Thalamocortical dynamics during nociception and endogenous analgesia

Project Summary Ineffective pain management is an urgent medical crisis impacting the lives of over 50 million Americans and millions more chronic pain patients around the world. Opiate analgesics can provide robust pain relief but can also produce life-threatening side effects and high rates of misuse, which contributes to the ongoing Opioid Epidemic. Unlike the off-target effects of opiates that act widely throughout the body to indiscriminately bind mu-opioid receptors (MOR) on many cell-types, endogenous opioid peptides mediating antinociception undergo controlled release at specific synapses from specific nociception-related cell-types. Identifying the precise noci-ceptive cell-types that express MORs, which are regulated by endogenous opioids, may lead to new research developments for effective circuit-targeted analgesic treatments to minimize the need for traditional opiate anal-gesics and reduce abuse liabilities. The rostral intralaminar thalamus {rlLN) is critical in this regard as it is known to relay nociceptive information from spinal cord and brainstem structures to cortical regions, such as the rostral anterior cingulate cortex (rACC). rlLN neurons express high densities of MORs {rlLNMOR), yet it remains unknown whether endogenous forms of pain relief modulate nociceptive activity within this rlLNMOR ➔ rACC circuit. To enhance our investigations into thalamocortical circuits in endogenous analgesia processes, we have developed an operant conditioning assay that leverages expectation-induced antinociception, i.e. placebo analgesia, in a drug-free manner. The F99 phase entails two subaims. In Aim 1a, the applicant will leverage in vivo fiber photometry calcium imaging to determine nociception and analgesia-related responses in the axonal projections of rlLNMOR ➔ rACC. In Aim 1b, to determine the necessity of MOR signaling in thalamocortical neurons for the endogenous analgesia response, the applicant will use an intersectional genetic and viral approach to selectively delete MORs from rlLN ➔ rACC neurons. The KOO phase, Aim 2, will help prepare the applicant for a successful academic research career investigating neurobiological mechanisms of gastrointestinal pain. This postdoctoral period will provide the applicant with expertise in techniques like 2-photon calcium imaging of neural population dynamics in the brain during visceral pain models, as well as sharpen managerial and mentoring skills necessary to succeed and thrive as an independent research scientist. In total, successful completion of this proposal will provide insight into neurobiological mechanisms underlying pain and analgesia, while also equipping the applicant, Lindsay Ejoh, to uncover brain circuit mechanisms of severe and chronic gastrointestinal pain disorders under her own independent research program.