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

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。最广泛研究的模型是 在细胞水平上实现的联想学习是突触的Hebbian修改。 然而，计算建模研究表明，这些形式的可塑性遵循 正反馈规则，使它们本质上不稳定。无需额外 特征，赫布可塑性可能让位于突触强度的“不受约束”的变化， 导致联想学习的中断。稳态突触可塑性假设 在学习驱动的突触强度变化过程中成为神经网络稳定性的基础。 突触缩放是稳态突触可塑性研究最广泛的形式， 作为一种负反馈机制，在细胞中双向调节突触强度， 自主的方式，以保持活动设定点。因此，假设突触缩放 限制Hebbian机制的正反馈性质，同时保持 电路特性允许学习。尽管它有可能影响我们目前的理解 联想学习过程，这一假设仍然没有得到验证， 破坏的突触缩放对学习的影响仍然未知。该提案旨在确定 内稳态突触缩放在联合学习和记忆中的作用 条件性味觉厌恶（CTA）模型。首先，我会确认我可以诱导 并使用体内慢性TTX输注和离体 急性切片电生理学其次，我的目标是表征突触缩放损失对 记忆痕迹兴奋性我将训练大鼠的CTA行为模式， 免疫荧光染色以表征CTA中学习驱动变化的时间过程 神经元兴奋性然后，我将使用离体急性切片电生理学 和病毒介导的靶向CTA印迹神经元，以表征阻断的 内稳态可塑性的基础细胞生理学的联想学习。最后，我将 使用行为记忆来确定内稳态可塑性在记忆获得和消失中的作用 CTA印迹细胞的训练和离体记录。这些实验将阐明 失去稳态可塑性的行为后果。此外，这项研究计划将 推进我们目前对联想学习和记忆机制的理解 潜在行为

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.