Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function

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.

P2Y 2 deficiency impacts adult neurogenesis and related forebrain functions

“…The cytoarchitecture of DG and OB was also analyzed using cresyl violet‐stained sections. The width of the respective cellular layers of OB was measured as described previously 50,51 …”

“…The width of the respective cellular layers of OB was measured as described previously. 50,51 BrdU + and DCX + cells were counted manually using the bright field mode with 40X objective on a KEYENCE BZ 900E microscope (Keyence). All settings were kept identical during image acquisition and processing.…”

Adult Neurogenesis under Control of the Circadian System

“…However, although Per2 seems to play an important role in adult neurogenesis (see above), hippocampus-dependent learning is not affected in Per1/Per2 mutants [ 200 , 201 ]. In forebrain-specific Bmal1 -deficient mice hippocampus-dependent learning and memory is impaired [ 202 ] while major olfactory function and adult neurogenesis in both neurogenic niches are intact [ 203 ], indicating a role of Bmal1 in hippocampal function in addition to its role in adult neurogenesis. Odor discrimination largely depends on integrated interneurons in the olfactory bulb [ 49 ].…”

Regulation of tissue regeneration by the circadian clock

“…Interestingly, young Bmal1 null mice showed increased survival of proliferating cells and decreased pyknotic cells in the SGZ, suggesting that pruning of new neurons may also require an intact cellular clock (Rakai et al., 2014). However, forebrain‐specific deletion of Bmal1 in mice produced no alteration in adult neurogenesis in the hippocampus or olfactory bulb (Ali et al., 2020), suggesting that arrhythmicity resulting from global Bmal1 deficiency may be the true mediator of disrupted neurogenesis.…”

“…Long‐term exposure (2–10 weeks) to a T7 photocycle (3.5 hr of darkness alternating with 3.5 hr of light), which lengthens circadian behavioural rhythms, but does not cause arrhythmicity or sleep deprivation, impaired mood and learning without affecting hippocampal neurogenesis (Duy & Hattar, 2017; LeGates et al., 2012). Likewise, forebrain‐specific deletion of Bmal1 in mice, which does not cause arrhythmicity, did not alter adult neurogenesis (Ali et al., 2020), but global Bmal1 deletion did, impairing performance in several hippocampal neurogenesis‐dependent learning tasks (Bouchard‐Cannon et al., 2013). Mice lacking Rev‐erbα resembled Bmal1 null mice, showing arrhythmically high levels of adult neurogenesis, along with deficits in cognition and mood (Schnell, Chappuis, et al., 2014).…”