REGULATION OF MESOLIMBIC DOPAMINE BY ENDOGENOUS COMPOUND

内源性化合物对中脑边缘多巴胺的调节

• 批准号: 6164982
• 负责人: Peter W Kalivas
• 金额: $ 20.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164982
• 关键词: behavioral /social science research tag; brain mapping; chordate locomotion; dopamine; enkephalins; experimental brain lesion; gamma aminobutyrate; glutamates; laboratory rat; limbic system; memory; microdialysis; microinjections; motivation; motor cortex; motor neurons; neural information processing; neural transmission; neuroanatomy; neurochemistry; neuropharmacology; nucleus accumbens; psychomotor function; stereotaxic techniques

A dysfunction of the brain circuitry mediating the translation of relevant environmental stimuli into adaptive motor responses is thought to have an etiologic or permissive role in many psychiatric disorders. Classic limbic structures provide emotional and cognitive context to environmental stimuli. The circuitry whereby this information is transferred to motor systems and the appropriate behavioral response initiated involves a series of nuclei possessing extensive reciprocal interconnectivity. This circuit is referred to as the 'motive circuit' and includes the ventral tegmental area, nucleus accumbens, ventral pallidum, mediodorsal thalamus, prefrontal cortex and pedunculopontine motor area. The goal of this continuation proposal is to functionally map the flow of information from limbic to motor nuclei through the motive circuit. This will be accomplished using three convergent technologies, 1) retrograde labeling of neurons combined with in situ hybridization for mRNA of relevant transmitter-related proteins, 2) intracranial infusions of transmitter analogues into the circuit to map the connections mediating behavioral activation, and 3) microinjecting transmitter analogues into the circuit and measuring changes in extracellular transmitter concentrations with microdialysis. The proposal is based upon three general hypotheses. 1) A detailed topography exists which permits the transfer of information into discrete compartments within nuclei comprising the motive circuit. 2) The selective transfer of information is, to some extent, chemically coded such that different neurotransmitters route information through different efferent projections. 3) The routing of information is under environmental/genetic control. This latter hypothesis relies on recent observations that the intensity of the motor response elicited by rats in a novel environment is correlated with neurochemical alterations in subnuclei of the motive circuit. Thus, prior to beginning all experiments, rats will be behaviorally screened in a novel open field to permit correlations between their motor response to novelty and other subsequent measures. Many behavioral symptoms defining psychiatric illnesses involve inappropriate behavioral responses to environmental stimuli. The motive circuit is responsible for translating environmental stimuli into adaptive motor responses. By understanding the anatomical and chemical organization of the motive circuit it will be possible to pharmacologically modulate inappropriate behaviors with greater accuracy. Furthermore, the anatomical and functional mapping of the motive circuit will provide a basis for interpreting future imaging studies in humans where attempts are made to correlate changes in spatially discrete nuclei.

调节相关基因翻译的大脑回路功能障碍 环境刺激转化为适应性运动反应被认为具有 在许多精神疾病中起病因学作用或允许作用。经典边缘 结构为环境提供了情感和认知语境 刺激物。将信息传输到马达的电路 系统和启动的适当的行为反应涉及一系列 具有广泛的相互联系的原子核。这条线路 被称为“运动回路”，包括腹侧被盖 伏隔核、苍白球腹侧区、丘脑背内侧、前额叶 大脑皮质和桥小脚运动区。这次续写的目标是 建议从功能上将信息流从边缘映射到 运动核团通过运动回路。这将通过以下方式完成 三种融合技术：1)联合逆行标记神经元 用原位杂交技术检测相关递质相关基因的mRNA 蛋白质，2)向脑内注入递质类似物 映射中介行为激活的连接的电路，以及3) 向电路中微注入发射器模拟物并测量变化 用微透析法测定细胞外递质浓度。 这项提议基于三个一般假设。1)详细说明 存在允许将信息传输到离散的地形图 构成运动回路的核内的隔室。2)精选 信息的传输在某种程度上是化学编码的，因此 不同的神经递质通过不同的传出通路传递信息 投射。3)信息的传递受环境/遗传因素的制约 控制力。后一种假设依赖于最近的观察结果，即 大鼠在新环境中诱发的运动反应强度是 与动机亚核的神经化学改变相关 巡回赛。因此，在开始所有实验之前，老鼠将被 在新的开阔领域进行行为筛选，以允许 他们对新奇事物和其他后续措施的运动反应。 定义精神疾病的许多行为症状包括 对环境刺激的不适当的行为反应。动机 电路负责将环境刺激转换为自适应 运动反应。通过了解解剖和化学组织 在运动回路中，将有可能通过药物调节 不恰当的行为更准确。此外，解剖学上的 而运动回路的功能图谱将为 解释未来的人类成像研究，试图 在空间上离散的原子核中的相关变化。