Novel neural activity imaging platform to discern sex hormone control of sexually dimorphic pain processing

University Of Delaware, Newark DE

Investigators

Abstract

Project Summary Novel neural activity imaging platform to discern sex hormone control of sexually dimorphic pain processing The lack of research on female physiology has led to a failure in the translation of therapeutics for women, especially across chronic and neuropathic pain conditions. Understanding the structural and functional differences between female and male pain systems is essential for developing sex-specific medical interventions. However, the complexity of these systems combined with the limitations of current technologies to assess neuronal activity prevent a complete view of sex-based pain processing. To address this gap, we propose a proteomic approach for high-throughput, multiplexed spatial analysis for single-cell neural activity sensing, signaling, and identity across nervous tissues that will advance our understanding of sex-based pain: MINDMAP (Mass cytometry Imaging of Neural activity by immediate early gene Detection with simultaneous Multiplexed marker Analysis Platform). This novel neural activity sensing platform is based on imaging mass cytometry – a tissue staining variant capable of 40+ protein measurements by antibody-based rare earth metal mass spectrometry detection, allowing identification of every neuron type that responds to painful stimuli (nociceptive population) – while sensing neural activity and reporting key signaling pathways. We will leverage this imaging platform to determine the role of sex hormones in driving sexually dimorphic nociceptive activity and behavior. In Aim 1, readout of neural activity sensors will produce molecular fingerprints of activity while simultaneously profiling cell identity, sex hormone signaling status, and oxidative stress (with RPL 3) in mono- sex neuronal cultures. Aim 2 will extend this spatial, single-cell neural activity sensing in vivo by combining genetic, surgical, and hormone treatments to directly assess the role of sex hormones in the structure, function, and behavior of pain systems. This proposal will have critical positive impact by 1) developing MINDMAP to revolutionize neural activity sensing and 2) leveraging MINDMAP to uncover the mechanisms of sex difference in pain perception. MINDMAP will be a crucial method for whole tissue, single cell neural function analysis, allowing hereto difficult interrogation of all cell types while linking key signaling pathways to activity, and thus be of broad interest to the neuroscience community. Further, this proposal’s results will provide evidence that sex hormone signaling governs the sexually distinctive functional and nocifensive responses to noxious stimuli. These results will identify crucial candidates for sex-specific therapeutics and interventions for chronic pain formation.