Two Types of Monoamine Oxidase

两种类型的单胺氧化酶

• 批准号: 8385579
• 负责人: Jean Chen Shih
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385579
• 关键词: ARHGEF5 gene; Acute; Address; Adult; Affect; Aggressive behavior; Alcohol abuse; Alleles; Amygdaloid structure; Animals; Applications Grants; Attenuated; Base of the Brain; Basic Science; Behavior; Brain; Brain imaging; Brunner syndrome; Chronic; Clinical Research; Dendrites; Dendritic Spines; Development; Diagnostic; Dopamine; Dose; Drug abuse; Elements; Embryo; Emotional; Enzymes; Fenclonine; Fluorescence Microscopy; Golgi Apparatus; HTR2A gene; High Pressure Liquid Chromatography; Hippocampus (Brain); Human; Knock-out; Knockout Mice; Label; Light; Long-Term Effects; Measures; Mediating; Mental disorders; Messenger RNA; Metabolism; Molecular; Monoamine Oxidase; Monoamine Oxidase A; Morphology; Mus; Neuronal Plasticity; Norepinephrine; Play; Preventive; Process; Prosencephalon; Regulation; Research; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Serotonin; Staging; Staining method; Stains; Stress; Testing; Therapeutic; Variant; Vertebral column; Wild Type Mouse; abstracting; base; brain morphology; density; frontal lobe; hippocampal pyramidal neuron; inhibitor/antagonist; innovation; light microscopy; monoamine; nerve supply; neurotransmission; postnatal; receptor; response; restraint stress; serotonin receptor; synaptogenesis; transmission process

Abstract The objective of this application is to test the hypothesis that: 1) early developmental stages are critically important for monoamine oxidase (MAO) A to induce long-term effects on neuroplasticity and aggression through the regulation of serotonin (5-hydroxytryptamine, 5-HT) levels and the activation of 5-HT receptors in forebrain regions; and 2) environmental stress interacts with MAO A to modulate these processes. MAO A is the key enzyme in 5-HT metabolism, and its deficiency results in increased 5-HT levels and increased aggression in humans and mice. 5-HT in forebrain regions (frontal cortex, amygdala and hippocampus) modulates aggression as well as dendrite and spine morphology in pyramidal neurons. The specific aims are outlined below: 1: To identify which early developmental stages are critical for the effects of 5-HT on aggression and dendritic morphology and spine density in pyramidal neurons of frontal cortex, amygdala and hippocampus in MAO A knockout (KO) mice. MAO A KO mice will be injected with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) during each of the 5 weeks of forebrain 5-HT innervation (E16-P28),to normalize the increased 5-HT levels in their forebrain regions. 5-HT levels will be determined by HPLC. Aggression and other related behaviors will be tested in adult mice (P60). Once we identify the critical stage for 5-HT role in behavior, we will study dendrite and spine morphology of 5-HT-targeted pyramidal neurons in forebrain regions, using light microscopy on Golgi-Cox stained brain sections as well as fluorescence microscopy on sections with 5-HT receptor labels and retrograde label of dendritic processes. 2: To identify what 5-HT receptors mediate the effects of 5-HT on aggression and dendritic morphology in forebrain regions of MAO A KO mice during the critical developmental stages. After treating MAO A KO mice with PCPA at the critical stages, we will quantify 5-HT1A, 5-HT1B and 5-HT2A receptors (mRNA levels) in their forebrain regions, by RT-PCR. To study the role of each receptor in behavior and morphology, we will inject MAO A KO mice with selective antagonists of specific 5-HT receptors during the specific critical stages, and determine which receptor blockade attenuates aggression and morphological alterations at P60. 3: To test the hypothesis that the interaction between MAO A and acute or chronic environmental stress induces specific changes in 5-HT in forebrain regions, which result in increased aggression and altered dendrite and spine morphology. We will study the impact of acute and chronic restraint stress on the behavior and brain morphology of MAO A KO mice. These studies will provide a significant contribution to basic and clinical research, by elucidating the impact of developmental mechanisms and stress on aggression, and shed light on new preventive and therapeutic strategies for aggression and other psychiatric disorders, including alcohol and drug abuse.

