Neural mechanisms of increased anxiety in serotonin 1A receptor-deficient mice

血清素 1A 受体缺陷小鼠焦虑增加的神经机制

基本信息

  • 批准号:
    8098690
  • 负责人:
  • 金额:
    $ 35.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-01 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key public health goal, as these disorders represent a large burden to society in morbidity and related costs. Data from human and animal studies implicate the serotonin system, and specifically one particular serotonin receptor, the 1A receptor (5-HT1AR), in the generation and/or regulation of anxiety. Agents which activate the 5-HT1AR, such as serotonin reuptake inhibitors or 5-HT1AR agonists, are anxiolytic both in humans and in animals. Accordingly, genetic deletion of the 5-HT1AR during development results in a robust adult phenotype of increased anxiety-like behavior. Understanding the precise mechanisms by which 5-HT1AR deficiency results in increased anxiety-related behavior promises to add to our understanding of the neurobiology of anxiety. We have recently found evidence of an anxiety-related increase in hippocampal activity, in the form of increased theta oscillations, in 5-HT1AR knockout mice. These data are in agreement with recent findings demonstrating that lesions of the ventral hippocampus increase anxiety. The proposed experiments will test the resulting hypothesis that the increased hippocampal activity accounts for the phenotype of increased anxiety in 5-HT1AR- deficient mice. In particular, we will combine molecular genetic and in vivo neural recordings in behaving mice to address three key questions. First, we will use tissue- specific expression of the 5-HT1AR to ask whether hippocampal receptors are sufficient to reverse the behavioral and physiological phenotypes seen in the knockouts. Second, we will record simultaneously from the ventral hippocampus and downstream structures in wild-type and knockout mice during anxiety-related tasks, to determine if and how these structures coordinate their activity. Third, we will test whether specifically increasing theta oscillations is necessary and sufficient to cause increased anxiety- related behavior. Addressing these three issues will clarify the mechanisms by which 5- HT1AR deficiency causes increased anxiety. Furthermore, they may identify specific patterns of activity in specific neural areas which generate anxiety, providing novel functional targets for therapeutic intervention. Public Health Relevance This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of brain activity which relate to anxiety. Establishing such relationships would set the stage for a novel approach to anxiolytic therapies, aimed at disrupting these specific patterns.
描述(由申请人提供):目前的建议旨在了解焦虑症的神经生物学机制。进一步了解焦虑症仍然是一个关键的公共卫生目标,因为这些疾病的发病率和相关成本对社会构成了巨大的负担。来自人类和动物研究的数据表明,5-羟色胺系统,特别是一种特定的5-羟色胺受体,1A受体(5-HT 1AR),参与了焦虑的产生和/或调节。激活5-HT 1AR的药物,如5-羟色胺再摄取抑制剂或5-HT 1AR激动剂,在人和动物中都是抗焦虑的。因此,在发育过程中5-HT 1AR的遗传缺失导致焦虑样行为增加的稳健成年表型。了解5-HT 1AR缺乏导致焦虑相关行为增加的确切机制有望增加我们对焦虑神经生物学的理解。我们最近在5-HT 1AR基因敲除小鼠中发现了海马活动与焦虑相关的增加的证据,其形式为增加的θ振荡。这些数据与最近的研究结果一致,表明腹侧海马的损伤会增加焦虑。拟议的实验将测试由此产生的假设,即海马活动增加是5-HT 1AR缺陷小鼠焦虑增加的表型的原因。特别是,我们将结合联合收割机分子遗传学和在行为小鼠体内的神经记录,以解决三个关键问题。首先,我们将使用5-HT 1AR的组织特异性表达来询问海马受体是否足以逆转敲除中所见的行为和生理表型。其次,我们将同时记录野生型和基因敲除小鼠在焦虑相关任务中的腹侧海马和下游结构,以确定这些结构是否以及如何协调它们的活动。第三,我们将测试特定地增加θ振荡是否是必要的和足够的,以引起增加的焦虑相关行为。解决这三个问题将阐明5-HT 1AR缺乏导致焦虑增加的机制。此外,它们可以识别产生焦虑的特定神经区域的特定活动模式,为治疗干预提供新的功能靶点。公共卫生相关性这一建议本质上是翻译性的,旨在阐明精神疾病的神经生物学基础。它旨在识别与焦虑有关的大脑活动的特定模式。建立这样的关系将为一种新的抗焦虑治疗方法奠定基础,旨在破坏这些特定的模式。

项目成果

期刊论文数量(0)
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Joshua A Gordon其他文献

Testing the glutamate hypothesis of schizophrenia
精神分裂症谷氨酸假说的检验
  • DOI:
    10.1038/nn0110-2
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Joshua A Gordon
  • 通讯作者:
    Joshua A Gordon
TREKing toward new antidepressants
朝着新型抗抑郁药迈进
  • DOI:
    10.1038/nn0906-1081
  • 发表时间:
    2006-09-01
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Joshua A Gordon;Rene Hen
  • 通讯作者:
    Rene Hen
Circuits in Sync: Decoding Theta Communication in Fear and Safety
同步电路:解码恐惧与安全中的θ通信
  • DOI:
    10.1038/npp.2013.228
  • 发表时间:
    2013-12-09
  • 期刊:
  • 影响因子:
    7.100
  • 作者:
    Ekaterina Likhtik;Joshua A Gordon
  • 通讯作者:
    Joshua A Gordon
Medicine and the Mind.
医学与心灵。
Once upon a spine: setting striatal dopamine
曾经在脊椎上:设置纹状体多巴胺
  • DOI:
    10.1038/nn.4029
  • 发表时间:
    2015-05-26
  • 期刊:
  • 影响因子:
    20.000
  • 作者:
    Christoph Kellendonk;Joshua A Gordon
  • 通讯作者:
    Joshua A Gordon

Joshua A Gordon的其他文献

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{{ truncateString('Joshua A Gordon', 18)}}的其他基金

Priming the Pump: Training Physician-Scientists for Translational Neuroscience
启动泵:培训医师科学家转化神经科学
  • 批准号:
    8240547
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Priming the Pump: Training Physician-Scientists for Translational Neuroscience
启动泵:培训医师科学家转化神经科学
  • 批准号:
    8089414
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Priming the Pump: Training Physician-Scientists in Translational Neuroscience
启动泵:转化神经科学领域的医师科学家培训
  • 批准号:
    8742189
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Priming the Pump: Training Physician-Scientists in Translational Neuroscience
启动泵:转化神经科学领域的医师科学家培训
  • 批准号:
    8894599
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Priming the Pump: Training Physician-Scientists for Translational Neuroscience
启动泵:培训医师科学家转化神经科学
  • 批准号:
    8431813
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Priming the Pump: Training Physician-Scientists for Translational Neuroscience
启动泵:培训医师科学家转化神经科学
  • 批准号:
    7877984
  • 财政年份:
    2009
  • 资助金额:
    $ 35.86万
  • 项目类别:
Exploring the pathophysiology of anxiety: the role of the hippocampus, amygdala a
探索焦虑的病理生理学:海马、杏仁核的作用
  • 批准号:
    8860240
  • 财政年份:
    2008
  • 资助金额:
    $ 35.86万
  • 项目类别:
Exploring the pathophysiology of anxiety: the role of the hippocampus, amygdala a
探索焦虑的病理生理学:海马、杏仁核的作用
  • 批准号:
    8667500
  • 财政年份:
    2008
  • 资助金额:
    $ 35.86万
  • 项目类别:
Neural mechanisms of increased anxiety in serotonin 1A receptor-deficient mice
血清素 1A 受体缺陷小鼠焦虑增加的神经机制
  • 批准号:
    7648163
  • 财政年份:
    2008
  • 资助金额:
    $ 35.86万
  • 项目类别:
Neural mechanisms of increased anxiety in serotonin 1A receptor-deficient mice
血清素 1A 受体缺陷小鼠焦虑增加的神经机制
  • 批准号:
    7884533
  • 财政年份:
    2008
  • 资助金额:
    $ 35.86万
  • 项目类别:

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