Dissociable roles of the mPFC-to-VTA Pathway in the control of iImpulsive Action and Risk-Related Decision-Making in Roman High- And Low-Avoidance Rats

Impulsivity is a multidimensional trait associated with various psychiatric disorders including drug abuse. Impulsivity facets, such as impulsive action and risk-related decision-making (RDM), have been associated with 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 the control of impulsive behaviors remains unexplored. Here, we used Positron Emission Tomography with [ ¹⁸ F]-Fluorodeoxyglucose to evaluate brain metabolic activity in Roman High-(RHA) and Low-avoidance (RLA) rats, which exhibit innate differences in impulsivity. Notably, we used a viral-based intersectional chemogenetic strategy to isolate, for the first time, the role of the mPFC-to-VTA pathway in controlling impulsive behaviors. We selectively activated the mPFC-to-VTA pathway in RHAs and inhibited it in RLAs, and assessed 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 RHAs, whereas chemogenetic inhibition had the opposite effect in RLAs. However, these manipulations did not affect RDM. Thus, by specifically and bidirectionally targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we were able to revert 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.