Calcium imaging reveals depressive- and manic-phase-specific brain neural activity patterns in a murine model of bipolar disorder: a pilot study

Min Chen,Jingjing Zhu,Suling Chen,Ce Chen,Langlang Cheng,Guoyong Huang,Fengyuan Zhao ,Deguo Jiang,Chunmian Chen,Xiaodong Lin,Gaungdong Chen,Huang Guixiu ,Chongguang Lin,Jianmin Shan,Ziyao Cai,Jing Ping,Chuanxin Liu,Hongjun Tian,Tao Fang,Chuanjun Zhuo

doi:10.1038/s41398-021-01750-8

Abstract

Brain pathological features during manic/hypomanic and depressive episodes in the same patients with bipolar disorder (BPD) have not been described precisely. The study aimed to investigate depressive and manic-phase-specific brain neural activity patterns of BPD in the same murine model to provide information guiding investigation of the mechanism of phase switching and tailored prevention and treatment for patients with BPD. In vivo two-photon imaging was used to observe brain activity alterations in the depressive and manic phases in the same murine model of BPD. Two-photon imaging showed significantly reduced Ca2+ activity in temporal cortex pyramidal neurons in the depression phase in mice exposed to chronic unpredictable mild stress (CUMS), but not in the manic phase in mice exposed to CUMS and ketamine. Total integrated calcium values correlated significantly with immobility times. Brain Ca2+ hypoactivity was observed in the depression and manic phases in the same mice exposed to CUMS and ketamine relative to naïve controls. The novel object recognition preference ratio correlated negatively with the immobility time in the depression phase and the total distance traveled in the manic phase. With recognition of its limitations, this study revealed brain neural activity impairment indicating that intrinsic emotional network disturbance is a mechanism of BPD and that brain neural activity is associated with cognitive impairment in the depressive and manic phases of this disorder. These findings are consistent with those from macro-imaging studies of patients with BPD. The observed correlation of brain neural activity with the severity of depressive, but not manic, symptoms need to be investigated further.

Highlights

Bipolar disorder (BPD) is a chronic psychiatric disorder affecting 1–4% of the global population [1]
chronic unpredictable mild stress (CUMS) and ketamine exposure evoked abnormal cortical transmission and behavior Compared with controls, mice exposed to CUMS and ketamine had significantly longer immobility times in the depression phase (P < 0.001; Fig. 1c) and significantly greater total distances traveled in the manic phase (P < 0.001; Fig. 2c)
Ca2+ hypoactivity was observed in the prefrontal cortex (PFC) in the depression and manic phases in mice exposed to CUMS and ketamine (Figs. 1e, f and 2e, f)

Summary

Introduction

Bipolar disorder (BPD) is a chronic psychiatric disorder affecting 1–4% of the global population [1]. The current evidence suggests that disturbances of macroand micro-brain connectivity and monoamine transmitters are the pathological features of BPD, and that these features are caused by neuronal axon, dendrite, brain transmitter, and brain electrical activity dysfunction, as well as genetics and epigenetics (reciprocal gene–environment interactions) [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. Macro- and micro-brain connectivity is correlated due to the disturbance of neural synapse connections in BPD [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]

Methods

Results

Conclusion