团队成员包括硕士生1名，博士生3名，博士后1名，本科生3名，实验室管理人员1名

一. 研究方向：

1.       5-HT递质系统对记忆的调节

----突触可塑性及神经网络节律性活动机制

2.       运动对认知记忆的调节以及运动改善神经退行性疾病记忆功能的机制

3.       饮食限制对学习记忆的影响

二. 研究进展：

1.       5-HT3受体通过CB1受体相关机制维持海马LTP参与空间记忆的调节

5-HT在精神情绪调节中扮演了关键的角色。认知损害是情绪障碍性疾病一个常见的临床特征，而改善认知损害也是治疗这类疾病的一个重要目的。作为5-HT受体家族唯一的离子通道型受体，5-HT3受体被提示参与脑内的情绪调节。但是，该受体在认知功能方面确切的作用以及潜在的机制仍不明确。我们发现，基因敲除及药理学阻断特异性表达在海马CCK中间神经元上的5-HT3受体的功能，通过易化锥体神经元的GABA能突触传入损害LTP。这种作用不依赖于中间神经元上胞体树突部位表达的5-HT3受体，而是由于与5-HT3受体共表达在中间神经元相同轴突末梢的CB1受体减少导致的CB1受体介导的GABA释放的紧张性抑制减弱，即GABA释放增加所引起。同时，5-HT3受体功能失调的小鼠表现出海马依赖的空间记忆的损害。以上结果证实了5-HT3受体在海马LTP中具有关键的作用并通过CB1R-GABA依赖的新机制调节空间记忆。该研究将为深入理解情绪障碍中的认知损害提供信息。

2.       5-HT3受体通过调控PV阳性中间神经元的同步性调节海马的γ震荡

γ震荡在很多脑区的信息整合中扮演了重要角色。很多精神性疾病的认知损害提示有γ震荡的异常，而5-HT3受体是治疗精神性疾病中认知损害的潜在治疗靶点。运用5-HT3R-GFP转基因小鼠，我们发现特异表达在CCK阳性中间神经元上的5-HT3受体激活后通过SK通道依赖的模式增加CCK中间神经元的后超极化（AHP）而抑制其放电并使放电去同步化，进而使PV中间神经元抑制性传入减少，放电增加但去同步化，从而去同步化锥体神经元放电，抑制γ震荡。这种作用不依赖于5-HT3受体介导的CCK的释放。我们的结果揭示了5-HT3受体在γ震荡中的重要作用并发现了不同类型中间神经元的cross-talk调控网络震荡的新机制。5-HT3受体和γ震荡的功能联系可能为深入理解精神障碍中认知损害提供依据。

3.       BDNF val66met基因多态性通过下调5-HT3受体损害海马LTD

脑源性神经营养因子（BDNF）是参与神经可塑性和认知功能调控的关键因子。BDNF val66met基因多态性是人类存在的一个BDNF基因pro-domain的单氨基酸多态性（SNP），该多态性与活性依赖的BDNF的分泌及海马依赖的记忆缺陷有关，但其潜在的机制有待阐明。我们发现在模拟人类SNP的BDNFMet/Met转基因小鼠中，海马部位BDNF的表达降低。海马CA1区的细胞数量减少，同时海马NR2a, 2b, GluR1, 2 及 GABAARb3 亚单位的mRNA表达上调。海马CA1区谷氨酸能的基本突触传递没有改变，而低频刺激诱导的LTD降低。BDNF能部分恢复损害的LTD。值得注意的是，在BDNFMet/Met小鼠中，海马5-HT3受体表达下调，而5-HT2c受体的表达上调。而且，5-HT3受体激动剂能恢复BDNFMet/Met小鼠海马中损害的LTD。以上结果提示BDNF val66met基因多态性通过下调5-HT3受体改变海马突触可塑性，该机制可能是导致Met携带者认知障碍的原因。

4.       内源性H2S在饮食限制促进学习记忆中的作用

记忆研究的终极目标之一就是通过某种方式提高人的认知记忆能力，使人变得更聪明。营养和记忆之间的关系始终是一个有趣的问题。人们可能会认为充足的营养有利于促进记忆，然而事实却可能并非如此。有证据证实一定程度的饮食限制能促进各器官内源性H2S的合成和释放，而脑内的H2S具有易化NMDA电流，促进记忆的作用。我们通过饮食限制的动物模型，发现饮食限制一定时间后，小鼠空间记忆能力明显提高，进一步的机制探讨目前正在进行中。

