Sex-Dependent Effects of Bmal1-Deficiency on Mouse Cerebral Cortex Infarction in Response to Photothrombotic Stroke

Abstract

Stroke is a leading cause of disability and death worldwide. There is increasing evidence that occurrence of ischemic stroke is affected by circadian system and sex. However, little is known about the effect of these factors on structural recovery after ischemic stroke. Therefore, we studied infarction in cerebral neocortex of male and female mice with deletion of the clock gene Bmal1 (Bmal1−/−) after focal ischemia induced by photothrombosis (PT). The infarct core size was significantly smaller 14 days (d) as compared to seven days after PT, consistent with structural recovery during the sub-acute phase. However, when sexes were analyzed separately 14 days after PT, infarct core was significantly larger in wild-type (Bmal1+/+) female as compared to male Bmal1+/+ mice, and in female Bmal1+/+, as compared to female Bmal1−/− mice. Volumes of reactive astrogliosis and densely packed microglia closely mirrored the size of infarct core in respective groups. Estradiol levels were significantly higher in female Bmal1−/− as compared to Bmal1+/+ mice. Our data suggests a sex-dependent effect and an interaction between sex and genotype on infarct size, the recruitment of astrocytes and microglia, and a relationship of these cells with structural recovery probably due to positive effects of estradiol during the subacute phase.

Wnt/β-Catenin Signaling Promotes Differentiation of Ischemia-Activated Adult Neural Stem/Progenitor Cells to Neuronal Precursors

“…The same three mouse strains as in our previous study elucidating the effect of Wnt signaling on neonatal NS/PCs ( Kriska et al, 2016 ), were used here; nevertheless, there were several differences in utilizing neonatal and adult mice in our experiments, as a variety of factors may influence the differentiation potential of adult NS/PCs. Among others, gender and age are the most important constituents in this process ( Lembach et al, 2018 ; Vancamp et al, 2019 ). More specifically, clinical observations as well as experimental stroke confirmed that a high amount of estrogen in females acts as an endogenous neuroprotectant after the induction of cerebral ischemia ( Hurn and Macrae, 2000 ), and that neurogenesis ceases with age ( Lupo et al, 2019 ).…”

Bmal1‐deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes

“…Astrocytes respond to oxidative stress with swelling leading to functional impairments (Norenberg, Rao, & Jayakumar, ). Nevertheless, scar formation and structural recovery after ischemic stroke was not impaired in 8–12 week old Bmal1−/− mice, suggesting that the general role of astrocytes in regeneration is not severely affected by Bmal1‐deficiency (Lembach, Stahr, Ali, Ingenwerth, & von Gall, ). In contrast to the older group, morphology of the GFAP + stem processes was not different as compared to Bmal1+/+ littermates.…”

Improved locomotor recovery after contusive spinal cord injury in Bmal1−/− mice is associated with protection of the blood spinal cord barrier

“…They also raise the question whether similar mechanisms may contribute to other BBB/BSCB-disruptive and/or bleeding-associated CNS pathologies such as stroke or TBI 46 . Indeed, a reduced proliferative response of glia and sex-dependent neuroprotection were reported in Bmal1 −/− mice after a photothrombotic cortical stroke 75 . However, given potentially pleiotropic and mutually opposing effects of BMAL1 on the pathogenesis of acute CNS injury, testing such an interesting possibility would require unequivocal identification of cells in which loss of Bmal1 results in neuroprotection and improved recovery.…”