For a long term, the neuropathological mechanisms of manic syndrome or manic episodes in bipolar disorder (BD) are poorly characterized, the main reason is the research progress is severely limited by the paucity of appropriate animal models, as well as, the behavioural assessments methods of the built disease relevant models are still not standardized and lack the representativeness of disease symptoms.
Our group has researched the pathological mechanism of mood disorders nearly to 20 years, specially focus on the cellular biological mechanisms of astrocytes. In some of our previous studies, the chronic unpredictable mild stress (CUMS) was the adopted mice models of major depressive disorders (MDD), CUMS is also the widely used and accepted MDD relavent models in the cellular molecular and biology researches of mental disorders. However, in the past decade of years, many of our experimental technicians and operators continuously discovered that the very few mice performed the manic-like behaviours after the random treatments in CUMS model mice, these few mice had obvious distinguish behaviours characteristic with the other mice with depressive-like behaviours. We curiously check the exact treatments to these few mice with manic-like performance, although the treatments were all randomly scheduled on every experimental mice, the stroboscopic illumination and noise were seems more operated on these few mice by chance. Then, we re-consider all exposed stressors used in chronic CUMS models, these stressors can be mainly separated and concluded into two categories, the life rhythm disturbance and the behavioural restraint. In hence, according to this discovery, we create a novel manic mice model treated with chronic unpredictable rhythm disturbances (CURD) and improve the previous CUMS mice model to chronic unpredictable mild restraint (CUMR).
In CURD model, to disturb the circadian rhythm, the sleep deprivation, exposure to cone light, with subsequent interference of followed spotlight, stroboscopic illumination, high temperature stress, noise disturbance and foot shock were randomly scheduled on the experimental mice. In CUMR model, to enhance the behavioural restraint, the restricting activity, damp bedding, cage shaking, tail suspension and forced swimming were randomly operated on the experimental mice.
To further assess the availability and representativeness of CURD and CUMR models, besides the traditional tests of depressive-like performance were used, three-chambered sociability test, pentobarbital induced sleep test, our created bite ability test and sucrose pellets preference test were also adopted to assess the manic-like and the depressive-like behaviours. In this work, the behaviours between CURD treated mice and CUMR treated mice were firstly compared, the amphetamine induced manic model and the corticosterone induced depressive model were also compared with these two new mice models. In pharmacological therapeutic experiments, the classical anti-mania medicines lithium salt (Li+) and valproic acid (VPA) were used to check the behavioural improvements and the indicators of molecular and neuronal signalling in the CURD treated mice. Furthermore, the blood samples of BD patients were also collected and compared with the blood and brain samples of CURD treated mice.
In the behavioural performance, the CURD treated mice had clear manic-like characters, such as the hyperactivity, hyperappetite, extra-exploration, disturbed rhythm of sleep and shortened sleep duration. The administration of Li+ or VPA can both effectively improve the manic-like behaviours in CURD model. Thus, the CUMR treated mice have depressive-like behaviours, likely the hopeless, anhedonia, decreased activies and exploration. In the cerebral molecular and signalling indicators, as the comparison with control group, the expression of neuronal c-fos and the level of extracellular serotonin (5-HT) were both significantly increased in the frontal cortex of CURD treated mice, but the expression of serotonin transporter SERT was decreased. CUMR treated mice had the opposite tendency in these three indicators. In the comparison with clinical BD patients and CURD treated mice, the levels of arachidonic acid (AA) and prostaglandin E2 (PGE2) and the ratios of the phosphorylated Ca2+-dependent phospholipase A2 (p-cPLA2)/cPLA2 and p-GSK3b/ GSK3b were all measured, these indicators all had high correlation in the plasmas and the sorted cerebral astrocytes of CURD treated mice and the plasma of BD patients. Meanwhile, Li+ or VPA also had effectively improvements on these indicators measured from CURD-treated mice.
This novel mania model (CURD) and the improved depression model (CUMR) are both only induced by the environmental disturbances, which are easy to replicate. The biological indicators measured in CURD- or CURM-treated mice agree well with the clinical data obtained from patients with mood disorders (BD and MDD). The administration of anti-manic drugs effectively improves the disease related indicators and behavioural performance. In this work, these two mice models, CURD and CUMR induced by environmental stressors and free from genetic or pharmacological interventions are the valuable tools for research into pathological mechanisms of BD and MDD, as well as, the adopted behavioural tests are also the useful methods for the studies of psychiatric diseases by mice models.