Pushing the Frontiers: Optogenetics for Illuminating the Neural Pathophysiology of Bipolar Disorder

Abstract

Bipolar disorder (BD), a disabling mental disorder, is featured by the oscillation between episodes of depression and mania, along with disturbance in the biological rhythms. It is on an urgent demand to identify the intricate mechanisms of BD pathophysiology. Based on the continuous progression of neural science techniques, the dysfunction of circuits in the central nervous system was currently thought to be tightly associated with BD development. Yet, challenge exists since it depends on techniques that can manipulate spatiotemporal dynamics of neuron activity. Notably, the emergence of optogenetics has empowered researchers with precise timing and local manipulation, providing a possible approach for deciphering the pathological underpinnings of mental disorders. Although the application of optogenetics in BD research remains preliminary due to the scarcity of valid animal models, this technique will advance the psychiatric research at neural circuit level. In this review, we summarized the crucial aberrant brain activity and function pertaining to emotion and rhythm abnormities, thereby elucidating the underlying neural substrates of BD, and highlighted the importance of optogenetics in the pursuit of BD research.

Keywords: Bipolar disorder; animal model; biological rhythms; frontal-limbic system; optogenetics; pathophysiology.

Figure 1

Changes in the amygdala activity and connectivity in BD subjects compared with healthy controls*. *Both increased and decreased amygdala activation have been found in euthymic BD and healthy controls, which is not showed in this figure. Evidence showed increased activation of amygdala in BD subjects compared to healthy controls. The activity of left amygdala increased significantly during mania stage of BD, while the trend of increased activity of left amygdala has been observed in BD depression. Higher connectivity between the amygdala and the DLPFC, as well as lower connectivity between the amygdala and VLPFC was found in BD, and heightened connectivity was also detected between the amygdala and ACC. BD = bipolar disorder; VLPFC = ventrolateral prefrontal cortex; DLPFC = dorsolateral prefrontal cortex; ACC = anterior cingulate cortex.

Figure 2

The relationship between fluctuant emotions of BD, SCN dysfunction, CLOCK genes abnormities, and disrupted circadian rhythms. Disruption of the biological circadian rhythms is commonly found in BD patients, for its correlation with the emotional fluctuation. Pre-clinical studies also demonstrated the disrupted circadian rhythms could lead to depression- or mania-like behaviors in animals. Studies based on fMRI suggest that BD patients have dysfunctions in the SCN rhythm pacemaker, while observed SCN dysfunctions could increase the susceptibility of BD in health population. In addition, pre-clinical studies have also found that there are two ways for the dysfunctional SCN to cause circadian rhythms disruption: i) Through the activity of molecular "clocks" and environmental stimuli; ii) Through the expression of CLOCK genes. Of note, abnormalities in the CLOCK genes expression could also increase the susceptibility of BD, which has previously been proven pre-clinically. BD = bipolar disorder; SCN = suprachiasmatic nucleus; fMRI = functional magnetic resonance imaging.