Departments of Psychiatry and Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Int J Neuropsychopharmacol. 2024 Oct 1;27(10). doi: 10.1093/ijnp/pyae034.
Impulsive action and risk-related decision-making (RDM) are associated with various psychiatric disorders, including drug abuse. Both behavioral traits have also been linked to reduced frontocortical activity and alterations in dopamine function in the ventral tegmental area (VTA). However, despite direct projections from the medial prefrontal cortex (mPFC) to the VTA, the specific role of the mPFC-to-VTA pathway in controlling impulsive action and RDM remains unexplored.
We used positron emission tomography with [18F]-fluorodeoxyglucose to evaluate brain metabolic activity in Roman high- (RHA) and low-avoidance (RLA) rats, which exhibit innate differences in impulsive action and RDM. Notably, we used a viral-based double dissociation chemogenetic strategy to isolate, for the first time to our knowledge, the role of the mPFC-to-VTA pathway in controlling these behaviors. We selectively activated the mPFC-to-VTA pathway in RHA rats and inhibited it in RLA rats, assessing the effects on impulsive action and RDM in the rat gambling task.
Our results showed that RHA rats displayed higher impulsive action, less optimal decision-making, and lower cortical activity than RLA rats at baseline. Chemogenetic activation of the mPFC-to-VTA pathway reduced impulsive action in RHA rats, whereas chemogenetic inhibition had the opposite effect in RLA rats. However, these manipulations did not affect RDM. Thus, by specifically targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we reverted innate patterns of impulsive action but not RDM.
Our findings suggest a dissociable role of the mPFC-to-VTA pathway in impulsive action and RDM, highlighting its potential as a target for investigating impulsivity-related disorders.
冲动行为和与风险相关的决策（RDM）与各种精神疾病有关，包括药物滥用。这两种行为特征也与前额皮质活动减少和腹侧被盖区（VTA）多巴胺功能改变有关。然而，尽管内侧前额叶皮层（mPFC）与 VTA 之间存在直接投射，但 mPFC 到 VTA 通路在控制冲动行为和 RDM 中的具体作用仍未得到探索。
我们使用正电子发射断层扫描与[18F]-氟脱氧葡萄糖评估罗马高回避（RHA）和低回避（RLA）大鼠的大脑代谢活性，这些大鼠在冲动行为和 RDM 方面表现出先天差异。值得注意的是，我们使用基于病毒的双重分离化学遗传策略，首次分离出 mPFC 到 VTA 通路在控制这些行为中的作用。我们选择性地激活 RHA 大鼠的 mPFC 到 VTA 通路，抑制 RLA 大鼠的 mPFC 到 VTA 通路，评估大鼠赌博任务中冲动行为和 RDM 的影响。
我们的结果表明，RHA 大鼠在基线时表现出更高的冲动行为、更差的最优决策和更低的皮质活动，而 RLA 大鼠则表现出相反的趋势。mPFC 到 VTA 通路的化学遗传激活降低了 RHA 大鼠的冲动行为，而化学遗传抑制则对 RLA 大鼠产生了相反的影响。然而，这些操作并不影响 RDM。因此，通过以表型依赖的方式特异性靶向 mPFC 到 VTA 通路，我们逆转了冲动行为的固有模式，但没有影响 RDM。
我们的发现表明，mPFC 到 VTA 通路在冲动行为和 RDM 中具有可分离的作用，突出了其作为研究与冲动相关的障碍的潜在靶点。
