Bmal1 Is Required for Normal Reproductive Behaviors in Male Mice

Abstract

Circadian rhythms synchronize physiological processes with the light-dark cycle and are regulated by a hierarchical system initiated in the suprachiasmatic nucleus, a hypothalamic region that receives direct photic input. The suprachiasmatic nucleus then entrains additional oscillators in the periphery. Circadian rhythms are maintained by a molecular transcriptional feedback loop, of which brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a key member. Disruption of circadian rhythms by deletion of the BMAL1 gene (Bmal1 knockout [KO]) induces a variety of disease states, including infertility in males, due to unidentified mechanisms. We find that, despite normal sperm function, Bmal1 KO males fail to mate with receptive females, indicating a behavioral defect. Mating is dependent on pheromone detection, as are several other behaviors. We determined that Bmal1 KO males also fail to display aggression and avoidance of predator scent, despite intact main olfactory function. Moreover, the vomeronasal organ, a specialized pheromone-responsive organ, was also functionally intact, as determined by calcium imaging in response to urine pheromone stimulus. However, neural circuit tracing using c-FOS activation revealed that, although Bmal1 KO males displayed appropriate activation in the olfactory bulb and accessory olfactory bulb, the bed nucleus of the stria terminalis and the medial preoptic area (areas responsible for integration of copulatory behaviors) failed to activate highly in response to the female scent. This indicates that neural signaling in select behavioral centers is impaired in the absence of BMAL1, likely underlying Bmal1 KO male copulatory defects, demonstrating the importance of the BMAL1 protein in the maintenance of neural circuits that drive pheromone-mediated mating behaviors.

Fish Oil Ameliorates High-Fat Diet Induced Male Mouse Reproductive Dysfunction via Modifying the Rhythmic Expression of Testosterone Synthesis Related Genes

“…Circadian rhythm has been thought to affect reproductive functions. Deficiency of the Bmal1 gene in mice resulted in disturbed reproduction, low testosterone levels and reduced the expression of Star and other testosterone synthesis associated genes [ 43 , 44 ]. In Bmal1 , Per2 or Per1/2 knockout mice, the testicular Star expression was significantly inhibited, whereas Per1 deficiency has no effects on Star expression [ 43 ].…”

The trophoblast clock controls transport across placenta in mice

“…Bmal1 is the only clock protein without a redundant partner, and the absence of this gene will lead to the absence of oscillations of the TTFL. However, assessing the role of the maternal clock is not possible with this mouse strain because Bmal1 homozygous knockouts are infertile (Boden et al, 2010;Schoeller et al, 2016). Per1 and Per2 have complementary functions; and both genes have to be knocked out to lead to the absence of TTFL oscillations.…”

The Contribution of the Circadian Gene Bmal1 to Female Fertility and the Generation of the Preovulatory Luteinizing Hormone Surge

“…Bmal1 floxed mice [ 18 ] were obtained from The Jackson Laboratory (Bar Harbor, ME) and used to generate the global and conditional Bmal1 KO lines [ 19 ]. Global Bmal1 KO mice were obtained by crossing a Bmal1 floxed mouse with a ZP3-Cre mouse [ 20 ], as described and validated in Schoeller et al [ 21 ]. Bmal1 KO mice were maintained through heterozygous matings, with WT littermates serving as controls.…”