Abstract
Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment.
Highlights
The circadian clock endogenously drives approximately 24-h rhythms in all animals.Circadian rhythms are fundamentally important in regulating gene expression, neurophysiology, and animal behavior across the lifespan [1]
To determine whether molecular diurnal rhythms were changed in the Short Day (SD) mice, we detected the levels of the clock proteins, PER1 and PER2, in the suprachiasmatic nucleus (SCN) at 1 h after light-on (ZT1) and 1 h after light-off (ZT13 for CTR, ZT 9 for SD)
Consistent with the published results, we found higher levels of PER1 and PER2 at ZT 13 compared with ZT 1 in the SCN of CTR mice, indicating the diurnal oscillations of the PER levels
Summary
The circadian clock endogenously drives approximately 24-h rhythms in all animals. Circadian rhythms are fundamentally important in regulating gene expression, neurophysiology, and animal behavior across the lifespan [1]. The circadian clock regulates neurogenesis, migration, and progenitor cell differentiation. Circadian rhythms regulate neuronal excitability, synaptic plasticity, learning and memory, mood, and social behaviors [2]. The expression of clock genes in different systems is orchestrated and synchronized by the master circadian pacemaker, the suprachiasmatic nucleus (SCN) in the hypothalamus. It is generally thought that circadian rhythms are essential for maintaining body health. Aberrant light exposure, such as light at night, shift work, or transmeridian travel can disrupt circadian rhythms and cause their desynchronization in different systems of the body. The molecular and cellular changes in the adult brain after chronic circadian disruption during neurodevelopment have never been investigated
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have