三．课题项目：

1. 5-HT3受体在有氧运动调控黑质-海马神经环路改善PD小鼠认知损害中的作用及机制, 国家自然科学基金面上项目, (Project No. 31972914)

2. 5-HT3受体调控空间学习记忆的突触及分子机制研究, 国家自然科学基金面上项目, (Project No.31771175)

3. 5-HT3A受体对抑制性突触的调控及其在记忆中的作用, 神经科学国家重点实验室开放课题(Project No. SKLN0201604)

4. 5-HT3A受体在空间记忆和海马LTP中的作用, 上海市自然科学基金 (Project No. 15ZR1402500)

5. 5-HT3受体调节海马γ震荡（gamma oscillation）的细胞机制和功能研究，国家自然科学基金面上项目（Project No. 31070931）

6. GSK化合物对BDNF变异小鼠(BDNFMet/Met)海马γ震荡的调节。葛兰素史克中国研发中心合作课题

四. 发表论文:

[*Corresponding author]

1.       Zhan TT#, Dong ZY#, Yi LS, Zhang Y, Sun HH, Zhang HQ, Wang JW, Chen Y, Huang Y*, Xu SC*. Tandospirone prevents stress-induced anxiety-like behavior and visceral hypersensitivity by suppressing theta oscillation enhancement via 5-HT 1A receptors in anterior cingulate cortex in rats. Frontiers in Cellular Neuroscience. 2022 Aug 22; doi: 10.3389/fncel.2022.922750

2.       Dong ZY#, Zhan TT#, Sun HH, Wang JW, Duan GB, Zhang Y, Chen Y, Huang Y*, Xu SC*. Astrocytic ERK/STAT1 signaling contributes to maintenance of stress-related visceral hypersensitivity in rats. J Pain. 2022 Jul 29; S1526-5900(22)00365-0. doi: 10.1016/j.jpain.2022.07.006. Online ahead of print.

3.       Yu Y, Li JJ, He XQ, Lai ZY, Hao R, Qi Y, Cao DQ, Fu M, Ma H, Xie QC, Sun M, Huang ZL, Jin LJ, Sun HH, Lu N, Wang R, Yung WH, Huang Y*. 5-HT3 A receptors maintain hippocampal LTP in a CB1 and GABAA receptor- dependent manner for spatial memory. Br J Pharmacol. 2022 Jun;179(12):2969-2985. doi: 10.1111/bph.15793. Epub 2022 Feb 14.

4.       Wang J, Hao R, Jiang T, Guo X, Zhou F, Cao L, Gao F, Wang G, Wang J, Ning K, Zhong C, Chen X*, Huang Y*, Xu J*, Gao S*. Rebuilding hippocampus neural circuit with hADSC-derived neuron cells for treating ischemic stroke. Cell Biosci. 2022 Apr 4;12(1):40. doi: 10.1186/s13578-022-00774-x.

5.       Wang S, Yao H, Xu Y, Hao R, Zhang W, Liu H, Huang Y, Guo W, Lu B. Therapeutic potential of a TrkB agonistic antibody for Alzheimer's disease. Theranostics. 2020 May 23;10(15):6854-6874. doi: 10.7150/thno.44165. eCollection 2020.

6.       Hao R, Qi Y, Hou DN, Ji YY, Zheng CY, Li CY, Yung WH, Lu B, Huang Y*. BDNF val66met Polymorphism Impairs Hippocampal Long-Term Depression by Down-Regulation of 5-HT3 Receptors. Front Cell Neurosci. 2017 11:306.

7.       Huang Y*, Yoon K, Ko H, Jiao S, Ito W, Wu JY, Yung WH, Lu B, Morozov A. 5-HT3a receptors modulate hippocampal gamma oscillations by regulating synchrony of parvalbumin-positive interneurons. Cerebral Cortex. 2016 26(2):576-585.

8.       Huang L, Yang XJ, Huang Y, Sun EY, Sun M*. Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD. PLoS One. 2016; 11(7):e0159192.

9.       Liu X, Zhang N, Ding Y, Cao D, Huang Y, Chen X, Wang R, Lu N*. Hydrogen Sulfide Regulates the [Ca2+]i Level in the Primary Medullary Neurons. Oxid Med Cell Longev. 2016: 2735347.

10.   Yu Y, Cao DQ, Xu HY, Sun M, Huang ZL, Yung WH, Lu N, Huang Y*. 5-HT3A receptors are required in long-term depression and AMPA receptor internalization. Neuroscience. 2014. 278:105-112.

