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南方医科大学,粤港澳大湾区脑科学与类脑研究中心主任 Southern Medical University, Director of the Great Bay Area Center for Brain Research
中国工程院院士 Academician of the Chinese Academy of Engineering
高天明教授,中国工程院院士。教育部“长江学者”特聘教授、国家杰出青年基金获得者。现任粤港澳大湾区脑科学与类脑研究中心主任、精神健康研究教育部重点实验室主任。兼任中国神经科学学会副理事长、《Pharmacol Res》及《Neurosci Bull》杂志副主编。主要从事抗抑郁/焦虑的基础和转化研究。先后主持了教育部创新团队项目、国家自然科学基金重点项目、973课题等基金课题。通讯作者论文发表在Nature Med、Nature Neurosci、Neuron、JCI等国际学术刊物上。以第一完成人获国家自然科学奖二等奖2项,广东省科技奖一等奖3项。培养的博士中,获国家杰青2人、长江学者1人、国家万人计划3人、青千1人、国家优青1人、广东省杰青3人、全国优博论文奖1人、全军/广东省优博论文奖5人。
Prof. Tianming Gao is an Academician of the Chinese Academy of Engineering, Chair Professor of Cheung Kong Scholars Program, Winner of National Science Fund for Outstanding Young Scholars. He is currently the Director of the Great Bay Area Center for Brain Research and the Director of the Key Laboratory of Mental Health of the Ministry of Education. He is also the Vice President of the Chinese Society of Neuroscience and the Associate Editor of “Pharmacological Research” and “Neuroscience Bulletin”. His research interests focus on basic and translational research on anti-depression/-anxiety disorders. He has published papers in Academic Journals such as Nature Medicine, Nature Neuroscience, Neuron, Journal of Clinical Investigation and so on. He was awarded two National Natural Science Research Awards (2nd Prize) by the State Council of PR. China and three Guangdong Science and Technology Award (1st Prize). He has presided over and completed a number of major projects, including the Innovation Team Project of Ministry of Education, the Key Project of National Natural Science Foundation of China, 973 projects and so on. He has trained dozens of excellent PhD and postdoc, many of whom have become outstanding scholars.
报告题目:
抗抑郁新药靶的研究进展
Advances in the novel targets for antidepressant
报告摘要:
重度抑郁症(MDD)影响着世界上大约16%的人口;然而,目前对MDD的生物学机制知之甚少,迫切需要发现新的抗抑郁治疗靶点。我们之前的研究发现ATP是星形胶质细胞调控抑郁样行为的关键因子,并在多个小鼠抑郁症模型上发现ATP具有快速抗抑郁作用。最近,通过筛查慢性应激后不同脑区的多种胞外ATP水解酶的表达水平,我们发现Entpd1 / CD39(一种来源于小胶质细胞的ATP水解酶)在抑郁小鼠的mPFC中表达增加。药理学和遗传学操纵该酶活性后发现其通过降解ATP参与调控抑郁样行为。之后我们探索了ATP调节抑郁行为的细胞和神经环路机制,发现细胞外ATP的缺乏导致mPFC脑区GABA能抑制功能降低和投射到外侧缰核(LHb)而不是中缝背核(DRN)的神经元兴奋性升高。并且,ATP通过GABA能中间神经元上的P2X2受体参与了mPFC-LHb神经环路对抑郁样行为的调控作用。值得注意的是,利用化学遗传学激活mPFC-LHb环路就足以在正常小鼠诱导出抑郁样行为,而抑制该环路可减轻抑郁小鼠的行为障碍。总之,我们的研究表明,由星形胶质细胞分泌和小胶质细胞来源的ATP水解酶共同控制着mPFC细胞外ATP水平,通过mPFC-LHb环路调控抑郁样行为,这些发现可能为治疗MDD提供了新的靶点。
Major depressive disorder (MDD) affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder and there is an urgent need for novel therapeutic targets for MDD. Our previous study identified ATP as a key factor involved in astrocytic modulation of depressive-like behaviors and found a fast antidepressant-like effect of ATP administration on a couples of mouse model of depression. Recently, by examining the expression level of various extracellular ATP hydrolase from different brain regions after chronic stress, we observed an increased expression of Entpd1/CD39, a microglia-derived ATP hydrolase, in the mPFC of depressed mice. Pharmacological and genetic manipulations demonstrated that this enzyme was also involved in modulating depressive-like behaviors by degrading ATP. Thereafter, we explored the cellular and neural circuit mechanisms underlying ATP modulation of these behaviors and observed that deficiency of extracellular ATP led to both reduced GABAergic inhibition and elevated excitability in lateral habenula (LHb)-projecting, but not dorsal raphe (DRN)-projecting, mPFC neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of LHb-projecting mPFC neurons and regulated depressive-like behaviors. Remarkably, chemogenetic activation of the mPFC-LHb pathway induced depressive-like behaviors in naive mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairments in depressed mice. Overall, our study indicates that the extracellular ATP level in the mPFC controlled by both astrocyte secretion and microglia-derived ATP hydrolase modulate depressive-like behaviors via mPFC-LHb circuit and these findings may provide novel therapeutic targets for MDD.
