From Molecules to Behavior: The Role of Homeostatic Synaptic Scaling in Associative Learning and Memory

从分子到行为：稳态突触缩放在联想学习和记忆中的作用

• 批准号: 9978157
• 负责人: Raul Arturo Ramos
• 金额: $ 3.14万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978157
• 关键词: Acute; Affect; Behavior; Behavioral; Behavioral Paradigm; Cell physiology; Cells; Chronic; Computer Models; Electrophysiology (science); Extinction (Psychology); Feedback; Goals; Infusion procedures; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Methods; Modeling; Modification; Nature; Neuraxis; Neurons; Neurosciences Research; Outcome; Output; Physiological; Physiology; Post-Traumatic Stress Disorders; Process; Rattus; Research; Research Project Grants; Research Proposals; Role; Schizophrenia; Slice; Stains; Study models; Synapses; Synaptic plasticity; Syndrome; Taste aversion; Testing; Time; Training; Virus; Visual Cortex; Work; autism spectrum disorder; classical conditioning; conditioned fear; experience; experimental study; in vivo; insight; memory acquisition; memory process; nervous system disorder; neural network; neuronal excitability; postsynaptic; preservation; response; sensory cortex; synaptic depression

Project Summary A central goal of neuroscience research is to advance our understanding of the cellular physiology underlying learning and memory processes. The most extensively studied model for how associative learning is achieved at the cellular level is the Hebbian modification of synapses. However, computational modeling studies have demonstrated that these forms of plasticity follow positive feedback rules, making them inherently destabilizing in nature. Without additional features, Hebbian plasticity could give way to “unconstrained” changes in synaptic strengths, resulting in the disruption of associative learning. Homeostatic synaptic plasticity is hypothesized to be the basis for neural-network stability during learning-driven changes of synaptic strength. Synaptic scaling, the most extensively studied form of homeostatic synaptic plasticity, functions as a negative-feedback mechanism, bidirectionally regulating synaptic strengths, in a cell- autonomous manner, to maintain an activity set point. Synaptic scaling is thus hypothesized to constrain the positive feedback nature of Hebbian mechanisms while simultaneously preserving circuit features permissive to learning. Despite its potential to impact our current understanding of associative learning processes, this hypothesis remains untested and the consequences of disrupted synaptic scaling on learning remain unknown. This proposal aims to determine the role of homeostatic synaptic scaling in associative learning and memory using a conditioned taste aversion (CTA) paradigm in rats. First, I will confirm that I can induce and block synaptic scaling in gustatory cortex using in-vivo chronic TTX infusions and ex-vivo acute slice electrophysiology. Second, I aim to characterize the effects of synaptic scaling loss on engram excitability. I will train rats on a CTA behavior paradigm and then perform immunofluorescent staining to characterize the time course of learning-driven changes in CTA engram neuron excitability. Then, I will use a combination of ex-vivo acute slice electrophysiology and virus mediated targeting of CTA engram neurons to characterize the impact of blocked homeostatic plasticity on the underlying cellular physiology of associative learning. Lastly, I will determine the role of homeostatic plasticity in memory acquisition & extinction using behavioral training and ex-vivo recordings of CTA engram cells. These experiments will elucidate the behavioral consequences of loss of homeostatic plasticity. Moreover, this research proposal will advance our current understanding of the associative learning and memory mechanisms underlying behavior.

项目摘要 神经科学研究的一个中心目标是促进我们对细胞生理学的理解。 潜在的学习和记忆过程。研究最广泛的模型 联想学习是在细胞水平上实现的，是突触的Hebbian修饰。 然而，计算模型研究表明，这些形式的可塑性如下 正反馈规则，使得它们本质上是不稳定的。没有额外的 特征，Hebbian的可塑性可能会让位于突触强度的“无约束”变化， 导致联想学习的中断。动态平衡突触可塑性假说 在学习驱动的突触强度变化过程中，作为神经网络稳定性的基础。 突触伸缩，最广泛研究的稳态突触可塑性形式，功能 作为一种负反馈机制，双向调节细胞中的突触强度- 自主方式，以保持活动设置点。因此，突触伸缩被假设为 约束Hebbian机制的正反馈性质，同时保持 电路的特点是允许学习。尽管它有可能影响我们目前的理解 在联想学习过程中，这一假设仍未得到检验，而 突触伸缩对学习的影响仍不清楚。这项提案旨在确定 动态平衡突触伸缩在关联学习和记忆中的作用 大鼠条件性味觉厌恶(CTA)范式。首先，我会确认我可以诱导 使用体内慢性TTX注射和体外注射阻断味觉皮质突触伸缩 急性脑片电生理学。第二，我的目标是描述突触缩放性丢失对 英格拉姆兴奋性。我将对老鼠进行CTA行为范式的培训，然后执行 免疫荧光染色表征学习驱动的CTA改变的时间进程 Engram神经元兴奋性。然后，我将使用体外急性切片电生理学的组合 并以病毒介导的CTA印迹神经元为靶点来表征阻断的影响 稳态可塑性对联想学习的潜在细胞生理学的影响。最后，我会 用行为学方法确定稳态可塑性在记忆获得和消退中的作用 CTA印迹细胞的培养和体外记录。这些实验将阐明 动态平衡可塑性丧失的行为后果。此外，这项研究提案将 加深我们目前对联想学习和记忆机制的理解 潜在的行为。