The pathogenesis of bipolar disorder (BD), which is characterized by alternating manic and depressive episodes, is not yet clear, and the lack of disease-related animal models is one of the reasons limiting the research on the pathogenesis and therapeutics.
Recently, Prof. Li Baoxingman's team from the School of Law, China Medical University, together with Prof. Xia Maosheng from the First Affiliated Hospital of China Medical University and Prof. Alexei Verkhratsky from the University of Manchester, UK, published a research paper entitled "A Novel Murine Model of Mania" online in Molecular Psychiatry.
The study created a chronic unpredictable rhythm disturbance (CURD) mouse model of mania that does not rely on genetics or pharmacological interventions. In addition, it improves the chronic unpredictable mild stress (CUMS) model, which is widely accepted and used in the field of depression research, by naming it the chronic unpredictable mild restraint (CUMR) model.
In the CURD model, researchers randomized experimental mice to sleep deprivation, cone light irradiation, follow spotlight interference, strobe lighting, heat stress, noise interference, and foot electroshock interventions to disrupt the normal life rhythm of the mice.
In the CUMR model, researchers randomized experimental mice to activity restriction, wet bedding, cage shaking, tail suspension, and forced swimming to enhance behavioral restraint disturbances and stripped the CUMS model of stimuli that disrupted the mice's life rhythm.
To further assess the representativeness and applicability of the CURD and CUMR models, the team used a three-box social test, a pentobarbital-induced sleep test, an original tearing ability test, and a sugar pill preference test to assess manic-like and depressive-like behaviors, in addition to traditional tests related to depressive-like behaviors.
In this study, the team also compared the behavioral differences between the CURD and CUMR models, as well as comparing the two new mouse models with the amphetamine-induced mania model and the corticosterone-induced depression model. In the pharmacological treatment experiments, on the other hand, the behavioral performance, molecular indicators, and neural signal transduction indicators of the CURD model mice were examined using the classical antimanic drugs lithium salt (Li+) and valproate (VPA). In addition, the team collected blood samples from BD patients and compared them with blood and brain tissue samples from CURD model mice.
Both Li+ and VPA were effective in improving the manic-like behaviors in the CURD model mice. In contrast, CUMR model mice showed depressive-like behaviors, including despair, absence of pleasure, reduced activity, and decreased desire for exploration. In the comparison of biological indices and brain functions of mice, both CURD and CUMR model mice showed significant differences from control mice, such as impaired circulatory function of the glial lymphatic system and abnormal neuronal activity.
The mouse CURD model was created by living environmental rhythm disturbance, and the mouse CUMR model was also established by environmental bound stress. The changes in biological indicators in peripheral blood and intracerebral astrocytes of the above two models of mice are highly similar to clinical data from peripheral blood of patients with clinical biphasic and monophasic depression, respectively. The CURD and CUMR mouse models created in this institute are effective tools for studying the pathological mechanisms, and pharmacological mechanisms of affective disorders.