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

共同设计赫布和稳态可塑性机制以诱导有针对性的功能性神经连接变化

• 批准号: 10754414
• 负责人: Karam Khateeb
• 金额: $ 4.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754414
• 关键词: Affect; Anatomy; Animal Model; Behavior; Brain; Categories; Cognition; Complex; Development; Disease; Educational process of instructing; Electric Stimulation; Engineering; Epilepsy; Exhibits; Feedback; Future; Genetic; Goals; Growth; Human; Injury; Lesion; Long-Term Potentiation; Macaca mulatta; Measures; Memory; Mentors; Methods; Nature; Neurologic Deficit; Neurons; Outcome; Phase; Physiological; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Protocols documentation; Publishing; Recovery of Function; Research; Research Personnel; Research Project Grants; Rodent; Role; Schizophrenia; Sensory Deprivation; Site; Stroke; Synapses; Synaptic plasticity; Technical Expertise; Techniques; Technology; Testing; Viral; behavior measurement; career; design; excitatory neuron; experience; experimental study; functional restoration; improved outcome; in vivo; injury recovery; insight; neglect; nervous system disorder; neural; neural circuit; neural stimulation; nonhuman primate; optogenetics; postsynaptic; postsynaptic neurons; presynaptic neurons; receptive field; skills; tool

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.

项目摘要： 我们的记忆和行为是由数万亿突触之间的连通性变化编码的 连接我们大脑中的神经元。精神分裂症，癫痫和中风等神经系统疾病经常 导致异常的神经元连通性导致衰弱的认知和行为定义。一种方法 治疗这些疾病是要利用大脑的自然可塑性机制来恢复损失的功能 通过神经刺激受伤。这些塑料连通性的变化通过两个主要确定的 机制：Hebbian和稳态可塑性。根据Hebbian可塑性机制， 当神经元之间的活动相关或不相关时，连接会加强或弱化， 基于刺激的方法试图利用这种机制进行诱导的塑料变化 有效增强连通性的有效性（长期增强，LTP），同时忽略了 稳态可塑性机制。稳态可塑性机制改变了连通性以保持一致 神经元活性水平通过修饰突触强度，抑制水平和LTP诱导阈值 基于先前的活动水平。在这里，我假设稳态可塑性在 确定Hebbian信息的模拟诱导的可塑性结果，并确定可塑性的两种机制 可以设计以改善这些结果来增强皮质皮质连通性。在AIM 1中，我 评估减少神经元活动对HEBBIAN信息模拟诱导的功能连通性的影响 健康和患病状态的变化。在患病状态下，我将衡量该策略对 靶向皮质病变后促进功能恢复。在AIM 2中，我探索了对 反对HEBBIAN信息模拟诱导的功能连接的稳态可塑性机制 更改。概述的研究策略将使我能够建立实验和专业技能，以推动 当我过渡到博士后职位时，我的职业生涯。通过将体内稳态可塑性机制纳入 基于HEBBIAN的仿真协议的设计，用于针对性神经连通性变化， 拟议的研究可以改变未来基于刺激的神经系统疾病的有效性。