Dopaminergic regulation of in vivo plasticity & memory retention

体内可塑性的多巴胺能调节

• 批准号: 9446017
• 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/9446017
• 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。 多巴胺能系统会导致许多认知障碍，例如精神分裂症、阿尔茨海默氏症 痴呆症和帕金森病，仅在美国每年就花费超过 2000 亿美元。成功治疗 缓解认知问题的方法应该针对大脑中适当的神经回路。基本的 神经科学研究提供了识别网络、神经递质和神经元所需的信息。 正常大脑功能的基础机制，也是潜在疗法的目标。恰当的 多巴胺能信号对于注意力、执行功能、学习和认知等认知过程至关重要。 记忆。这些过程的复杂性以及与这些过程相关的突触和细胞数据的缺乏 系统级行为激发了拟议的研究。 我们早期的工作表明，体内突触可塑性的诱导与学习任务相关 需要与传入多巴胺信号相结合的兴奋性电路的局部去抑制。最近的结果来自 我们的实验室支持这样的观点：海马体中的多巴胺信号传导降低了突触的阈值 学习的可塑性。我们的初步结果表明，局部多巴胺能活动是 体内海马长期突触增强与不同的学习范式相关，例如厌恶 记忆保留和新物体识别。但目前，关于该问题存在争议 海马多巴胺能神经支配的来源、密度和意义以及多巴胺能调节 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 使用多种独立的病毒标记方法研究海马体的神经传递。那么，我们将 检查特定记忆任务期间多巴胺能对不同海马回路的影响。我们的工作 假设是多巴胺在关键时间窗口内起作用并控制突触可塑性的大小 在调节不同类型学习的特定回路中。多巴胺通常有助于提高效率 学习由环境线索激发的适当行为反应。工作假设， 然而，也有助于解释多巴胺信号失衡期间出现的认知功能障碍 发现于不适当的感觉门控、注意力和学习会产生适应不良行为的疾病中。 将采用跨神经整合水平的多学科方法来理解 厌恶性记忆保留和新颖性检测背后的突触机制。我们将使用一个数组 解剖追踪和分析技术，以确定作用于多巴胺信号的起源 海马回路。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，并实时测量体内突触可塑性。这些关键神经回路中描绘的机制将为未来的发展提供目标 减少认知障碍的治疗策略。