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

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.

Brain Neural Activity Patterns in an Animal Model of Antidepressant-Induced Manic Episodes

“…This study has several limitations. First, the model used in this study and others, in which ketamine is used to induce the manic phase, is valid, but the accuracy of this assessment has not been discussed in past years, although the aims of previous studies were to explore new methods for the improvement of treatment effects in patients with treatment-resistant depression and to rapidly reduce suicide attempts due to severe depressive symptoms in BP (Valvassori et al, 2019 ; Kim and Monteggia, 2020 ; McIntyre et al, 2020 ; Chen et al, 2021 ; Dean et al, 2021 ; Keilp et al, 2021 ; Magalhães et al, 2021 ; Nikayin and Sanacora, 2021 ; Wilkowska et al, 2021 ). A reviewer of this article led us to rethink the validity of the use of ketamine to induce the manic phase when studying BP (a physiopathological process), as drug-induced manic behavior may have different underlying mechanisms, Strictly speaking, a ketamine-induced manic phase can only represent such a phase induced by antidepressants, which is usually observed in clinical practice.…”

Lithium produces bi-directionally regulation of mood disturbance, acts synergistically with anti-depressive/-manic agents, and did not deteriorate the cognitive impairment in murine model of bipolar disorder

“…As described previously [ 28 ], mice received daily single intraperitoneal injections of 25 mg/kg ketamine for 10 consecutive days. This protocol provokes the expression of manic-like behavior.…”

“…The BP model was designed to mimic a protocol for mania prevention [ 26 – 28 ]. Because BP patients usually experience a depression episode before their first mania episode, we established a depressive phase prior to establishing a manic phase.…”

CaMKK2 as an emerging treatment target for bipolar disorder

“…An alternative view that has emerged from recent studies in mice suggest a link between reduced brain Ca 2+ activity and bipolar disorder. For example, a two-photon imaging study of a ketamine and stress-induced mouse model of bipolar disorder, demonstrated that brain Ca 2+ activity measured in situ was reduced in mice displaying both manic and depressive-like behaviours [ 26 ]. Similarly, conditional knockout mice lacking Cacna1c in the cerebral cortex, which encodes the L-type, voltage-dependent, Ca 2+ -channel, alpha 1 C subunit that is among the most commonly identified risk genes for bipolar disorder, have reduced spontaneous cortical Ca 2+ activity and display hyperactive, manic-like behaviour [ 27 , 28 ].…”