CIRCADIAN RHYTHM AND BIPOLAR DISORDER Investigation the roles of SCN and Extra- SCN circadian oscillators in the Myshkin mouse model of mania

Abstract

Bipolar disorder (BPD) is a highly debilitating, heritable, neuropsychiatric mood disorder, characterised by mood that vacillates between mania and depression episodes. Patients with BPD exhibit disturbed circadian rhythms noticeable in their irregular sleep cycles and mood behaviours. A recent animal model, the Myshkin mouse, has been validated as the good mouse model of mania due to its satisfaction of face, predictive and construct validity. Hence, Myshkin mice have been utilized for scientific research into mania. The purpose of the research presented in this thesis is to identify circadian oscillators are putatively involved in the pathogenesis of BPD. This was done by investigating the master circadian clock, the suprachiasmatic nucleus (SCN), and extra-SCN oscillators that potentially participate in the regulation of the manic behaviours. The Myshkin mice and their congenic controls (wild-type) were used in this study to assess: 1) the stability of the SCN rhythms under seasonal variation in daylength, 2) behavioural resetting response to an external stimulus, and 3) other extra-SCN brain regions potentially involved in the pathology of BPD. Behavioural experiments and in-vitro tests were used to achieve these objectives. Firstly, mice in wheel-running cages were exposed to gradually increased daylength to study the effects of light on the SCN regulation; secondly, mice were exposed to prolonged light pulses using an Aschoff type II protocol; moreover, a molecular investigation into the expression of PERIOD2::LUCIFERASE in the SCN region was conducted. Lastly, comparison immunohistochemistry tests were run on the brains of wild-type and Myshkin mice to identify neurochemical differences between the extra-SCN brain regions in the two genotypes. The behavioural experiments on the mutant mice demonstrate disturbed circadian profile, altered negative masking behaviour and abnormal reset following long light pulses. The ex-vivo and in-vitro test analysis revealed no variances between the two genotypes. Overall, the Myshkin mice, exhibit various alterations to circadian behaviours that are likely due to abnormalities in the photic input pathway to the SCN. Further research work is required to study the photic input to the SCN, to identify the exact difference between the brain anatomies of the two genotypes and to attempt to manipulate the circadian rhythms in the manic mice.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gigg (Supervisor) & Hugh Piggins (Supervisor)