Unpredictable circadian rhythm disruption in Wistar rats: biological and behavioural changes reflecting bipolar disorder pathophysiology

Abstract Circadian disturbances are implicated in dysregulation of arousal and general neurobiological function, contributing to conditions such as bipolar disorder (BD). However, the behavioural and biological consequences of circadian disruption on arousal dysfunction remain poorly quantified. Here, we developed a novel unpredictable circadian disruption (UCD) protocol – consisting of unpredictable exposure to light and sound – to investigate its impact on locomotor activity and its association with metabolic, inflammatory, stress, and circadian markers in the nucleus accumbens (NAc). Forty-eight Wistar rats were exposed to UCD or control conditions, with or without corticosterone administration, for five weeks. Body weight was tracked throughout the study. Locomotor activity was assessed over the final two weeks (nine sessions) in an open-field arena. Real-time PCR was used to quantify NAc gene expression of inflammatory, metabolic, stress, and circadian markers, while liquid chromatography-mass spectrometry (LC-MS) measured neurotransmitter and central carbon metabolite concentrations. UCD animals exhibited initial hyperactivity at three weeks, followed by hypoactivity at four weeks. UCD was associated with increased NAc expression of inflammatory, stress, and circadian markers. Male UCD animals showed significant weight gain, an effect reversed in females. UCD also induced increases in NAc insulin resistance markers and reductions in central carbon metabolites, indicating disrupted striatal glucose metabolism. These findings highlight the central effects of circadian disruption on locomotor behaviour, stress, and immunometabolic signalling, offering mechanistic insights into arousal dysfunction in BD. Highlights: Unpredictable circadian disruption (UCD) triggers a biphasic shift in locomotor behaviour UCD alters levels of striatal inflammatory, circadian, stress, and metabolic markers UCD has sex-specific effects on behaviour, weight, and molecular biomarkers Corticosterone administration mitigates key molecular disruptions induced by UCD Competing Interest Statement The authors have declared no competing interest. Footnotes CRediT author statement: Heather Macpherson: Conceptualisation, Methodology, Investigation, Formal Analysis, Visualisation, Writing – Original draft preparation, Project administration. Roger Varela: Conceptualisation, Methodology, Investigation, Writing – Review and Editing, Supervision. Sebastian McCullough: Investigation, Writing – Reviewing and Editing. Tristan Houghton: Investigation. Isha Chawla: Investigation. Ning Wang: Investigation. Venea Daygon: Investigation, Writing – Reviewing and Editing. Xiaoying Cui: Resources, Writing – Reviewing and Editing. Susannah Tye: Conceptualisation, Methodology, Resources, Writing – Reviewing and Editing, Supervision, Project administration, Funding acquisition.