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.

项目概要： 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 导致异常的神经连接，导致认知和行为的衰弱性缺陷。的一种方法 治疗这些疾病是利用大脑的自然可塑性机制，以恢复失去的功能， 神经刺激造成的损伤。这些塑料连接性的变化通过两个主要的识别发生 机制：赫布和稳态可塑性。根据Hebbian塑性机制， 当神经元之间的活动相关或不相关时，连接被加强或减弱， 分别基于刺激的方法试图利用这种机制来诱导塑性变化， 有限的效力，以加强连接（长时程增强，LTP），而忽略的影响， 稳态可塑性机制稳态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诱导阈值来调节神经元活动水平 根据以往的活动水平。在这里，我假设稳态可塑性在 确定赫布知情的刺激诱导的可塑性结果， 可以被设计来改善这些结果，以加强皮质皮质连接。在目标1中，我 评估减少神经元活动对Hebbian知情刺激诱导的功能连接的影响 健康和疾病状态的变化。在患病状态下，我将测量这种策略对 促进靶向皮质损伤后的功能恢复。在目标2中，我探讨了抑制 对抗赫布式刺激诱导的功能连接性的稳态可塑性机制 变化概述的研究策略将使我能够建立实验和专业技能，将推动 我的职业生涯，因为我过渡到一个博士后的位置。通过将稳态可塑性机制纳入 设计基于赫布的刺激方案，以改变目标神经连接， 拟议的研究可以改变未来神经系统疾病刺激疗法的疗效。