11.   Huang Y, Wang JJ, Yung WH*. Coupling between GABA-A receptor and chloride transporter underlies ionic plasticity in cerebellar Purkinje neurons. Cerebellum. 2013,12(3):328-330.

12.   Huang Y*, Ko H, Cheung ZH, Yung KK, Yao T, Wang JJ, Morozov A, Ke Y, Ip NY, Yung WH*. Dual actions of brain-derived neurotrophic factor on GABAergic transmission in cerebellar Purkinje neurons. Experimental Neurology. 2012, 233(2):791-798.

13.   Huang Y, Morozov A*. Hippocampal deletion of BDNF gene attenuates Gamma oscillations in area CA1 by up-regulating 5-HT3 receptor. PLoS ONE. 2011, 6(1): e16480.

14.   Ma YY, Li KY, Wang JJ, Huang YL, Huang Y, Sun FY. Vascular endothelial growth factor acutely reduces calcium influx via inhibition of the Ca2+ channels in rat hippocampal neurons. J Neurosci Res. 2009 87(2):393-402.

15.   Huang Y, Huang YL, Lai B, Zheng P, Zhu YC, Yao T*. Raloxifene acutely reduces glutamate-induced intracellular calcium increase in cultured rat cortical neurons via inhibition of high voltage-activated calcium current. Neuroscience 2007; 147:334-341.

16.   He Y, Huang Y, Zhou L, Lu LM, Zhu YC, Yao T*. All-trans retinoic acid inhibited angiotensin II-induced increase in cell growth and collagen secretion of neonatal cardiac fibroblasts. Acta Pharmacologica Sinica. 2006;27:423-429.

17.   Zhang S, Huang Y, Yao T*. Estrogen stimulates the release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway. Acta Pharmacologica Sinica. 2005; 26: 171-176.

Huang Y, Huang YL, Zhang S, Zhu YC, Yao T*. Estradiol acutely attenuates glutamate-induced calcium overload in primarily cultured rat hippocampal neurons through a membrane receptor-dependent mechanism. Brain Research. 2004; 1026: 254-260.

1. 5-HT3受体在有氧运动调控黑质-海马神经环路改善PD小鼠认知损害中的作用及机制,国家自然科学基金面上项目, (Project No.31972914)

2. 5-HT3受体调控空间学习记忆的突触及分子机制研究,国家自然科学基金面上项目, (Project No.31771175)

3. 5-HT3A受体对抑制性突触的调控及其在记忆中的作用,神经科学国家重点实验室开放课题(Project No. SKLN0201604)

4. 5-HT3A受体在空间记忆和海马LTP中的作用, 上海市自然科学基金 (Project No. 15ZR1402500)

5. 5-HT3受体调节海马γ震荡（gamma oscillation）的细胞机制和功能研究，国家自然科学基金面上项目（Project No. 31070931）

6. GSK化合物对BDNF变异小鼠(BDNFMet/Met)海马γ震荡的调节。葛兰素史克中国研发中心合作课题

部分发表论文：

1.      ZhanTT#, Dong ZY#, Yi LS, Zhang Y, Sun HH, Zhang HQ, Wang JW, Chen Y, Huang Y*,Xu SC*. Tandospirone prevents stress-induced anxiety-like behavior and visceralhypersensitivity by suppressing theta oscillation enhancement via 5-HT 1Areceptors in anterior cingulate cortex in rats. Frontiers in CellularNeuroscience. 2022 Aug 22. Doi:10.3389/fncel.2022.922750 (IF: 6.147)

2.      DongZY#, Zhan TT#, Sun HH, Wang JW, Duan GB, Zhang Y, Chen Y, Huang Y*, XuSC*. Astrocytic ERK/STAT1 signaling contributes to maintenance ofstress-related visceral hypersensitivity in rats. J Pain. 2022 Jul 29;S1526-5900(22)00365-0. doi: 10.1016/j.jpain.2022.07.006. Online ahead of print.(IF: 5.383)

3.      5-HT3A receptors maintain hippocampal LTP in a CB1 and GABAA receptor- dependentmanner for spatial memory. Yu Y, Li JJ, He XQ, Lai ZY, Hao R, Qi Y, Cao DQ, FuM, Ma H, Xie QC, Sun M, Huang ZL, Jin LJ, Sun HH, Lu N, Wang R, Yung WH, HuangY*. Br J Pharmacol. 2022 Jun;179(12):2969-2985. doi: 10.1111/bph.15793.Epub 2022 Feb 14. (IF: 9.473)

