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βCaMKII in lateral habenula mediates core symptoms of depression. Science (New York, N.Y.) The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent protein kinase type II (βCaMΚΙΙ) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing β-, but not α-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of βCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify βCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression. 10.1126/science.1240729
Lateral habenula in the pathophysiology of depression. Yang Yan,Wang Hao,Hu Ji,Hu Hailan Current opinion in neurobiology Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and discomfort without a clear cause. Depression has been suggested to be the result of maladaptive changes in specific brain circuits. Recently, the lateral habenula (LHb) has emerged as a key brain region in the pathophysiology of depression. Increasing evidence from rodent, non-human primate and human studies indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Revealing the molecular, cellular and circuit properties of the LHb will help explain how abnormalities in LHb activity are linked to depressive disorders, and shed light on developing novel strategies for depression treatment. 10.1016/j.conb.2017.10.024
Decoding Depression: Insights from Glial and Ketamine Regulation of Neuronal Burst Firing in Lateral Habenula. Cui Yihui,Yang Yan,Dong Yiyan,Hu Hailan Cold Spring Harbor symposia on quantitative biology The rapid antidepressant effect of ketamine is arguably one of the most significant advances in the mental health field in the last half century. However, its mechanism of action has remained elusive. Here, we describe our latest discovery on how ketamine blocks -methyl-D-aspartate receptor (NMDAR)-dependent burst firing of an "antireward" center in the brain, the lateral habenula (LHb), to mediate its antidepressant effects. We also discuss a novel structure-function mechanism at the glia-neuron interface to account for the enhanced LHb bursting during depression. These results reveal new molecular targets for the therapeutic intervention of major depression. 10.1101/sqb.2018.83.036871
Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Cui Yihui,Yang Yan,Ni Zheyi,Dong Yiyan,Cai Guohong,Foncelle Alexandre,Ma Shuangshuang,Sang Kangning,Tang Siyang,Li Yuezhou,Shen Ying,Berry Hugues,Wu Shengxi,Hu Hailan Nature Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression. 10.1038/nature25752
Advances in Molecular and Circuitry Mechanisms of Depressive Disorder-A Focus on Lateral Habenula. Hu Hailan Advances in experimental medicine and biology Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and discomfort without a clear cause. Depression has been suggested to be the result of maladaptive changes in specific brain circuits. Recently, the lateral habenula (LHb) has emerged as a key brain region in the pathophysiology of depression. Increasing evidence from rodent, nonhuman primate, and human studies indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Revealing the molecular, cellular, and circuit properties of the LHb will help explain how abnormalities in LHb activity are linked to depressive disorders and shed light on developing novel strategies for depression treatment. 10.1007/978-981-32-9271-0_7
Cannabinoid CB receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior. Shen Chen-Jie,Zheng Di,Li Ke-Xin,Yang Jian-Ming,Pan Hao-Qi,Yu Xiao-Dan,Fu Jia-Yu,Zhu Yi,Sun Qi-Xin,Tang Meng-Yu,Zhang Ying,Sun Peng,Xie Yi,Duan Shumin,Hu Hailan,Li Xiao-Ming Nature medicine Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCK-D2 circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CBR). Knockdown of CBR in the CCK-D2 circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCK-D2 circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression. 10.1038/s41591-018-0299-9
Publisher Correction: Cannabinoid CB receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior. Shen Chen-Jie,Zheng Di,Li Ke-Xin,Yang Jian-Ming,Pan Hao-Qi,Yu Xiao-Dan,Fu Jia-Yu,Zhu Yi,Sun Qi-Xin,Tang Meng-Yu,Zhang Ying,Sun Peng,Xie Yi,Duan Shumin,Hu Hailan,Li Xiao-Ming Nature medicine In the version of this article originally published, there were several errors in Fig. 4. In Fig. 4a, the title read '3D repeated optical inhibition after CSDS.' It should have read '3-day repeated optical inhibition after CSDS.' In Fig. 4c, two labels that should have been aligned with the time axis appeared in the wrong place in the figure. The ticks labeled 'SI' and 'Fiber implant' should have also been labeled with '10' and '14,' respectively. Additionally, in Fig. 4j, a label that should have been aligned with the time axis appeared in the wrong place in the figure. The tick labeled 'Fiber implant' should have also been labeled with '14.' The errors have been corrected in the print, PDF and HTML versions of the manuscript. 10.1038/s41591-019-0372-z
Lateral Habenular Burst Firing as a Target of the Rapid Antidepressant Effects of Ketamine. Cui Yihui,Hu Shaohua,Hu Hailan Trends in neurosciences The revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants that often take weeks to months to show efficacy, ketamine causes rapid antidepressant effects, emerging as early as within 1h after administration. However, how ketamine improves mood symptoms so quickly has remained elusive. Here, we first introduce the historical background of ketamine as a rapid antidepressant. We then discuss current hypotheses underlying ketamine's rapid antidepressant effects, with a focus on our latest discovery that ketamine silences NMDAR-dependent burst firing in the 'anti-reward center', the lateral habenula. While ketamine may act on many brain regions, we argue that its rapid antidepressant effects are critically dependent on ketamine's action in the lateral habenula, with this brain region acting as a primary site of action (or one among a few primary nodes). This molecular-, cellular-, and circuit-based mechanism advances our understanding of the etiology of depression and suggests a new conceptual framework for the rapid antidepressant effects of ketamine. 10.1016/j.tins.2018.12.002