Targeting the Mesocortical Glutamatergic Pathway for Chronic Pain Treatment

Project Summary The malfunction of the mesocortical pathway, connecting the ventral tegmental area (VTA) to the prefrontal cortex (PFC), has been associated with nerve injury-induced neuropathic pain. While extensive research has focused on dopamine transmission in reward and aversion within this pathway, the specific role of glutamate signaling in pain modulation remains largely unknown. Previous studies from our lab and others have demonstrated that pyramidal neuronal activity is substantially reduced in the mouse PFC after peripheral nerve injury, and restoring PFC activity alleviates neuropathic pain. Our recent work suggests that optogenetic stimulation of VTA glutamatergic projections in the PFC alleviates nociceptive allodynia and pain aversion. Based on these findings, we hypothesize that the VTA-to-PFC glutamatergic pathway plays a crucial role in the development and maintenance of chronic neuropathic pain. In this application, we will test this hypothesis by combining in vivo imaging of calcium activity, VTA cell type- and projection-specific chemogenetics, and the CRISPR/Cas9 gene editing approach. The proposal has two specific aims. In the first aim, we will examine the alterations in VTA glutamatergic inputs to the PFC after peripheral nerve injury and their contribution to the development of chronic pain. This will test whether reduced VTA glutamatergic inputs deactivate the PFC, thus contributing to pain chronicity. Additionally, previous studies have shown that a fraction of VTA glutamatergic neurons co-release dopamine. In the second aim, we will employ CRISPR/Cas9 gene editing to selectively deplete tyrosine hydroxylase, an enzyme involved in dopamine biosynthesis, to determine whether activating the VTA-to-PFC glutamatergic pathway reverses established neuropathic pain independently of dopamine co- release. The proposed project will determine the pivotal role of a non-conventional mesocortical glutamatergic pathway in the development and maintenance of neuropathic pain. The successful completion of the project will provide novel insights into targeting the VTA-to-PFC glutamate signaling as a therapeutic strategy for chronic pain treatment.