Circadian clock in glial cells: modulation of circadian rhythmicity and brain redox homeostasis

? DESCRIPTION (provided by applicant): The objective of this proposal is to examine the role of the intrinsic circadian clock in glial cells on the generation of body circadian rhythms and regulation of brain redox homeostasis. Glial cells have emerged as key players in brain information processing given the extensive neuronal-glial and glial-neuronal communication that takes place at central synapses. Glial cells also express an intrinsic molecular clock and release the neuromodulator ATP in a circadian fashion. Also disruption of glial signaling in fruit flies severely disrupt behavioral circadian rhythms. Collectively, these data suggest that glial cells and their intrinsic circadian rhythms have an important role in modulating circadian rhythmicity of central and peripheral clocks. The focus of this exploratory proposal is to examine mice in which glial cell circadian rhythmicity is ablated to examine such hypothesis. Experiments in Specific Aim 1 will examine the circadian rhythmicity at cellular and at whole animal level from mice in which the canonical clock gene Bmal1 is selectively disrupted in astrocytes. Experiments in Specific Aim 2 will examine the oxidative damage and generation of reactive oxygen species in brains of mice in which expression of Bmal1 is selectively ablated in astrocytes. These experiments will explore the role of the intrinsic circadian clock in glial cellsin behavioral and cellular rhythmicity and its role in neuroprotection in mammals. Results from proposed studies may challenge the dogma that the central pacemaker is exclusively driven by neuronal networks by providing the direct experimental evidence that glial intrinsic clock plays a vital role in circadian rhythmicity.