Identifying the Neural Substrates of Stereotypy

描述（由申请人提供）： 拟议的研究将评估的假设，即自发发生的刻板表现为沿着皮质-纹状体-苍白球黑质-丘脑-皮质反馈电路的神经元活动升高的结果。将使用Peromyscus maniculatus（鹿鼠）评价该假设，鹿鼠是一种在标准实验室笼中饲养时自发表现出异常重复行为的小鼠物种。将在这些小鼠中进行一系列体内和体外操作。体内实验将包括位点特异性脑内药理学操作，其将被执行以试图调节鹿小鼠中发出的刻板印象。这些操作将是假设驱动的，使得基于现有的化学结构理解，预期所有配体将分别经由沿着假设介导这些异常重复行为的表达的反馈回路的活性的沿着的激发或抑制来加剧或减弱定型。体外实验将包括免疫组织化学操作，旨在测量指标的神经元活动的关键位点的牵连反馈电路。首先，纹状体神经肽强啡肽和脑啡肽的比例，这是差异表达的活性沿不同（直接和间接）的基底神经节途径的函数，将在刻板和非刻板小鼠。该研究预期揭示沿着这些途径的活性平衡的变化，使得刻板型小鼠沿着直接途径表现出更大的相对活性沿着。所提出的研究的最终目的是测量Fos相关抗原（FRA）（慢性神经元活动的推定标志物）在包括所涉及的皮质-基底神经节-皮质回路的位点中的表达。将在刻板和非刻板鹿小鼠之间进行FRA表达水平的比较，并且预期揭示包括刻板小鼠的直接途径的皮质基底神经节反馈回路中FRA表达升高。总之，这些研究将提供所需的数据，以批判性地评估上述神经回路在异常重复行为的调解中的假设参与。

DESCRIPTION (provided by applicant): The proposed research will evaluate the hypothesis that spontaneously occurring stereotypy is expressed as a consequence of elevated neuronal activity along cortico-striato-pallidonigro-thalamo-cortical feedback circuits. This hypothesis will be evaluated using Peromyscus maniculatus (deer mice), a mouse species that spontaneously exhibits abnormal repetitive behaviors when reared in standard laboratory cages. A series of in vivo and in vitro manipulations will be performed in these mice. In vivo experiments will consist of site-specific intracerebral pharmacological manipulations, which will be performed in an attempt to modulate the stereotypies emitted in the deer mice. These manipulations will be hypothesis-driven such that, based on existing chemoarchitectural understanding, all ligands will be expected to either exacerbate or attenuate stereotypies via excitation or inhibition, respectively, of activity along the feedback circuit hypothesized to mediate the expression of these abnormal repetitive behaviors. In vitro experiments will consist of immunohistochemical manipulations designed to measure indices of neuronal activity in key loci of the implicated feedback circuit. First, the ratio of striatal neuropeptides dynorphin and enkephalin, which are differentially expressed as a function of activity along the distinct (direct and indirect) pathways of the basal ganglia, will be measured in stereotypic and nonstereotypic mice. This study is expected to reveal shifts in the balance of activity along these pathways, such that stereotypic mice demonstrate greater relative activity along the direct pathway. The final objective of the proposed research is to measure the expression of Fos-related antigen (FRA}, a putative marker of chronic neuronal activity, in the loci comprising the implicated cortico-basal ganglia-cortical circuit. Comparison of the expression levels of FRA will be made between stereotypic and nonstereotypic deer mice, and are expected to reveal elevated FRA expression in the cortico-basal ganglia feedback circuit comprising the direct pathway of stereotypic mice. Taken together, these studies will provide the data needed to critically evaluate the hypothesized involvement of the aforementioned neural circuits in the mediation of abnormal repetitive behaviors.