Dissecting the neural and molecular mechanisms of trigeminal low temperature sensation

About This Grant

PROJECT SUMMARY / ABSTRACT Orofacial neuropathic pain, often stemming from somatosensory nervous system dysregulation, frequently manifests in conditions such as chemotherapy-induced neuropathy and trigeminal neuralgia. This pain commonly results in altered somatosensory experiences, including orofacial cold allodynia (pain from normally innocuous cool stimuli) and cold hyperalgesia (exaggerated pain in response to noxious cold). Current treatments often fail to alleviate these cold-sensation symptoms because the underlying cellular and molecular mechanisms for low temperature sensation are not well defined. Recent single-cell sequencing has revealed new layers of molecularly distinct somatosensory neuron populations, yet how the coding logic underlying low temperature sensation and cold-nociception is distributed across these neurons remains severely understudied. This proposal aims to delineate the neural and molecular logic underlying low temperature sensation, revealing fundamental principles essential for informing development of new strategies for cold allodynia and neuropathic pain. To accomplish this, we will apply an intersectional genetic strategy in mice, combining state-of-the-art thermoelectric cooling (TEC) probes, in vivo trigeminal (TG) functional imaging, multiplexed in situ hybridization, neural tracing, and advanced AI-based behavioral analyses. Preliminary data reveal Chrna7+ TG Aδ-nociceptors encode noxious cold sensation in teeth independent of the canonical cool receptor Trpm8, providing direct evidence that low temperature encoding is distributed across several TG classes. This proposal will 1) define molecular and neural mechanisms underlying orofacial low temperature sensation and 2) characterize behavioral outputs and central projections of low temperature encoding TG populations using optogenetics and AI-based machine learning, and mapping associated afferent brainstem nuclei.This research will launch the candidate’s independent research program aimed at elucidating low temperature encoding mechanisms throughout the periphery. This will set the stage for future directions examining higher-order circuit mechanisms of cold sensation versus pain, and how sensation is transformed in disease/pain models. This work will bring new perspectives and hypotheses towards the development of pain treatment strategies, including those for neuropathic cold allodynia and hyperalgesia. During the mentored stage, the candidate will gain valuable training in: 1) intersectional genetic techniques for neuroscience studies, 2) advanced computational analysis for calcium imaging and behavior, and 3) guidance from the formal advisory committee in lab leadership, grant writing, networking, and presentation skills. This award will set the candidate up for success in transitioning to independence and making significant discoveries towards understanding and treating pain.