摘要 本申请的目的是检验以下假设：1）早期发育阶段是关键的 单胺氧化酶（MAO）A对神经可塑性和攻击性诱导长期效应的重要性 通过调节血清素（5-羟色胺，5-HT）水平和激活5-HT受体， 前脑区域;和2）环境应激与MAO A相互作用以调节这些过程。 MAO A是5-HT代谢的关键酶，其缺乏导致5-HT水平升高， 人类和小鼠的攻击性增加。5-HT在前脑区域（额叶皮质，杏仁核和 海马）调节攻击性以及锥体神经元中的树突和棘形态。 具体目标概述如下： 1：确定哪些早期发育阶段对5-HT对攻击性的影响至关重要， 额叶皮质、杏仁核和海马锥体神经元树突形态和棘密度 MAOA敲除（KO）小鼠中的海马。MA 0 A KO小鼠将注射5-HT合成物 在前脑5-HT神经支配的5周（E16-P28）中的每一周， 使他们前脑区域增加的5-HT水平正常化。将通过HPLC测定5-HT水平。 将在成年小鼠中测试攻击性和其他相关行为（P60）。一旦我们确定了 5-HT在行为中的作用，我们将研究5-HT靶向锥体神经元的树突和棘形态， 前脑区域，使用Golgi-Cox染色脑切片上的光学显微镜以及荧光 用5-HT受体标记和树突状突起逆行标记的切片显微镜观察。 2：确定什么样的5-HT受体介导5-HT对攻击性和树突形态的影响 在关键发育阶段的MAOA KO小鼠的前脑区域中。处理后的MAO A 在关键阶段用PCPA KO小鼠，我们将定量5-HT 1A、5-HT 1B和5-HT 2A受体（mRNA水平） 在他们的前脑区域，通过RT-PCR。为了研究每个受体在行为和形态学中的作用，我们 将在特定的关键期间用特异性5-HT受体的选择性拮抗剂注射MAO A KO小鼠。 阶段，并确定哪些受体阻断减弱侵略和形态学改变P60。 3：验证了单胺氧化酶A与急性或慢性环境因素的相互作用 应激诱导前脑区域5-HT的特定变化，这导致攻击性增加， 树突和棘形态改变。我们将研究急性和慢性束缚应激对 MAOA KO小鼠的行为和脑形态。 这些研究将通过阐明 发展机制和压力对攻击的影响，并阐明新的预防和 针对攻击性和其他精神疾病的治疗策略，包括酗酒和吸毒。

项目成果

Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence.

• DOI: 10.1016/b978-0-12-386467-3.00002-9
• 发表时间: 2011
• 期刊: INTERNATIONAL REVIEW OF NEUROBIOLOGY
• 作者: Bortolato, Marco;Shih, Jean C.
• 通讯作者: Shih, Jean C.

Monoamine oxidase A (MAO A) inhibitors decrease glioma progression.

• DOI: 10.18632/oncotarget.7283
• 发表时间: 2016-03-22
• 期刊: Oncotarget
• 作者: Kushal S;Wang W;Vaikari VP;Kota R;Chen K;Yeh TS;Jhaveri N;Groshen SL;Olenyuk BZ;Chen TC;Hofman FM;Shih JC
• 通讯作者: Shih JC

The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake.

• DOI: 10.1016/j.jpsychires.2014.04.014
• 发表时间: 2014-09
• 期刊: JOURNAL OF PSYCHIATRIC RESEARCH
• 影响因子: 4.8
• 作者: Godar, Sean C.;Bortolato, Marco;Castelli, M. Paola;Casti, Alberto;Casu, Angelo;Chen, Kevin;Ennas, M. Grazia;Tambaro, Simone;Shih, Jean C.
• 通讯作者: Shih, Jean C.

A transient placental source of serotonin for the fetal forebrain.

• DOI: 10.1038/nature09972
• 发表时间: 2011-04-21
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Bonnin, Alexandre;Goeden, Nick;Chen, Kevin;Wilson, Melissa L.;King, Jennifer;Shih, Jean C.;Blakely, Randy D.;Deneris, Evan S.;Levitt, Pat
• 通讯作者: Levitt, Pat

NMDARs mediate the role of monoamine oxidase A in pathological aggression.

• DOI: 10.1523/jneurosci.0225-12.2012
• 发表时间: 2012-06-20
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Bortolato M;Godar SC;Melis M;Soggiu A;Roncada P;Casu A;Flore G;Chen K;Frau R;Urbani A;Castelli MP;Devoto P;Shih JC
• 通讯作者: Shih JC