Ontogeny of caudate-putamen functioning: behavioral relevance

尾壳核功能的个体发育：行为相关性

• 批准号: 8474639
• 负责人: Sanders McDougall
• 金额: $ 35.75万
• 依托单位: CALIFORNIA STATE UNIV SAN BERNARDINO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-16 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8474639
• 关键词: Acetylcholine; Address; Adenylate Cyclase; Adolescence; Adolescent; Adult; Affect; Age; Agonist; Applications Grants; Attention deficit hyperactivity disorder; Attenuated; Autistic Disorder; Basal Ganglia; Behavior; Behavioral; Binding; Biological Assay; Brain; Chemosensitization; Childhood; Conduct Disorder; Data; Development; Disease; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Dorsal; Employee Strikes; Exhibits; Functional disorder; Gilles de la Tourette syndrome; Goals; Growth; Guanosine Triphosphate; Immunoblotting; Left; Link; Locomotion; Mediating; Mental disorders; Microinjections; Modification; Motor; Motor Activity; Neurons; Obsessive-Compulsive Disorder; Pattern; Pharmaceutical Preparations; Procedures; Process; Proteins; Rattus; Research; Research Project Grants; Research Proposals; Role; Syndrome; System; Techniques; Testing; Tic disorder; age group; age related; base; clinically relevant; developmental disease; dopamine system; innovation; insight; interest; nervous system disorder; neuromechanism; neuropsychiatry; orofacial; psychopharmacologic; public health relevance; putamen; receptor; relating to nervous system; research study; response; stereotypy

DESCRIPTION (provided by applicant): The caudate-putamen (CPu) is the major input and processing component of the basal ganglia. Dysfunctions involving the basal ganglia, and the CPu in particular, have been linked to a number of neuropsychiatric disorders, including Tourette's syndrome, ADHD, autism, and pediatric obsessive-compulsive disorder. The goal of this project is to employ an ontogenetic research strategy to examine the maturation of dopamine (DA) mediated behaviors in preweanling, adolescent, and adult rats. In the first set of experiments (Specific Aim 1), locomotor activity and stereotypy will be assessed after DA drugs are infused into discrete subregions of the CPu. It is anticipated that DA agonists and antagonists will induce a different pattern of behavioral effects in the three age groups, thus indicating that the neural mechanisms mediating behavior undergo substantial ontogenetic modification. In Specific Aims 2 and 3, EEDQ will be utilized because it is a drug known to cause pronounced age-dependent behavioral effects in preweanling and adult rats. Specifically, infusing EEDQ into the dorsal CPu attenuates the DA agonist-induced locomotion of adult rats, while potentiating the locomotor activity of preweanling rats. In the behavioral experiments (Specific Aim 2), D1 and/or D2 receptors will be selectively protected from EEDQ-induced inactivation in order to determine which receptor type is responsible for causing locomotor potentiation in preweanling and adolescent rats. NonDA drugs will also be used to determine whether DA receptor inactivation causes a generalized increase in behavioral responsiveness or whether the locomotor potentiation exhibited by preweanling rats is unique to DA agonists. The neural basis of EEDQ's paradoxical behavioral effects will be determined in Specific Aim 3. One explanation is that preweanling rats have a substantial D2 receptor reserve that allows them to exhibit DA agonist-induced behaviors even after a large number of receptors are inactivated by EEDQ. Alternatively, it is possible that surviving or newly synthesized DA receptors are supersensitive and, thus, are capable of mediating a potentiated locomotor response. To test these ideas, D1 agonist-stimulated adenylyl cyclase activity and D2 agonist-modulated acetylcholine release will be used to estimate the size of D1 and D2 receptor reserves in the CPu of preweanling, adolescent, and adult rats. Various techniques will be used to assess receptor super sensitivity, including agonist competition and GTP?S binding assays, as well as G?olf and RGS9 immunoblotting (these proteins are associated with super sensitized D1 and D2 receptors). We predict that age- dependent changes in EEDQ-induced receptor super sensitivity, perhaps caused by a rapid repopulation of D2 receptors, is responsible for the paradoxical behavioral effects produced by DA receptor inactivation. In summary, the goal of this grant proposal is to employ an innovative combination of established techniques to examine ontogenetic changes in the way the CPu mediates behavior. This type of ontogenetic research is necessary to determine the neural bases of developmental neuropsychiatric disorders.

描述（由申请人提供）：尾状驾驶员（CPU）是基底神经节的主要输入和处理成分。涉及基础神经节的功能障碍，尤其是CPU，与许多神经精神疾病有关，包括Tourette的综合征，ADHD，自闭症和儿科强迫症。该项目的目的是采用一个个体遗传学研究策略来检查在开心，青少年和成年大鼠中多巴胺（DA）介导的行为的成熟。在第一组实验（特定目标1）中，将在DA药物注入CPU的离散子区域后，将评估运动活性和刻板印象。预计DA激动剂和拮抗剂将在三个年龄组中诱导不同的行为效应模式，因此表明介导行为的神经机制经历了实质性的个体发生修饰。在特定的目标2和3中，将使用EEDQ，因为它是已知的一种药物，可引起明显的年龄依赖性行为效应，并在开胃前和成年大鼠中。具体而言，将EEDQ注入背侧CPU会减弱DA激动剂诱导的成年大鼠的运动，同时增强了前断奶大鼠的运动活性。在行为实验（特定的目标2）中，D1和/或D2受体将被选择性保护，以免EEDQ诱导的失活，以确定哪种受体类型负责在前干和青少年大鼠中引起运动性增强。 NONDA药物还将用于确定DA受体失活是否会导致行为反应性的普遍增加，或者是前断层大鼠所表现出的运动增强功能是DA激动剂所独有的。 EEDQ的矛盾行为效应的神经基础将在特定的目标3中确定。一种解释是，预断层大鼠具有大量的D2受体储备，即使在EEDQ被EEDQ灭活大量受体之后，也可以表现出DA激动剂诱导的行为。另外，幸存或新合成的DA受体可能具有超敏感性，因此能够介导增强的运动反应。为了测试这些思想，D1激动剂刺激的腺苷酸环化酶活性和D2激动剂调节的乙酰胆碱释放将用于估计预先配套，青少年和成年大鼠CPU中D1和D2受体储备的大小。各种技术将用于评估受体超级灵敏度，包括激动剂竞争和GTP的结合测定，以及G？olf和RGS9免疫印迹（这些蛋白质与超敏化的D1和D2受体有关）。我们预测，EEDQ诱导的受体超级灵敏度的年龄依赖性变化可能是由于D2受体快速重生引起的，这是DA受体失活引起的矛盾行为效应。总而言之，该赠款提案的目的是利用既定技术的创新组合来检查CPU介导行为的方式的个体发生变化。对于确定发育神经精神疾病的神经基础，这种类型的种植研究是必要的。