Dopaminergic regulation of in vivo plasticity & memory retention

体内可塑性的多巴胺能调节

• 批准号: 9542381
• 负责人: John A. Dani
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542381
• 关键词: Aging; Alzheimer' s Disease; Anatomy; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Avoidance Learning; Behavior; Behavioral; Brain; Catecholamines; Chemosensitization; Cognition Disorders; Cognitive; Cognitive deficits; Complex; Coupled; Cues; Data; Detection; Disease; Disinhibition; Dopamine; Functional disorder; Future; Goals; Health; Hippocampus (Brain); Hyperactive behavior; Impaired cognition; Individual; Label; Learning; Link; Long-Term Potentiation; Measures; Memory; Mental disorders; Methods; Microdialysis; Midbrain structure; Mus; Nature; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurosciences Research; Neurotransmitters; Norepinephrine; Parkinson Disease; Pattern; Performance; Physiological; Process; Publishing; Regulation; Role; Schizophrenia; Signal Transduction; Source; Substantia nigra structure; Synapses; Synaptic plasticity; System; Techniques; Therapeutic; Time; Ventral Tegmental Area; Viral; Work; anatomical tracing; behavioral response; cognitive process; conditioned fear; cost; density; dentate gyrus; dopamine D5 receptor; dopaminergic neuron; executive function; in vivo; interdisciplinary approach; locus ceruleus structure; long term memory; memory consolidation; memory retention; nerve supply; neural circuit; neurophysiology; neurotransmission; noradrenergic; novel; object recognition; optogenetics; pars compacta; receptor; relating to nervous system; sensory gating

Cognitive deficits associated with neuronal dysfunction and aging constitute a serious health problem. Dopaminergic systems contribute to a number of cognitive disorders, such as schizophrenia, Alzheimer's dementia, and Parkinson's disease, which cost > $200 billion a year in the USA alone. Successful therapeutic approaches to alleviate cognitive problems should target appropriate neural circuits in the brain. Basic neuroscience research provides that information necessary to identify the networks, neurotransmitters, and mechanisms that underlie proper brain function and are the targets for potential therapies. Proper dopaminergic signaling is essential for cognitive processes such as attention, executive function, learning, and memory. The complex nature of these processes and the paucity of synaptic and cellular data linked to the systems-level behaviors have spurred the proposed studies. Our earlier work showed that induction of in vivo synaptic plasticity associated with a learning task requires local disinhibition of excitatory circuits coupled with an afferent dopamine signal. Recent results from our lab support the view that dopamine signaling in the hippocampus lowers the threshold for synaptic plasticity that underlies learning. Our preliminary results show that local dopaminergic activity is required for in vivo hippocampal long-term synaptic potentiation associated with diverse learning paradigms, such as aversive memory retention and novel object recognition. Presently however, there is a controversy regarding the source, density, and significance of hippocampal dopaminergic innervation and about dopaminergic regulation of synaptic plasticity and memory. In the proposed studies, we will identify the sources of dopaminergic neurotransmission in the hippocampus using multiple independent viral labeling methods. Then, we will examine dopaminergic influences over distinct hippocampal circuits during specific memory tasks. Our working hypothesis is that dopamine acts within critical time windows and controls the magnitude of synaptic plasticity within specific circuits that regulate different types of learning. Dopamine normally contributes to the efficient learning of appropriate behavioral responses motivated by environmental cues. The working hypothesis, however, also helps to explain the cognitive dysfunctions that arise during dopamine signaling imbalances found in diseases where inappropriate sensory gating, attention, and learning produce maladaptive behavior. A multidisciplinary approach that crosses neural levels of integration will be applied to understand the synaptic mechanisms underlying aversive memory retention and novelty detection. We will use an array of anatomical tracing and analytical techniques to determine the origin of dopamine signals that act upon hippocampal circuits. During the performance of behavioral tasks, these endogenous dopaminergic signals will be temporally controlled using optogenetic approaches, and in vivo synaptic plasticity will be measured in real-time. The delineated mechanisms within these critical neural circuits will provide targets for developing future therapeutic strategies that diminish cognitive impairments.

与神经元功能障碍和衰老相关的认知缺陷构成了严重的健康问题。 多巴胺能系统有助于多种认知障碍，例如精神分裂症，阿尔茨海默氏症 痴呆症和帕金森氏病，仅在美国，每年耗资2000亿美元。成功的治疗性 减轻认知问题的方法应针对大脑中适当的神经回路。基本的 神经科学研究提供了确定网络，神经递质和 具有适当大脑功能并成为潜在疗法的靶标的机制。恰当的 多巴胺能信号传导对于注意力，执行功能，学习和 记忆。这些过程的复杂性质以及与该过程相关的突触和蜂窝数据的匮乏 系统级行为刺激了拟议的研究。 我们较早的工作表明，与学习任务相关的体内突触可塑性的诱导 需要局部对兴奋回路以及传入多巴胺信号的局部抑制作用。最新结果 我们的实验室支持这样的观点，即海马中的多巴胺信号降低了突触的阈值 构成学习的可塑性。我们的初步结果表明，在IN中需要局部多巴胺能活性 与多种学习范式相关的体内海马长期突触增强，例如厌恶 记忆保留和新颖的对象识别。但是目前，关于 海马多巴胺能神经和多巴胺能调节的来源，密度和意义 突触可塑性和记忆。在拟议的研究中，我们将确定多巴胺能的来源 使用多个独立的病毒标记方法在海马中进行神经传递。然后，我们会的 在特定的记忆任务中，检查对不同海马电路的多巴胺能影响。我们的工作 假设是多巴胺在关键的时间窗口内作用，并控制着突触可塑性的大小 在调节不同类型学习的特定电路中。多巴胺通常有效 学习由环境线索促进的适当行为反应。工作假设， 但是，还有助于解释多巴胺信号失衡期间出现的认知功能障碍 在不适当的感觉门控，注意力和学习的疾病中发现会导致适应不良的行为。 跨越神经融合水平的多学科方法将应用于了解 厌恶记忆保留和新颖性检测的基础的突触机制。我们将使用一个数组 解剖学跟踪和分析技术，以确定作用于多巴胺信号的起源 海马电路。在执行行为任务期间，这些内源性多巴胺能信号将 使用光遗传学方法进行时间控制，并将实时测量体内突触可塑性。这些关键神经回路中的划定的机制将为发展未来提供目标 减少认知障碍的治疗策略。