Cotransmitters and the Regulation of Behavior

协同递质和行为调节

基本信息

批准号：
6766631
负责人：
MARK W MILLER
金额：
$ 11.58万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6766631
关键词：
Aplysia aquatic organism behavioral /social science research tag biological signal transduction brain regulatory center dopamine eating disorders electrophysiology gamma aminobutyrate immunocytochemistry interneurons motivation motor neurons neural plasticity neuropsychology neuroregulation neurotransmitters nutrition related tag

项目摘要

Our present understanding of several neurological movement disorders relates to pathologies of specific neurotransmitter systems. For example, substantial evidence indicates that the motor deficits associated with Parkinson's Disease result from the degeneration of the dopaminergic nigrostriatal pathway. In Huntington's Disease, motor deficits are associated with degeneration of striatal GABAergic neurons. Our most effective treatments for these disorders rely on agents that are thought to exert their effects on the synaptic signaling mediated by these neurotransmitters. Relating the activities of such neurotransmitter systems and therapeutic agents directly to human behavior, however, poses formidable challenges. The tong-term objective of this research program is to examine interactions between two major neurotransmitters, dopamine (DA) and GABA, in the regulation of feeding behavior. These two "conventional" neurotransmitters are thought to play key roles in the regulation of appetite, satiation, consummatory behaviors, and food reward in species ranging from invertebrates to man. The proposed studies will use an experimentally favorable model, Aplysia, in which it is possible to identify neurons that exhibit a specific transmitter phenotype, and to relate the activity of those neurons to specific behavior patterns. The three Specific Aims focus on the union of these two neurotransmitter systems in five specific identified interneurons in which DA and GABA are colocalized. The proposed experiments will (1) determine the contributions of colocalized DA and GABA to synaptic signaling, (2) explore the roles of DA and GABA in the modulation of intrinsic synaptic plasticities (metaplasticity), (3) investigate interactions between the cells in which DA and GABA are colocalized and other neurons that converge on common postsynaptic targets (heterosynaptic modulation). Recent advances in our understanding of behaviors related to feeding underscore the utility of this approach. In common with most organisms, the ingestive and egestive behaviors of this system are mediated by a single peripheral "physical plant" that is differentially activated by a multi-functional central pattern generator (CPG) circuit. The capability of a single CPG to achieve such motor program switching is often attributable to neuromodulatory cotransmitters that produce broad and coordinated reconfiguration of patterned motor output. Consequently, by increasing our understanding of cotransmission in this system, these experiments can be expected to reveal mechanistic and organizational principles that are applicable to the performance and dysfunction of motor behavior in more complex nervous systems.

我们目前对几种神经运动障碍的理解与特定神经递质系统的病理学有关。例如，大量证据表明，与帕金森病相关的运动缺陷是由多巴胺能黑质纹状体通路的退化引起的。在亨廷顿病中，运动缺陷与纹状体 GABA 能神经元的退化有关。我们对这些疾病最有效的治疗方法依赖于对这些神经递质介导的突触信号发挥作用的药物。然而，将此类神经递质系统和治疗剂的活动直接与人类行为联系起来，提出了巨大的挑战。该研究计划的长期目标是检查两种主要神经递质多巴胺 (DA) 和 GABA 在调节进食行为中的相互作用。这两种“传统”神经递质被认为在从无脊椎动物到人类等物种的食欲、饱腹感、完美行为和食物奖励的调节中发挥着关键作用。拟议的研究将使用一种实验上有利的模型，Aplysia，其中它可以识别表现出特定递质表型的神经元，并将这些神经元的活动与特定的行为模式联系起来。三个具体目标侧重于这两种神经递质系统在五个特定的中间神经元中的结合，其中 DA 和 GABA 共定位。拟议的实验将（1）确定共定位的 DA 和 GABA 对突触信号传导的贡献，（2）探索 DA 和 GABA 在调节内在突触可塑性（化塑性）中的作用，（3）研究细胞之间的相互作用，其中DA 和 GABA 是共定位的，其他神经元聚集在共同的突触后目标上（异质突触调制）。我们对喂养相关行为的理解的最新进展强调了这种方法的实用性。与大多数人相同在生物体中，该系统的摄取和消化行为是由单个外围“物理植物”介导的，该植物由多功能中央模式发生器（CPG）电路差异激活。单个 CPG 实现此类运动程序切换的能力通常归因于神经调节共递质，其产生模式化运动输出的广泛且协调的重新配置。因此，通过增加我们对该系统中共同传递的理解，这些实验有望揭示适用于更复杂的神经系统中运动行为的表现和功能障碍的机械和组织原理。