Molecular and cellular mechanisms for bidirectional control of pain in the brain

National Center For Complementary & Integrative Health

Investigators

Linked publications, trials & patents

Abstract

In previous years, we showed that the central amygdala (CeA) functions as a pain rheostat system that can amplify or suppress pain. We further showed that the directionality of pain modulation is dependent on the activity of two subsets of genetically distinct CeA neurons, with activity of one population increasing pain responses and activity of the second population decreasing pain-related responses. At the cellular level, we have also shown that these genetically distinct CeA neurons are electrophysiologically and morphologically distinct. Using the results from our electrophysiological experiments, we contributed to building an agent-based computational model that allows dynamic simulation of nociceptive signal propagation through the CeA network- a project led by the Kolber lab. The main focus of our research program during FY22 was to expand our findings on CeA modulation of pain by investigating the neural circuits contributing to bidirectional control of pain in the CeA. We characterized the anatomical efferent projections of CeA neurons expressing PKC-delta, which included 17 brain regions throughout the basal forebrain, striatum, thalamus, hypothalamus, midbrain, pons and medulla. Among the brain structures that receive inputs from CeA-PKCd neurons was the zona incerta, a subthalamic structure previously linked to pain processing. Combining behavioral assays with electrophysiological, chemogenetic and optogenetic approaches, we further show that the projection from CeA-PKCd neurons to the zona incerta is inhibitory and that CeA-PKCd-mediated inhibition of the zona incerta contributes to neuropathic pain-like responses. A separate circuit-level study was focused on evaluating the contribution of afferent inputs to the CeA in the modulation of pain. We began by confirming the functional connectivity between the parabrachial nucleus (PbN) and the CeA. We further show that CeA-projecting PbN neurons are activated by peripheral noxious stimuli and that activation of this pathway is both necessary and sufficient for pain-related behaviors. Lastly, during FY22, we continued our efforts towards the inclusion of sex as a biological variable in pain processing. We published a study that demonstrated important sex differences in a behavioral visceral responses, disease progression and bowel pathology in a model of colitis.