Brain-immune crosstalk via circadian regulation of glymphatic and lymphatic fluid movement

About This Grant

Project Summary Improved treatments for chronic neuropathic pain are needed but hindered by an incomplete understanding of the biological mechanisms of pain development. Sleep disruptions are associated with increased chronic neuropathic pain. Thus, understanding processes critical to sleep may be the key to understanding chronic pain. The glymphatic system is a network of perivascular spaces alongside blood vessels, which facilitates cerebrospinal fluid (CSF) movement into, and interstitial fluid through the brain, ultimately draining into the meningeal lymphatic system. CSF movement between the glymphatic system and the cervical lymphatic system follows circadian (~24h) timing. During sleep, CSF influx and brain solute clearance increase, while direct CSF drainage to peripheral lymphatics predominates during the active phase. The glymphatic system presents a novel therapeutic target for neuropathic pain. This proposal introduces the hypothesis that circadian timing governs CSF movement between the glymphatic and lymphatic systems, driving cytokine redistribution across neuroimmune tissues, regulating nociception and the development of chronic pain. Aim 1 will test whether the daily glymphatic/lymphatic CSF switch deteriorates during the development of chronic pain, altering cytokine distribution across neuroimmune tissues and increasing nociception and hyperalgesia. Aim 2 will test whether the molecular clock controls daily glymphatic/lymphatic CSF distribution and cytokine distribution across neuroimmune tissue, influencing nociception across the day. Aim 3 will assess whether reinforcing circadian timing through food restriction attenuates chronic pain. Aligning peripheral rhythms with central timing provides a non-invasive therapy for chronic pain. These experiments will reveal new insights into chronic pain pathology and explore non-pharmacological interventions for a critical unmet need.