Advancing systems thinking in implementation science: An epidemiologic perspective.

The choroid plexus (ChP) is a highly vascularized tissue, located within cerebral ventricles, that produces cerebrospinal fluid (CSF). ChP function is critical for maintaining CSF ionic homeostasis, delivering trophic factors to surrounding neuronal tissue, providing a brain–CSF barrier, immune surveillance, waste clearance, and supporting overall brain health. Indeed, impaired CSF dynamics are proposed to promote pathological processes such as aberrant protein aggregation, inflammation, and neuronal dysfunction. Physiologically, the protein, metabolite, and ionic composition within CSF is dynamic, with fluctuating concentrations over the 24 h cycle and with sleep states. In humans, CSF production is highest at night, which may be related to more rapid glymphatic CSF–interstitial solute exchange and clearance. In ex vivo rodent experiments, the ChP has exhibited circadian regulation, with communication to and from the suprachiasmatic nucleus (SCN). Importantly, this circadian regulation within the ChP has been corroborated with recent transcriptional, translational, and CSF proteomic and metabolomic evidence. Choroid plexus dysfunction, defined by reduced blood–CSF barrier function, epithelial atrophy, proinflammatory cytokine secretion, and depleted mitochondrial metabolism, has been reported in animal models of aging and amyloid β (Aβ) pathology, in human studies of aging and Alzheimer’s disease (AD), and in clinical cohorts measuring ChP volume with MRI. Similarly, CSF production rates decrease with age and are significantly reduced in the setting of AD. Together, these findings support the notion that impaired ChP function and dysregulated CSF dynamics may be early factors driving pathological processes in neurodegenerative conditions. Sleep and circadian disruption are common in human populations, worsen with age, and are prevalent across neurodegenerative disease states, including AD. Longitudinal studies show that short sleep duration, poor sleep quality, and circadian disorders can increase neurodegenerative disease risk. While impaired CSF dynamics have been linked to sleep disruption and neurodegenerative processes, whether sleep plays a role in ChP function has not been examined. In this study, we aimed to confirm prior findings of diurnal ChP regulation, but in the context of sleep disruption, in the setting of aging, and in a model of Aβ pathology. Diurnal ChP gene expression was examined using RNA sequencing of ChP tissue from 3-month old male mice during their normal active or normal resting period, with or without acute sleep disruption. These data were then compared to diurnal gene expression data in aged 12-month-old wildtype (WT), and 12-month-old J20 male mice with Aβ pathology. Transcriptomic data revealed functional differences in diurnal regulation with age and Aβ pathology. Functionally, both NKCC1 protein levels and CSF K vary across the circadian cycle in both an age- and sex-dependent manner, suggesting age-related changes in ChP rhythmicity may be involved in disrupted CSF K homeostasis.