Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy.

Patients with Alzheimer’s disease (AD) exhibit a progressive disruption of entrained circadian rhythms that first appears long before cognitive symptoms develop. Additionally, work combining analyses of actigraphy and hypothalamic tissue from AD patients suggests that an input to the circadian system may underlie such dysfunction, rather than the presence of pathology and neurodegeneration in the master circadian pacemaker (the suprachiasmatic nucleus, SCN), itself. Here we examined the accumulation of Tau and beta-amyloid pathology and its association with circadian dysfunction in the TAPP (also called APPSwe-Tau) mouse model. We particularly focused on whether sex differences in the development of such pathology influence the onset of circadian dysfunction and investigated which neural areas affected by such pathology also project to the circadian system. We show that TAPP mice, which express mutant human Tau and amyloid precursor protein mutations, exhibit phase delays in rhythms of both body temperature (Tb) and locomotor activity (LMA), revealed by later bathyphases (troughs) and later acrophases (peaks) of these rhythms, which are commonly seen in AD patients. TAPP mice notably showed increases in Tb and LMA around the transition between their active and resting phases (late dark to early light period transition). This is temporally consistent with when AD patients frequently exhibit sundowning, which is characterized by wandering, agitation, and aggression in the late afternoon and early evening. Indeed, sundowning has also been shown to be strongly associated with the reported phase delay in AD patients. We showed these disruptions of entrained rhythms coincide with the development of intracellular neurofibrillary tangles expressing hyperphosphorylated Tau (pTau). Interestingly, we found that both circadian dysfunction and associated pathology develop earlier in female TAPP mice than in males. Additionally, the presence of LPB pTau and circadian dysfunction in older TAPP males is associated with an increase in behavioral aggression just before the active-resting phase transition, which is temporally analogous to when AD patients show sundowning-related aggression. While AD pathology can be detected in numerous brain areas in TAPP mice, we find that the appearance of such physiological and behavioral rhythm disturbances is most consistently associated with the expression of pTau in the lateral parabrachial nucleus (LPB). Using retrograde tracing combined with in situ hybridization, and genetically targeted anterograde tracing, we further show that dynorphin-expressing LPB neurons (LPBdyn) project to the circadian system and are particularly affected by pTau in TAPP mice. Finally, we demonstrated that genetically targeted ablation of LPBdyn neurons resulted in increases in body temperature that partially recapitulated the phenotype of TAPP mice. These findings suggest that a loss of LPBdyn cells is an important part of AD pathogenesis related to circadian dysfunction and sundowning-related disturbances. Importantly, the LPB region has been shown to exhibit pTau and neurodegeneration in AD patients. This study is the first to demonstrate a specific subset of LPB neurons that projects to the circadian system and is associated with AD-related circadian dysfunction.