Neurobiology of Spatial Reversal Learning

空间逆转学习的神经生物学

• 批准号: 7222851
• 负责人: DEBORAH JEAN WATSON
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2009-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222851
• 关键词: NMDA receptors; animal developmental psychology; autism; behavioral /social science research tag; corpus striatum; developmental disease /disorder; developmental neurobiology; disease /disorder model; fetal alcohol syndrome; hippocampus; infant animal; inhibitor /antagonist; juvenile animal; laboratory rat; learning disorders; mental health epidemiology; predoctoral investigator; prefrontal lobe /cortex; receptor expression

DESCRIPTION (provided by applicant): The present proposal will investigate the neural mechanisms of spatial discrimination reversal in developing rats. This research will improve the utility of animal models of developmental disorders such as autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD) in which impaired reversal learning is a prominent feature. Spatial discrimination reversal is operationally simple, is readily administered across ontogeny in both rodents and humans, and is sensitive to a variety of developmental insults. Developmental assessment is important in the study of developmental disorders for several reasons (e.g., Stanton, 1994). It permits analysis of the ontogenetic time course of the disorder which is important for revealing parallels with the human disorder, for understanding mechanisms, and for developing effective therapeutic interventions. It also often increases sensitivity of behavioral assessments (especially in FASD) and can guide interventions at early stages of development when they are more likely to be effective. Although there is some understanding of the neural mechanisms of reversal learning in adults, this understanding is rather limited in developing animals. This proposal will use a preparation for studying T-maze reversal in periweanling and juvenile rats that has been recently established (Pagani, Brown & Stanton, 2005; Watson, Sullivan, Frank & Stanton, 2006) and demonstrated to be sensitive to acute, systemic administration of the noncompetitive NMDA receptor antagonist, MK-801 (Chadman, Watson & Stanton, submitted). It will test the hypothesis that NMDA receptor action in specific regions of the brain is necessary for reversal learning. Acquisition and reversal of a T-maze discrimination will be studied in weanling rats that have been intracranially infused (via bilaterally implanted cannulas) with the competitive NMDA antagonist, AP5 into the dorsal hippocampus (Aim 1); the medial prefrontal cortex (Aim 2), or the dorsomedial striatum (Aim 3). In most Aims, a 2 (Acquisition treatment) x 2 (Reversal treatment) factorial design will be used in which AP5 (or vehicle) will be administered during acquisition, reversal, both or neither. Additional studies may be pursued under each aim to further explore the neural, behavioral, and developmental determinants of effects that are found in these initial experiments. This research will advance the developmental psychobiology of learning and memory and contribute to the development of rodent models that can be applied to the early identification and treatment of developmental disorders, such as FASD and ASD. These goals serve the mission of a variety of NIH agencies (e.g., NICHD, NIMH, NIDA, NIHS, and NIAAA).

描述（由申请人提供）：本提案将研究发育中的大鼠空间歧视逆转的神经机制。这项研究将改善发育障碍动物模型（例如自闭症谱系障碍（ASD）和胎儿酒精谱系障碍（FASD））的效用，其中逆转学习是一个突出的特征。空间歧视逆转在操作上很简单，在啮齿动物和人类中都很容易施用跨个体发育，并且对各种发育侮辱都很敏感。出于多种原因，发育评估在发育障碍的研究中很重要（例如Stanton，1994）。它允许分析该疾病的个体发育时间过程，这对于揭示与人类障碍的相似之处，了解机制以及开发有效的治疗干预措施很重要。它通常还会提高行为评估的敏感性（尤其是在FASD中），并且在更有可能有效的情况下，可以在开发的早期阶段进行干预措施。尽管对成年人逆转学习的神经机制有一些了解，但这种理解在发展中的动物中受到限制。该提案将使用一项准备工作来研究最近已建立的杂草和少年大鼠的T迷宫逆转（Pagani，Brown＆Stanton，2005; Watson，Sullivan，Frank＆Stanton，2006年），并证明对非竞争性NMDA受体抗体式抗体及其STONN＆Stann＆Stann＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan＆Stantan，Mk-801（Chadan＆Stant），提交）。它将检验以下假设：大脑特定区域的NMDA受体作用对于逆转学习是必要的。将在断奶大鼠（通过双侧植入的插管）中研究与竞争性NMDA拮抗剂AP5在颅内注入（通过双侧植入的插管）中，对T迷宫歧视的获取和逆转将研究（AIM 1）；内侧前额叶皮层（AIM 2）或背侧纹状体（AIM 3）。在大多数目的中，将使用2（收购处理）x 2（逆转处理）阶乘设计，其中将在收购，逆转，或不均不进行AP5（或车辆）。每个目标都可以在每个目标下进行其他研究，以进一步探索这些最初实验中发现的效应的神经，行为和发育决定因素。这项研究将推动学习和记忆的发展心理生物学，并有助于啮齿动物模型的发展，这些模型可以应用于FASD和ASD等发育障碍的早期鉴定和治疗。这些目标符合各种NIH机构的使命（例如NICHD，NIMH，NIDA，NIHS和NIAAA）。