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<p>Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTA<sub>DA</sub>), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTA<sub>DA</sub> activity and GABA input across punishment learning, and test their causal contribution to behavior. VTA<sub>DA</sub> activity and GABA input phasically increased to response-elicited outcomes, with VTA<sub>DA</sub> activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABA<sub>A</sub> receptors in VTA or chemogenetically activating VTA<sub>DA</sub> neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTA<sub>DA</sub> inhibition during punishment learning.</p>

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Disinhibition of ventral tegmental area during initial punishment learning causes enduring punishment insensitivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Shannen Y. S. Tan,
  • Michelle H. Shen,
  • Luke J. Keevers,
  • Matthew Williams-Spooner,
  • Gavan P. McNally,
  • Simon Killcross,
  • Philip Jean-Richard-dit-Bressel

摘要

Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTADA), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTADA activity and GABA input across punishment learning, and test their causal contribution to behavior. VTADA activity and GABA input phasically increased to response-elicited outcomes, with VTADA activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABAA receptors in VTA or chemogenetically activating VTADA neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTADA inhibition during punishment learning.