Neurobiology of Spatial Reversal Learning

空间逆转学习的神经生物学

基本信息

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
项目类别：
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

项目摘要

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大鼠空间辨别逆转的神经机制。这项研究将提高发育障碍动物模型的实用性，例如自闭症谱系障碍（ASD）和胎儿酒精谱系障碍（FASD），其中逆转学习受损是一个显着特征。空间歧视逆转操作简单，很容易在啮齿动物和人类的个体发育过程中进行管理，并且对各种发育损伤敏感。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）。它可以分析疾病的个体发生时间过程，这对于揭示与人类疾病的相似之处、理解机制和制定有效的治疗干预措施非常重要。它还通常会提高行为评估的敏感性（尤其是 FASD），并可以指导干预措施在发展的早期阶段更有可能有效。尽管人们对成人逆向学习的神经机制有一些了解，但这种了解在发育中的动物中相当有限。该提案将使用最近建立的用于研究断奶期和幼年大鼠 T 迷宫逆转的制剂（Pagani，Brown & Stanton，2005；Watson，Sullivan，Frank & Stanton，2006），并被证明对急性、全身性疾病敏感。给予非竞争性 NMDA 受体拮抗剂 MK-801（Chadman、Watson & Stanton，已提交）。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。将在断奶大鼠中研究 T 迷宫辨别力的获得和逆转，这些断奶大鼠已通过颅内注射（通过双侧植入插管）竞争性 NMDA 拮抗剂 AP5 进入背侧海马（目标 1）；内侧前额叶皮质（目标 2）或背内侧纹状体（目标 3）。在大多数 Aims 中，将使用 2（获取处理）x 2（逆转处理）因子设计，其中 AP5（或媒介物）将在获取、逆转、两者或两者都不进行期间施用。可以在每个目标下进行额外的研究，以进一步探索这些初始实验中发现的影响的神经、行为和发育决定因素。这项研究将推进学习和记忆的发育心理生物学，并有助于开发可用于早期识别和治疗发育障碍（如 FASD 和 ASD）的啮齿动物模型。这些目标服务于各个 NIH 机构（例如 NICHD、NIMH、NIDA、NIHS 和 NIAAA）的使命。