4.      Rebuildinghippocampus neural circuit with hADSC-derived neuron cells for treatingischemic stroke. Wang J, Hao R, Jiang T, Guo X, Zhou F, Cao L, Gao F, Wang G,Wang J, Ning K, Zhong C, Chen X*, Huang Y*, Xu J*, Gao S*. Cell Biosci.2022 Apr 4;12(1):40. doi: 10.1186/s13578-022-00774-x. (IF: 9.584)

5.      Therapeuticpotential of a TrkB agonistic antibody for Alzheimer's disease. Wang S, Yao H,Xu Y, Hao R, Zhang W, Liu H, Huang Y, Guo W, Lu B. Theranostics. 2020May 23;10(15):6854-6874. doi: 10.7150/thno.44165. eCollection 2020. (IF：11.556)

6.      HaoR, Qi Y, Hou DN, Ji YY, Zheng CY, Li CY, Yung WH, Lu B, Huang Y*. BDNF val66met Polymorphism Impairs hippocampal Long-TermDepression by Down-Regulation of 5-HT3 Receptors. Front Cell Neurosci. 201711:306. (IF: 4.555)

7.      Huang Y*, Yoon K, Ko H, Jiao S, Ito W, WuJY, Yung WH, Lu B, Morozov A. 5-HT3a receptors modulate hippocampal gammaoscillations by regulating synchrony of parvalbumin-positive interneurons. CerebralCortex. 2016 26(2):576-585.(IF: 8.285)

8.      YuY, Cao DQ, Xu HY, Sun M, Huang ZL, Yung WH, Lu N, Huang Y*. 5-HT3A receptors are required in long-term depression andAMPA receptor internalization. Neuroscience. 2014. 278:105-112. (IF: 3.327)

9.      Huang Y, Wang JJ, Yung WH*. Couplingbetween GABA-A receptor and chloride transporter underlies ionic plasticity incerebellar Purkinje neurons. Cerebellum. 2013,12(3):328-330. (IF:2.60)

10.  Huang Y*, Ko H, Cheung ZH, Yung KK, Yao T,Wang JJ, Morozov A, Ke Y, Ip NY, Yung WH*. Dual actions of brain-derivedneurotrophic factor on GABAergic transmission in cerebellar Purkinje neurons. ExperimentalNeurology. 2012,233(2):791-798. (IF: 4.65).

11.  Huang Y, Morozov A*. Hippocampal deletionof BDNF gene attenuates Gamma oscillations in area CA1 by up-regulating 5-HT3receptor. PLoS ONE. 2011, 6(1): e16480. (IF: 4.09)

12.  Huang Y, Huang YL, Lai B, Zheng P, ZhuYC, Yao T*. Raloxifene acutely reduces glutamate-induced intracellular calciumincrease in cultured rat cortical neurons via inhibition of highvoltage-activated calcium current. Neuroscience 2007; 147:334-341. (IF:3.35)

13.  Huang Y, Huang YL, Zhang S, Zhu YC, YaoT*. Estradiol acutely attenuates glutamate-induced calcium overload inprimarily cultured rat hippocampal neurons through a membranereceptor-dependent mechanism. Brain Research. 2004; 1026: 254-260.(IF: 2.39)

14.  Huang L, Yang XJ, Huang Y, Sun EY, Sun M*. Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD. PLoS One. 2016; 11(7):e0159192. (IF: 3.06)

15.   Liu X,Zhang N, Ding Y, Cao D, Huang Y,Chen X, Wang R, Lu N. Hydrogen Sulfide Regulates the [Ca2+]iLevel in the Primary Medullary Neurons. OxidMed Cell Longev. 2016;2016: 2735347. (IF: 4.492)

16.  ZhangS, Huang Y, Yao T*. Estrogenstimulates the release of secreted amyloid precursor protein from primary ratcortical neurons via protein kinase C pathway. Acta Pharmacologica Sinica.2005; 26: 171-176. (IF:1.12)

17.  HeY, Huang Y, Zhou L, Lu LM, Zhu YC,Yao T*. All-trans retinoic acid inhibited angiotensin II-induced increase incell growth and collagen secretion of neonatal cardiac fibroblasts. ActaPharmacologica Sinica. 2006;27:423-429. (IF: 1.40)

18.  FengH, Lu LM, Huang Y, Zhu YC, Yao T*.Blockade of NMDA receptor enhances corticosterone-induced downregulation ofbrain-derived neurotrophic factor gene expression in the rat hippocampusthrough cAMP response element binding protein pathway. Acta Physiologica Sinica.2005;57:537-544.