Abstract
The circadian system is an endogenous timekeeping system that synchronizes physiology and behavior with the 24 h solar day. Mice with total deletion of the core circadian clock gene Bmal1 show circadian arrhythmicity, cognitive deficits, and accelerated age-dependent decline in adult neurogenesis as a consequence of increased oxidative stress. However, it is not yet known if the impaired adult neurogenesis is due to circadian disruption or to loss of the Bmal1 gene function. Therefore, we investigated oxidative stress and adult neurogenesis of the two principle neurogenic niches, the hippocampal subgranular zone and the subventricular zone in mice with a forebrain specific deletion of Bmal1 (Bmal1 fKO), which show regular circadian rhythmicity. Moreover, we analyzed the morphology of the olfactory bulb, as well as olfactory function in Bmal1 fKO mice. In Bmal1 fKO mice, oxidative stress was increased in subregions of the hippocampus and the olfactory bulb but not in the neurogenic niches. Consistently, adult neurogenesis was not affected in Bmal1 fKO mice. Although Reelin expression in the olfactory bulb was higher in Bmal1 fKO mice as compared to wildtype mice (Bmal1 WT), the olfactory function was not affected. Taken together, the targeted deletion of Bmal1 in mouse forebrain neurons is associated with a regional increase in oxidative stress and increased Reelin expression in the olfactory bulb but does not affect adult neurogenesis or olfactory function.
Highlights
In mammals, the circadian system is the internal timekeeping system that coordinates physiology and behavior with the 24 h solar day
We addressed the question if the forebrain specific deletion of Bmal1 affects the neurogenic brain niches and adult neurogenesis
In Bmal1 fKO mice, there is no activation of astrocytes or generalized increase in oxidative stress, as shown in this study
Summary
The circadian system is the internal timekeeping system that coordinates physiology and behavior with the 24 h solar day. An essential part of this system is the master circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). The phase and period of the circadian pacemaker can be entrained by external environmental cues such as the daily light changes. The SCN contains a neuronal network that provides rhythmic signals to other brain regions and to the entire body. The SCN neurons and almost all other cells in the body contain cell-autonomous circadian molecular clocks [1]. The transcriptional activators’ brain and muscle Arnt-like protein (BMAL1) and circadian locomotor output cycles (CLOCK) heterodimerize and activate the transcription of other clock genes, e.g., Period (Per) and Cryptochrome (Cry). PER and CRY proteins translocate into the nucleus, heterodimerize and inhibit CLOCK:BMAL1 and, in turn, their own transcription. CLOCK: BMAL1 complex enhances transcription of nuclear receptors, REV-ERBa, and RORa, which control Bmal transcription [2,3,4]
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