Dissecting the Neural Substrate of Decreased Reward Sensitivity in a Model of Chronic Pain

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      Chronic pain is a debilitating condition that shades the lives of approximately 20% of the global population. Patients with chronic pain often display impairments in cognitive function, such as cognitive inflexibility, that negatively affect treatment efficacy. Understanding the mechanism underlying chronic pain and its behavioral impacts is therefore crucial for the development of successful treatments on symptoms beyond the physical aspect. However, current study on the circuitous underpinning of pain-associated behavioral inflexibility is still insufficient. Chronic pain is associated with a hypodopaminergic state in patients and animal models; the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh) are two brain regions that receive dense dopaminergic innervation, and dopamine exquisitely modulates synaptic plasticity and excitability in this pathway. Projections from the medial prefrontal cortex (mPFC) to nucleus accumbens shell (NAcSh) specifically are essential for encoding reward associations and flexibly updating behavior in response to reward. Therefore, we hypothesize that a pain-associated hypodopaminergic state would modulate function of the mPFC–NAcSh pathway and lead to impairment in reward-related behavioral flexibility. Whether maladaptive plasticity of the mPFC–NAc pathway contributes to the behavioral inflexibility associated with chronic pain has not been well understood. Here, we will test the hypothesis that decreased synaptic strength of the mPFC–NAcSh pathway leads to decreased reward-based effort allocation following induction of a chronic pain and impaired behavioral flexibility under conditions of reward uncertainty. These behavioral deficits were associated with decreased excitatory synaptic transmission into the nucleus accumbens in a cell-type-specific manner, providing a potential neural substrate of these effects. Together, these results provide evidence linking a pain-associated hypodopaminergic state to downstream dopamine-dependent adaptations in cortico-striatal circuits that could contribute to impairments in reward-based behavior. In the future, it is possible that this pathway could be harnessed for neuromodulation strategies to treat cognitive or affective symptoms of chronic pain. Grant support from Rita Allen Scholar Award in Pain (to M.C.C.).
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