Survival of Adult Generated Hippocampal Neurons Is Altered in Circadian Arrhythmic Mice

Abstract

The subgranular zone of the hippocampal formation gives rise to new neurons that populate the dentate gyrus throughout life. Cells in the hippocampus exhibit rhythmic clock gene expression and the circadian clock is known to regulate the cycle of cell division in other areas of the body. These facts suggest that the circadian clock may regulate adult neurogenesis in the hippocampus as well. In the present study, neurogenesis in the hippocampal subgranular zone was examined in arrhythmic Bmal1 knockout (-KO) mice and their rhythmic heterozygous and wildtype littermates. Proliferation and survival of newly generated subgranular zone cells were examined using bromodeoxyuridine labelling, while pyknosis (a measure of cell death) and hippocampal volume were examined in cresyl violet stained sections. There was no significant difference in cellular proliferation between any of the groups, yet survival of proliferating cells, 6 weeks after the bromodeoxyuridine injection, was significantly greater in the BMAL1-KO animals. The number of pyknotic cells was significantly decreased in Bmal1-KO animals, yet hippocampal volume remained the same across genotypes. These findings suggest that while a functional circadian clock is not necessary for normal proliferation of neuronal precursor cells, the normal pruning of newly generated neurons in the hippocampus may require a functional circadian clock.

Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

“…Adult Bmal1 −/− mice show a higher survival rate of NPCs in the DG as compared to Bmal1 +/+ mice. This is consistent with the previously observed enhanced survival in young adult Bmal1 −/− mice interpreted as impaired pruning of newly generated neurons [ 15 ]. Moreover, adult Bmal1 −/− mice showed a significantly lower number of apoptotic cells with no change in DG volume consistent with the decline in cell death during aging in combination with a stable DG volume from 6 weeks of age onwards [ 40 ].…”

“…Oxidative stress leads to decreased proliferation and neuronal differentiation capacity, and induces cellular senescence in NPCs [ 33 , 49 ]. It also activates compensatory mechanisms to minimize cell death by interference with apoptotic signalling pathways [ 49 ]; which is consistent with enhanced survival of NPCs shown in this study and observed previously in Bmal1 −/− mice [ 15 ].…”

“…Using mathematical models, they postulated that dysregulated clock-driven expression of a cell cycle inhibitor targets is attributed to enhanced entry and diminished cell cycle exit in Bmal1 −/− progenitors. In contrast to 5 weeks old mice, no difference in proliferating capacity of hippocampal NPCs was found in 8 weeks old Bmal1 −/− mice [ 15 ], indicating that the promoting effect of Bmal1-deficiency on mitotic activity is transient and age-dependent. In our study, we used adult mice (10-15 weeks old); this age is of particular interest, as it is before the onset of systemic growth retardation as a hallmark of accelerated aging in 16-18 weeks old Bmal1 −/− mice [ 23 ], and before the development of neuropathologies in 24 weeks old Bmal1 −/− mice [ 25 ].…”

“… In young (5 weeks old) Bmal1 ‐/‐ mice there was an enhanced proliferation of hippocampal NPCs probably due to dysregulated cell cycle [ 17 ]. In young adult (8 weeks old) Bmal1 ‐/‐ mice, no difference in proliferating hippocampal NPCs was found [ 15 ], indicating that the promoting effect of Bmal1‐deficiency on NPC mitotic activity is transient and age‐dependent. In our study, adult Bmal1 ‐/‐ (10‐15 weeks old) mice showed a significant decrease in the pool of hippocampal NPCs indicating a dramatic down‐regulation in proliferation activity of NPCs presumably due to ROS‐induced accelerated aging/senescence.…”

Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

“…However, others found no significant difference in the cellular proliferation in Bmal1 knockout mice, yet survival of proliferating cells, was significantly greater in Bmal1 knockout animals (Rakai et al, 2014).…”