ABSTRACT
Individuals with neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder, exhibit various sleep and circadian rhythm disturbances that often persist and worsen throughout the lifespan. To study the interaction between circadian rhythm disruption and neurodevelopmental disorders, we utilized a mouse model based on prenatal maternal immune activation (MIA). We hypothesized that MIA exposure would lead to impaired circadian locomotor activity rhythms in adult mouse offspring. We induced MIA by injecting pregnant dams with polyinosinic:polycytidylic acid (poly IC) at embryonic day 9.5, then aged resulting offspring to adulthood. We first confirmed that poly IC injection in pregnant dams elevated plasma levels of pro- and anti-inflammatory cytokines and chemokines. We then placed adult offspring in running wheels and subjected them to various lighting conditions. Overall, poly IC-exposed male offspring exhibited altered locomotor activity rhythms, reminiscent of individuals with neurodevelopmental disorders. In particular, we report increased (subjective) day activity across 3 different lighting conditions: 12 h of light, 12 h of dark (12:12LD), constant darkness (DD) and constant light. Further data analysis indicated that this was driven by increased activity in the beginning of the (subjective) day in 12:12LD and DD, and at the end of the day in 12:12LD. This effect was sex-dependent, as in utero poly IC exposure led overall to much milder alterations in locomotor activity rhythms in female offspring than in male offspring. We also confirmed that the observed behavioral impairments in adult poly IC-exposed offspring were not due to differences in maternal behavior. These data further our understanding of the link between circadian rhythm disruption and neurodevelopmental disorders and may have implications for mitigating risk to the disorders and/or informing the development of circadian-based therapies.
Subject(s)
Autism Spectrum Disorder , Neurodevelopmental Disorders , Prenatal Exposure Delayed Effects , Animals , Circadian Rhythm , Disease Models, Animal , Female , Male , Mice , Poly I-C , PregnancyABSTRACT
Most individuals with neurodevelopmental disorders (NDDs), including schizophrenia and autism spectrum disorders, experience disruptions in sleep and circadian rhythms. Epidemiological studies indicate that exposure to prenatal infection increases the risk of developing NDDs. We studied how environmental circadian disruption contributes to NDDs using maternal immune activation (MIA) in mice, which models prenatal infection. Pregnant dams were injected with viral mimetic poly IC (or saline) at E9.5. Adult poly IC- and saline-exposed offspring were subjected to 4 weeks of each of the following: standard lighting (LD1), constant light (LL) and standard lighting again (LD2). Behavioral tests were conducted in the last 12 days of each condition. Poly IC exposure led to significant behavioral differences, including reduced sociability (males only) and deficits in prepulse inhibition. Interestingly, poly IC exposure led to reduced sociability specifically when males were tested after LL exposure. Mice were exposed again to either LD or LL for 4 weeks and microglia were characterized. Notably, poly IC exposure led to increased microglial morphology index and density in dentate gyrus, an effect attenuated by LL exposure. Our findings highlight interactions between circadian disruption and prenatal infection, which has implications in informing the development of circadian-based therapies for individuals with NDDs.
Subject(s)
Prenatal Exposure Delayed Effects , Schizophrenia , Pregnancy , Female , Male , Humans , Mice , Animals , Poly I-C/pharmacology , Prepulse Inhibition , Behavior, Animal , Disease Models, AnimalABSTRACT
Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in postnatal development. Since peripheral oscillators can be influenced by maternal feeding and behavior, we investigated whether exposure to the adverse environmental conditions of limited bedding (LB) during postnatal life would alter rhythmicity in the SCN, adrenal gland and liver in neonatal (postnatal day PND10), juvenile (PND28) and adult rats. We also examined locomotor activity in adults. Limited bedding increased nursing time and slightly increased fragmentation of maternal behavior. Exposure to LB reduced the amplitude of Per2 in the SCN on PND10. Adrenal clock gene expression (Bmal1, Per2, Cry1, Rev-erbα, Dbp) and corticosterone secretion were rhythmic at all ages in NB offspring, whereas rhythmicity of Bmal1, Cry1 and corticosterone was abolished in neonatal LB pups. Circadian gene expression in the adrenal and liver was well established by PND28. In adults, liver expression of several circadian genes was increased at specific daytimes by LB and the microstructure of locomotor behavior was altered. Thus, changes in maternal care and behavior might provide important signals to the maturing peripheral oscillators and modify, in particular their output functions in the long-term.
Subject(s)
Circadian Clocks , Circadian Rhythm , Female , Rats , Animals , Circadian Rhythm/genetics , Corticosterone/metabolism , ARNTL Transcription Factors/metabolism , Circadian Clocks/genetics , Suprachiasmatic Nucleus/metabolismABSTRACT
Mistimed exposure to light has been demonstrated to negatively affect multiple aspects of physiology and behavior. Here we analyzed the effects of chronic exposure to abnormal lighting conditions in mice. We exposed mice for 1 year to either: a standard light/dark cycle, a "light-pollution" condition in which low levels of light were present in the dark phase of the circadian cycle (dim light at night, DLAN), or altered light cycles in which the length of the weekday and weekend light phase differed by 6 h ("social jetlag"). Mice exhibited several circadian activity phenotypes, as well as changes in motor function, associated particularly with the DLAN condition. Our data suggest that these phenotypes might be due to changes outside the core clock. Dendritic spine changes in other brain regions raise the possibility that these phenotypes are mediated by changes in neuronal coordination outside of the clock. Given the prevalence of artificial light exposure in the modern world, further work is required to establish whether these negative effects are observed in humans as well.
ABSTRACT
Schizophrenia is a multifactorial disorder caused by a combination of genetic variations and exposure to environmental insults. Sleep and circadian rhythm disturbances are a prominent and ubiquitous feature of many psychiatric disorders, including schizophrenia. There is growing interest in uncovering the mechanistic link between schizophrenia and circadian rhythms, which may directly affect disorder outcomes. In this review, we explore the interaction between schizophrenia and circadian rhythms from 2 complementary angles. First, we review evidence that sleep and circadian rhythm disturbances constitute a fundamental component of schizophrenia, as supported by both human studies and animal models with genetic mutations related to schizophrenia. Second, we discuss the idea that circadian rhythm disruption interacts with existing risk factors for schizophrenia to promote schizophrenia-relevant behavioral and neurobiological abnormalities. Understanding the mechanistic link between schizophrenia and circadian rhythms will have implications for mitigating risk to the disorder and informing the development of circadian-based therapies.