Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of Tau pathology

Abstract

Tauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brains central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were unchanged in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself.