Profiling direct/indirect basal ganglia cells in restricted repetitive behavior

分析受限重复行为中的直接/间接基底神经节细胞

基本信息

  • 批准号:
    8465301
  • 负责人:
  • 金额:
    $ 4.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-04-21 至 2013-03-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Restricted repetitive behaviors are seen in many different neurodevelopmental, neurological, and psychiatric disorders (e.g. autism, Fragile X syndrome, Rett syndrome, dementias, OCD, and schizophrenia). These behaviors are classified as highly repetitive, invariant, and without obvious function. In neurodevelopmental disorders specifically, there is a wide array of repetitive behaviors exhibited, ranging from rhythmic hand flapping or head banging to circumscribed interests and insistence of sameness. Although these behaviors are extremely common in these patient populations, the neurobiological basis of the behavior disorder is relatively unknown and treatment is challenging. The overarching goals of our lab are to elucidate the neurobiological mechanisms responsible for the expression of restricted repetitive behaviors and to reduce these behaviors in individuals with neurodevelopmental disorders. Animal models of restricted repetitive behaviors allow researchers to identify the neurobiological basis of these particular maladaptive behaviors without the influence or complication of other biological problems associated with the neurodevelopmental disorders. Animal models also allow for the determination of clinical efficacy of potential pharmacological therapies before clinical experimentation is attempted in these very vulnerable populations. Evidence from a mouse model of restricted repetitive behavior indicates that specific pathways in the brain that make up cortico-basal ganglia circuitry are disregulated. These two pathways, the direct and indirect pathways, normally work in a coordinated, yet antagonistic fashion to control cortical activation and behavioral output. Data from our lab suggests that the activation of the indirect pathway is reduced in mice that exhibit repetitive behavior and this leaves the direct pathway to overexcite the cortex and produce aberrant behaviors. To achieve our goals of elucidating the neurobiological basis of repetitive behavior, we will use mice that exhibit spontaneous repetitive behaviors and profile the gene and protein expression within the direct and indirect basal ganglia pathways. First, we will use fluorescence assisted cell sorting to separate direct from indirect pathway cells. Then we will use RT-PCR arrays to simultaneously measure the expression of 41 G-protein coupled receptors and 44 signal transduction molecules in the separate cell groups. We will then analyze the amount of those receptors that are inserted in to the cell membrane (and are therefore biologically active) and the amount of those receptors that are packaged in to intracellular vesicles. Measures from mice that exhibit high rates of repetitive behavior (C58/J mice) will be compared to measures from a closely related mouse strain (C57BL/6J mice) that express no repetitive behavior. Based on the results of our gene and protein analyses we will design drug challenge experiments to identify whether any of the targets elucidated by the first two experiments offer potential pharmacotherapy for restricted repetitive behaviors. PUBLIC HEALTH RELEVANCE: Many people with developmental disabilities, neurological problems, or psychiatric issues show restricted repetitive behaviors. These behaviors are repetitive in nature and serve no obvious function (e.g. hand flapping, head banging, insistence on sameness, and compulsions). We are investigating what genes and proteins are expressed differently in mice that show these kinds of behaviors and in mice that do not in order to learn how the brain controls these behaviors and what kind of drugs may be used to reduce them.
描述(由申请人提供):限制性重复行为见于许多不同的神经发育、神经和精神疾病(例如自闭症、脆性X综合征、Rett综合征、痴呆、强迫症和精神分裂症)。这些行为被归类为高度重复,不变,没有明显的功能。特别是在神经发育障碍中,表现出广泛的重复行为,从有节奏的拍手或头部撞击到有限的兴趣和坚持相同。虽然这些行为在这些患者人群中非常常见,但行为障碍的神经生物学基础相对未知,治疗具有挑战性。我们实验室的首要目标是阐明负责限制性重复行为表达的神经生物学机制,并减少神经发育障碍患者的这些行为。限制性重复行为的动物模型使研究人员能够确定这些特定适应不良行为的神经生物学基础,而不会受到与神经发育障碍相关的其他生物学问题的影响或并发症。动物模型还允许在这些非常脆弱的人群中尝试临床实验之前确定潜在药物治疗的临床疗效。来自限制性重复行为小鼠模型的证据表明,大脑中构成皮质基底神经节回路的特定通路失调。这两条通路,直接通路和间接通路,通常以协调但对抗的方式控制皮层激活和行为输出。我们实验室的数据表明,在表现出重复行为的小鼠中,间接途径的激活减少,这使得直接途径过度兴奋皮质并产生异常行为。为了实现我们阐明重复行为的神经生物学基础的目标,我们将使用表现出自发重复行为的小鼠,并分析直接和间接基底神经节通路内的基因和蛋白质表达。首先,我们将使用荧光辅助细胞分选来分离直接途径细胞和间接途径细胞。然后,我们将使用RT-PCR阵列同时测量41个G蛋白偶联受体和44个信号转导分子在不同细胞群中的表达。然后,我们将分析插入细胞膜(因此具有生物活性)的受体的数量以及包装在细胞内囊泡中的受体的数量。将表现出高重复行为率的小鼠(C58/J小鼠)的测量值与不表现重复行为的密切相关小鼠品系(C57 BL/6 J小鼠)的测量值进行比较。基于我们的基因和蛋白质分析的结果,我们将设计药物挑战实验,以确定前两个实验阐明的任何靶点是否为限制性重复行为提供潜在的药物治疗。 公共卫生关系:许多有发育障碍、神经问题或精神问题的人表现出受限的重复行为。这些行为本质上是重复的,没有明显的功能(例如,拍打手,头部撞击,坚持相同和强迫)。我们正在研究哪些基因和蛋白质在表现出这些行为的小鼠和没有表现出这些行为的小鼠中表达不同,以了解大脑如何控制这些行为,以及可以使用什么样的药物来减少它们。

项目成果

期刊论文数量(1)
专著数量(0)
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会议论文数量(0)
专利数量(0)

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AMBER M Muehlmann其他文献

AMBER M Muehlmann的其他文献

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{{ truncateString('AMBER M Muehlmann', 18)}}的其他基金

Profiling direct/indirect basal ganglia cells in restricted repetitive behavior
分析受限重复行为中的直接/间接基底神经节细胞
  • 批准号:
    8004526
  • 财政年份:
    2011
  • 资助金额:
    $ 4.67万
  • 项目类别:
Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms
自残行为的脆弱性:神经生物学机制
  • 批准号:
    7485861
  • 财政年份:
    2008
  • 资助金额:
    $ 4.67万
  • 项目类别:
Vulnerability for Self-Injurious Behavior: Neurobiological Mechanisms
自残行为的脆弱性:神经生物学机制
  • 批准号:
    7673624
  • 财政年份:
    2008
  • 资助金额:
    $ 4.67万
  • 项目类别:

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