Deciphering Thalamocortical Circuit Dynamics Underlying Pain and Sleep Interactions - ABSTRACT │ Chronic pain affects approximately 20% of the global population, significantly diminishing quality of life and posing a substantial socioeconomic burden. One of the most debilitating aspects of chronic pain is sleep disruption, which affects up to 90% of pain patients. Poor sleep worsens pain sensitivity and contributes to other health issues, creating a vicious cycle where pain disrupts sleep, and poor sleep exacerbates pain. Recent research has identified key brain regions involved in both pain processing and sleep regulation, particularly the centrolateral thalamus (CL) and anterior cingulate cortex (ACC), which are central to pain perception and sleep maintenance. Dysregulation of these regions in chronic pain may underlie the sleep disturbances experienced by patients. Projections from the CL to the ACC (CL→ACC) are implicated in both pain-related arousals and the affective-motivational aspects of pain. Our R21 study will be led by a collaborative team including Dr. Gregory Corder, an expert in pain biology and neural circuit mechanisms; Dr. Franz Weber, specializing in sleep electrophysiology and closed-loop optogenetics; and Dr. Raquel Adaia Sandoval Ortega, an expert in pain-sleep interactions leveraging electrophysiology, calcium imaging, and deep-learning behavior tracking. This project aims to provide the first direct evidence of how chronic pain disrupts the CL→ACC pathway, contributing to sleep fragmentation and heightened pain sensitivity. We will use advanced techniques, including in vivo calcium imaging, closed-loop optogenetics, and the LUPE deep-learning behavior tracking system, to investigate this neural circuit and assess how its modulation can alleviate both pain and sleep disturbances. Aim 1 will focus on the electrophysiological characterization of CL and ACC activity during sleep and wake states as chronic pain develops. Mice will be implanted with electroencephalography (EEG), electromyography (EMG), and intracranial electrodes targeting the CL and ACC to monitor neural oscillatory activity. Using LUPE, we will analyze pain- and sleep-related behaviors and correlate them with neural dynamics over 24-hour recording periods, mapping how nerve injury alters neural circuits over time. Aim 2 will explore bidirectional modulation of CL→ACC projection neurons using closed-loop optogenetics to either enhance or reduce pain and sleep disturbances in a peripheral nerve injury model. Excitatory and inhibitory opsins will be used to manipulate pain- active CL→ACC neurons, and we will assess the effects of optogenetic modulation on neural activity and behavior through in vivo miniscope calcium imaging of the ACC, alongside behavioral tracking with LUPE. By identifying the neural mechanisms driving pain-induced sleep disturbances, this project aims to uncover the role of thalamocortical nociceptive processes in both pain and sleep. This work will provide the foundation for future grants focused on improving sleep as a strategy to reduce chronic pain, ultimately offering new therapeutic targets and an integrated approach to pain management.
