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

National Center For Complementary & Integrative Health

Investigators

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Abstract

We have previously demonstrated that the central amygdala (CeA) has a dual and opposite function in the modulation of pain. We further demonstrated that these two subsets of CeA neurons bidirectionally modulate pain-related behaviors, with activity of one population increasing pain responses and activity of the second population decreasing pain-related responses. The main focus of our research program during FY21 was to investigate the cellular and circuit level mechanisms for bidirectional control of pain in the CeA. To do this, we aimed at identifying the distinguishing physiological and morphological features of genetically distinct CeA neurons as well as the functional contribution of cell-type-specific CeA afferents and efferents to the modulation of pain-related responses. During FY21, we completed a study at the cellular level that demonstrated that genetically-distinct populations of CeA neurons are electrophysiologically and morphologically distinct, further supporting cell-type-specific function within the CeA. Using the data from our ex-vivo experiments and in collaboration with the Kolber lab, we also built an agent-based computational model of two genetically distinct neuronal populations in the amygdala that allows dynamic simulation of nociceptive signal propagation through the network. During FY21, we also made significant strides on our goal of identifying the circuit mechanisms for bidirectional control of brain in the CeA. We completed a study that identified a previously unrecognized inhibitory efferent pathway from CeA neurons expressing PKC-delta to the zona incerta, a subthalamic structure previously linked to pain processing. We further completed a second set of experiments that that demonstrated that injury-induced plasticity in the excitatory afferent pathway from the parabrachial nucleus to the central amygdala is necessary for pain-related behavioral responses. Parallel efforts during FY21 were dedicated to evaluating sex as a biological variable in pain processing. Despite the well-known sex differences in pain in both clinical and preclinical settings, most preclinical studies in the pain field, including those in the CeA, have focused on male subjects. Our goal is to include both males and females in all our experiments and address potential mechanistic sex differences in the brain modulation of pain-related behaviors. To that end, we are currently completing much needed foundational descriptive experiments addressing sex differences at the behavioral and anatomical levels. During FY21, we completed a study that demonstrated important sex differences in behavioral visceral responses, disease progression and bowel pathology in a model of colitis, stressing the importance of considering sex as a biological variable for preclinical pain studies and for the development of treatment strategies in patients.