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，都必须区分需要注意的行为重要事件和其他刺激的事件。适当的感官门控对于处理复杂的信息以及在简单但至关重要的任务中保持警报至关重要。有选择地参加相关刺激的能力对于有效学习也至关重要。相反，不适当的感觉彩控是导致与几种精神病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。确实，包括精神分裂症，自闭症和注意力缺陷多动障碍在内的许多疾病与感觉门控和注意力的缺陷有关。值得注意的是，任何系统中注意力的分子基础都没有理解。我们已经在感觉神经元突触中确定了一种分子机制，该机制有助于感官门控在简单的模型系统，海洋无脊椎动物无脊椎动物中介导的注意力样过程。最近，我们在分析负责在主动状态和无声状态之间切换感觉突触的机制方面取得了重大进展。这种双态突触开关涉及共发性抑郁症，其中单个释放位点被沉默，并对抑郁症的爆发依赖保护（BDP），其中一小爆发的动作电位阻止了释放位点的沉默。我们最近的分析暗示了BDP中的经典，钙激活的蛋白激酶C（PKC APL-1）和小的G蛋白ARF以及其上游调节剂GEF在释放位点的沉默中。通过这种机制，动物对具有生物学重要性的显着刺激保持敏感或专注，并且忽略了行为无关紧要的刺激。尽管感觉信号传导的这些变化是非缔合性的，但动物也会改变其对经典调节过程中刺激的重要性的反应。 Aplysia中的条件涉及相同感觉突触下的关联可塑性。在我们对关联突触可塑性的分析中，我们已经克隆并表征了4个在Aplysia神经系统中表达的4个腺苷酸环化酶（AC）同工型。现在，我们可以检验一个关于这些AC在调节过程中这些AC对关联可塑性的贡献的新假设。在AIM 1中，我们将测试特定ARF GEF（催化GTP与ARF结合并激活ARF）和特定ARF同工型在沉默感觉神经元突触中的作用。在AIM 2中，我们将研究这些信号分子的精确共定位，包括PKC APL-1，脚手架蛋白pick1和ARF GEF，并在释放位点具有钙通道。为了图像单分子，我们将使用新颖的培养技术与光活化荧光标签结合使用。在AIM 3中，我们将检验一个新的假设，即钙抑制的AC还有助于启动突触可塑性期间刺激配对的要求。