Exposure to Circadian Disruption During Adolescence Interacts With a Genetic Risk Factor to Modify Schizophrenia-relevant Behaviors in a Sex-dependent Manner

Abstract

DTNBP1 is a gene associated with schizophrenia. Postmortem studies found a reduced expression of DTNBP1 in regions associated with schizophrenia in patients’ brains. Sandy (Sdy) mice have a loss-of-function mutation in Dtnbp1 gene, resulting in behavioral deficits and brain changes similar to those seen in patients with schizophrenia. We previously showed that exposing adult Sdy mice to circadian disruption led to an exacerbation of schizophrenia-relevant behaviors. Here we asked whether the interaction between this genetic risk factor and circadian disruption occurs during adolescence, a period when environmental insults can promote schizophrenia symptoms, and whether sex affects this interaction. Starting at postnatal day 21, wild-type (WT) and Sdy males and females were housed for 4 weeks either in a 12 h light:12 h dark (LD 12:12) cycle or under chronic jetlag (CJL). Then, after 2 weeks in LD 12:12, behavioral assessments were conducted, including elevated plus maze (EPM), novel object recognition (NOR), social interaction, and prepulse inhibition (PPI) of acoustic startle. NOR and social novelty tests showed that, surprisingly, CJL during adolescence had opposite effects on WT and Sdy males, that is, behavioral deficits in WT males while rescuing preexisting deficits in Sdy mice. CJL led to decreased sociability in WT and Sdy mice while decreasing PPI only in females. Sdy mice showed decreased anxiety-like behavior compared with wild-type (WT), which was further accentuated by CJL in males. Thus, circadian disruption during adolescence, on its own or in association with Dtnbp1 mutation, can influence cognition, sociability, sensorimotor gating, and anxiety-like behaviors in a sex-dependent manner.

Behavioral and cellular responses to circadian disruption and prenatal immune activation in mice

“…Here, we found interactions between MIA and circadian disruption at the behavioral and microglial level. Our data supports a role for circadian disruption as a risk factor for NDDs, which has already been shown in a genetic mouse model for schizophrenia 35 , 36 . Future research should address the mechanisms that underlie this interaction to inform the development of circadian-based therapies that aim to prevent or mitigate these serious diseases.…”

“…In many individuals with NDDs, circadian disturbances precede the onset of psychosis 30 , 34 , which supports a role for circadian disruption as a risk factor for NDDs. This hypothesis is reinforced in a genetic mouse model for SCZ, where SCZ-related behaviors worsened after altered light exposure 35 , 36 . If circadian disruption is a risk factor for NDDs, individuals with NDDs may be vulnerable to the effects of environmental circadian disruption (e.g., shift work), in ways that affects the expression of symptoms experienced.…”

Effects of prenatal maternal immune activation and exposure to circadian disruption during adolescence: exploring the two-hit model of neurodevelopmental disorders

“…Previous work from our group found that in males, LL exposure during adulthood led to reduced sociability in poly IC exposed mice but had no effect on saline-exposed(35), whereas chronic jetlag exposure reduced sociability in both males and females (33). These data suggest an interplay between prenatal poly IC and LL exposure in males on both anxiety-like behavior and sociability.…”

“…Interestingly, in many individuals with SCZ, circadian disruptions precede the onset of psychosis(31, 32), suggesting that circadian disruption may be a risk factor for neurodevelopmental disorders. This hypothesis is supported by some mouse models for SCZ, where SCZ-related behaviors worsened after altered light exposure(33–35).…”

The circadian system: A neglected player in neurodevelopmental disorders

“…CJL led to sociability deficits in Sandy mice. Sex‐specific differences were also present, wherein CJL resulted in reduced anxiety‐like behaviour and decreased PPI in males and females, respectively (Cloutier et al, 2022).…”