Function of the Parabrachial Nucleus to Central Amydala Pathway in Pain-Related Plasticity

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PROJECT SUMMARY The annual national health cost for chronic pain conditions ranges between 560 to 635 billion dollars, which is higher than the combined costs for cancer, diabetes, and cardiovascular diseases. Chronic pain patients live with a lower quality of life that is further aggravated by patients’ frequent comorbidities with mental health disorders and substance abuse problems. Despite being a significant health concern, the biological mechanisms underlying chronic pain conditions have not been completely identified. Recently, the central amygdala (CeA) has been identified as an important center for pain modulation, with a dual function on pain perception through the activity of two separate cell populations: pain-promoting (pronociceptive) protein kinase c delta-expressing cells (CeA-PKCδ+) and antinociceptive somatostatin-expressing cells. The purpose of this research proposal is to further understand the circuit mechanisms underlying those findings by studying the synaptic connectivity changes behind CeA-PKCδ+ cells pronociceptive function. The central hypothesis of this proposal is that selective strengthening of nociceptive inputs to CeA-PKCδ+ neurons underlies behavioral hypersensitivity following injury. It is known that nociceptive information is conveyed to the CeA by projections sent from the lateral parabrachial nucleus (LPB), a pontine structure critical for pain-related information processing. Therefore, this proposal will test whether injury-related potentiation of the LPB to CeA pathway is specific to CeA-PKCδ+ neurons, whether this potentiation drives pain-related behavioral hypersensitivity, and whether this potentiation is necessary for injury-induced behavioral hypersensitivity. In Aim 1, the preliminary data showing injury-induced potentiation of excitatory synaptic transmission onto CeA-PKCδ+ neurons will be further investigated by dissecting the function of excitatory LPB inputs using ex vivo optogenetically-assisted circuit mapping. In Aim 2, the in vivo dynamics of the LPB to CeA pathway in freely behaving animals in terms of CeA-PKCδ+ neuronal activity and pain-related behavioral hypersensitivity will be established. Furthermore, the goal in Aim 3 is to establish a causal link between LPB to CeA pathway function, pain-related behaviors, and CeA-PKCδ+ cells neuronal activation. The experiments of Aim 1 will provide the trainee the opportunity to improve his current ex vivo electrophysiological skills. The experiments of Aims 2 and 3 will provide the trainee the opportunity to receive training in cutting-edge in vivo neurocircuitry tools to complete the experiments proposed and to address the biological questions in these aims. The findings obtained from the proposed research will expand our understanding of how the brain modulates pain, which might ultimately lead to the identification of better treatment options for individuals suffering from chronic pain conditions.