter L. Tomsick, Ryan A. Young, Shantanu P. Jadhav
Journal of Neuroscience 17 March 2025, e1670242025; DOI: 10.1523/JNEUROSCI.1670-24.2025
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