Co-engineering Hebbian and Homeostatic Plasticity Mechanisms to Induce Targeted Functional Neural Connectivity Changes

项目总结： 我们的记忆和行为是由数万亿个突触之间连接的可塑性变化编码的 连接我们大脑中的神经元。神经性疾病，如精神分裂症、癫痫和中风 导致异常的神经连接，导致认知和行为的衰弱缺陷。一种方法是 治疗这些疾病的方法是利用大脑的自然可塑性机制来恢复失去的功能 通过神经刺激造成的伤害。这些塑料连通性的变化通过两个主要确定的 机制：Hebbian和动态平衡可塑性。根据Hebbian塑性机制， 当神经元之间的活动相关或不相关时，连接会加强或减弱， 分别进行了分析。基于刺激的方法试图利用这种机制来诱导塑料变化 加强连通性的效果有限(长时程增强，LTP)，同时忽略了 动态平衡可塑性机制。动态平衡可塑性机制改变连接性以保持一致性 通过改变突触强度、抑制水平和LTP诱导阈值来提高神经元活性水平 基于之前的活动水平。在这里，我假设动态平衡可塑性在 确定Hebbian信息刺激诱导的可塑性结果以及可塑性的两种机制 可以设计成改善这些结果，以加强皮质连接。在目标1中，我 评估神经元活动减少对Hebbian信息刺激诱导的功能连接的影响 健康和患病状态的变化。在患病的状态下，我将衡量这一战略对 促进靶向皮质损伤后的功能恢复。在目标2中，我探索了抑制 对抗Hebbian信息刺激诱导的功能连接的稳态可塑性机制 改变。概述的研究战略将使我能够建立实验和专业技能，从而推动 当我过渡到博士后职位时，我的职业生涯。通过将动态平衡可塑性机制整合到 针对靶向神经连接改变的基于Hebbian的刺激方案的设计，研究结果 拟议的研究可以改变未来以刺激为基础的治疗神经疾病的疗效。

Project Summary: Our memories and behaviors are encoded by the plastic changes in connectivity between the trillions of synapses connecting the neurons in our brains. Neurological disorders such as schizophrenia, epilepsy, and stroke often result in aberrant neural connectivity that causes debilitating deficits in cognition and behavior. One approach to treating these disorders is to harness the brain’s natural plasticity mechanisms to restore lost function following injury through neural stimulation. These plastic connectivity changes occur through two main identified mechanisms: Hebbian and homeostatic plasticity. In accordance with Hebbian plasticity mechanisms, connections are strengthened or weakened when activity between neurons is correlated or uncorrelated, respectively. Stimulation-based approaches attempt to utilize this mechanism for inducing plastic changes with limited efficacy to strengthen connectivity (long-term potentiation, LTP), while neglecting the effects of homeostatic plasticity mechanisms. Homeostatic plasticity mechanisms alter connectivity to maintain consistent neuronal activity levels by modifying synaptic strengths, levels of inhibition, and the threshold for LTP induction based on previous activity levels. Here, I hypothesize that homeostatic plasticity plays a significant role in determining Hebbian-informed stimulation-induced plasticity outcomes and that both mechanisms of plasticity can be engineered to improve these outcomes towards strengthening corticocortical connectivity. In aim 1, I assess the impact of reducing neuronal activity on Hebbian-informed stimulation-induced functional connectivity changes in healthy and diseased states. In the diseased state, I will measure the impact of this strategy on promoting functional recovery following targeted cortical lesioning. In aim 2, I explore the suppression of homeostatic plasticity mechanisms that oppose Hebbian-informed stimulation-induced functional connectivity changes. The outlined research strategy will allow me to build experimental and professional skills that will propel my career as I transition into a postdoctoral position. By incorporating homeostatic plasticity mechanisms in the design of Hebbian-based stimulation protocols for targeted neural connectivity change, the findings of the proposed study can transform the efficacy of future stimulation-based therapies for neurological disorders.