Nonassociative and Associative Neuroplasticity

非联想和联想神经可塑性

基本信息

批准号：
8644883
负责人：
Thomas W Abrams
金额：
$ 37.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644883
关键词：
Action Potentials Adenylate Cyclase Affect Afferent Neurons Animals Aplysia Attention Attention deficit hyperactivity disorder Autistic Disorder Behavioral Binding Binding Sites Biological Biological Models Calcium Calcium Channel Complex Culture Techniques Decision Making Development Disease Dominant-Negative Mutation Environment Equilibrium Event GTP Binding Guanine Nucleotide Exchange Factors Homosynaptic Depression Human Image Imaging Techniques Impaired cognition Individual Invertebrates Lead Learning Maintenance Marine Invertebrates Mediating Mental Depression Mental disorders Modeling Molecular Molecular Analysis Molecular Models Monomeric GTP-Binding Proteins Mutate Nervous system structure Neuronal Plasticity Participant Pattern Population Process Protein Isoforms Protein Kinase C Proteins Relative (related person)Research Role Scaffolding Protein Schizophrenia Sensory Series Signal Transduction Signaling Molecule Site Stimulus Synapses Synaptic plasticity System Testing Work adenylyl cyclase 4 base chronic pain citrate carrier classical conditioning conditioning detector knock-down molecular modeling nervous system disorder novel novel therapeutic intervention paired stimuli presynaptic prevent research study response sensory gating single molecule submicron synaptic depression

项目摘要

DESCRIPTION (provided by applicant): All animals, including humans, must distinguish between behaviorally important events that require attention and other stimuli that do not. Appropriate sensory gating is critical for processing complex information and for remaining alert during simple, but critical tasks. The ability to selectively attend to relevant stimuli is also critical for effective learning. Conversely, inappropriate sensory gating is an important contributor to cognitive dysfunction associated with several psychiatric and neurological disorders as well as chronic pain. Indeed a number of disorders, including schizophrenia, autism and attention deficit hyperactivity disorder, are associated with deficits in sensory gating and attention. Remarkably, nothing is understood about the molecular basis of attention in any system. We have identified a molecular mechanism at sensory neuron synapses that contributes to sensory gating that mediates an attention-like process in a simple model system, the marine invertebrate Aplysia. We have recently made substantial progress in analyzing the mechanism responsible for switching sensory synapses between active and silent states. This bistable synaptic switch involves homosynaptic depression, in which individual release sites are silenced, and burst dependent protection (BDP) from depression, in which a small burst of action potentials prevents the silencing of release sites. Our recent analysis has implicated classical, calcium-activated protein kinase C (PKC Apl-1) in BDP and the small G protein Arf, together with its upstream regulator GEF, in the silencing of release sites. Through this mechanism, animals remain responsive or attentive to salient stimuli that have biological importance and ignore stimuli that are behaviorally irrelevant. Whereas these changes in sensory signaling are non-associative, animals also alter their responsiveness to importance of stimuli during classical conditioning. Conditioning in Aplysia involves associative plasticity at the same sensory synapses. In our analysis of associative synaptic plasticity, we have cloned and characterized 4 adenylyl cyclase (AC) isoforms expressed in the nervous system of Aplysia. We can now test a novel hypothesis about the contribution of one of these ACs to associative plasticity during conditioning. In Aim 1, we will test the roles of specific Arf GEFs (that catalyze GTP binding to and activating Arf) and specific Arf isoforms in silencing sensory neuron synapses. In Aim 2 we will use study the precise colocalization of these signaling molecules, including PKC Apl-1, a scaffolding protein PICK1 and Arf GEF, with calcium channels at release sites. To image single molecules we will use novel culture techniques in combination with photoactivatable fluorescent tags. In Aim 3, we will test a new hypothesis that calcium- inhibited AC also contributes to requirements for stimulus pairing during initiation of synaptic plasticity.

描述（由申请人提供）：所有动物，包括人类，必须区分需要注意的行为重要事件和其他不需要注意的刺激。适当的感觉门控对于处理复杂信息以及在简单但关键的任务中保持警觉至关重要。有选择地关注相关刺激的能力对于有效学习也至关重要。相反，不适当的感觉门控是导致与多种精神和神经系统疾病以及慢性疼痛相关的认知功能障碍的重要因素。事实上，许多疾病，包括精神分裂症、自闭症和注意力缺陷多动障碍，都与感觉门控和注意力缺陷有关。值得注意的是，我们对任何系统中注意力的分子基础一无所知。我们已经确定了感觉神经元突触的一种分子机制，该机制有助于感觉门控，在一个简单的模型系统（海洋无脊椎动物海兔）中介导类似注意力的过程。我们最近在分析负责在活动和沉默状态之间切换感觉突触的机制方面取得了实质性进展。这种双稳态突触开关涉及同突触抑制（其中各个释放位点被沉默）和突发依赖性抑制保护（BDP）（其中动作电位的小爆发阻止释放位点的沉默）。我们最近的分析表明，BDP 中的经典钙激活蛋白激酶 C (PKC Apl-1) 和小 G 蛋白 Arf 及其上游调节剂 GEF 参与了释放位点的沉默。通过这种机制，动物对具有生物学重要性的显着刺激保持反应或关注，并忽略与行为无关的刺激。尽管感觉信号的这些变化是非关联性的，但动物在经典条件反射过程中也会改变它们对刺激重要性的反应。海兔的条件反射涉及相同感觉突触的关联可塑性。在我们对关联突触可塑性的分析中，我们克隆并表征了海兔神经系统中表达的 4 种腺苷酸环化酶 (AC) 亚型。我们现在可以测试一个关于这些 AC 之一在调节过程中对联想可塑性的贡献的新假设。在目标 1 中，我们将测试特定 Arf GEF（催化 GTP 结合并激活 Arf）和特定 Arf 亚型在沉默感觉神经元突触中的作用。在目标 2 中，我们将研究这些信号分子（包括 PKC Apl-1、支架蛋白 PICK1 和 Arf GEF）与释放位点钙通道的精确共定位。为了对单分子进行成像，我们将结合使用新颖的培养技术和光激活荧光标签。在目标 3 中，我们将测试一个新假设，即钙抑制 AC 也有助于突触可塑性启动过程中刺激配对的需求。