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高天明教授,中国工程院院士。教育部“长江学者”特聘教授、国家杰出青年基金获得者。现任粤港澳大湾区脑科学与类脑研究中心主任、精神健康研究教育部重点实验室主任。兼任中国神经科学学会副理事长、《Pharmacol Res》及《Neurosci Bull》杂志副主编。主要从事抗抑郁/焦虑的基础和转化研究。先后主持了教育部创新团队项目、国家自然科学基金重点项目、973课题等基金课题。通讯作者论文发表在Nature Med、Nature Neurosci、Neuron、JCI等国际学术刊物上。以第一完成人获国家自然科学奖二等奖2项,广东省科技奖一等奖3项。培养的博士中,获国家杰青2人、长江学者1人、国家万人计划3人、青千1人、国家优青1人、广东省杰青3人、全国优博论文奖1人、全军/广东省优博论文奖5人。
Prof. Tianming Gao is an Academician of the Chinese Academy of Engineering, Chair Professor of Cheung Kong Scholars Program, Winner of National Science Fund for Outstanding Young Scholars. He is currently the Director of the Great Bay Area Center for Brain Research and the Director of the Key Laboratory of Mental Health of the Ministry of Education. He is also the Vice President of the Chinese Society of Neuroscience and the Associate Editor of “Pharmacological Research” and “Neuroscience Bulletin”. His research interests focus on basic and translational research on anti-depression/-anxiety disorders. He has published papers in Academic Journals such as Nature Medicine, Nature Neuroscience, Neuron, Journal of Clinical Investigation and so on. He was awarded two National Natural Science Research Awards (2nd Prize) by the State Council of PR. China and three Guangdong Science and Technology Award (1st Prize). He has presided over and completed a number of major projects, including the Innovation Team Project of Ministry of Education, the Key Project of National Natural Science Foundation of China, 973 projects and so on. He has trained dozens of excellent PhD and postdoc, many of whom have become outstanding scholars.
报告题目:
抗抑郁新药靶的研究进展
Advances in the novel targets for antidepressant
报告摘要:
重度抑郁症(MDD)影响着世界上大约16%的人口;然而,目前对MDD的生物学机制知之甚少,迫切需要发现新的抗抑郁治疗靶点。我们之前的研究发现ATP是星形胶质细胞调控抑郁样行为的关键因子,并在多个小鼠抑郁症模型上发现ATP具有快速抗抑郁作用。最近,通过筛查慢性应激后不同脑区的多种胞外ATP水解酶的表达水平,我们发现Entpd1 / CD39(一种来源于小胶质细胞的ATP水解酶)在抑郁小鼠的mPFC中表达增加。药理学和遗传学操纵该酶活性后发现其通过降解ATP参与调控抑郁样行为。之后我们探索了ATP调节抑郁行为的细胞和神经环路机制,发现细胞外ATP的缺乏导致mPFC脑区GABA能抑制功能降低和投射到外侧缰核(LHb)而不是中缝背核(DRN)的神经元兴奋性升高。并且,ATP通过GABA能中间神经元上的P2X2受体参与了mPFC-LHb神经环路对抑郁样行为的调控作用。值得注意的是,利用化学遗传学激活mPFC-LHb环路就足以在正常小鼠诱导出抑郁样行为,而抑制该环路可减轻抑郁小鼠的行为障碍。总之,我们的研究表明,由星形胶质细胞分泌和小胶质细胞来源的ATP水解酶共同控制着mPFC细胞外ATP水平,通过mPFC-LHb环路调控抑郁样行为,这些发现可能为治疗MDD提供了新的靶点。
Major depressive disorder (MDD) affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder and there is an urgent need for novel therapeutic targets for MDD. Our previous study identified ATP as a key factor involved in astrocytic modulation of depressive-like behaviors and found a fast antidepressant-like effect of ATP administration on a couples of mouse model of depression. Recently, by examining the expression level of various extracellular ATP hydrolase from different brain regions after chronic stress, we observed an increased expression of Entpd1/CD39, a microglia-derived ATP hydrolase, in the mPFC of depressed mice. Pharmacological and genetic manipulations demonstrated that this enzyme was also involved in modulating depressive-like behaviors by degrading ATP. Thereafter, we explored the cellular and neural circuit mechanisms underlying ATP modulation of these behaviors and observed that deficiency of extracellular ATP led to both reduced GABAergic inhibition and elevated excitability in lateral habenula (LHb)-projecting, but not dorsal raphe (DRN)-projecting, mPFC neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of LHb-projecting mPFC neurons and regulated depressive-like behaviors. Remarkably, chemogenetic activation of the mPFC-LHb pathway induced depressive-like behaviors in naive mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairments in depressed mice. Overall, our study indicates that the extracellular ATP level in the mPFC controlled by both astrocyte secretion and microglia-derived ATP hydrolase modulate depressive-like behaviors via mPFC-LHb circuit and these findings may provide novel therapeutic targets for MDD.