The impact of prolonged environmental stress on homeostatic plasticity in the intact human cortex

人类的大脑能够深刻而迅速地适应环境变化。这种能力是学习和记忆不可或缺的一部分，并得到无数结构和功能机制的支持，这些机制统称为突触可塑性。重要的是，突触可塑性依赖于一个正反馈回路，如果不加以控制，它有可能通过诱导过度的神经放电（突触功效的不受控制的长期电位[LTP]）或完全的神经沉默（突触功效的不受控制的长期抑制[LTD]）来破坏神经网络的稳定。为了防止不稳定，第二种类型的可塑性，称为稳态可塑性，维持神经稳定在生理稳定的范围内。尽管内稳态可塑性对健康的大脑功能很重要，但我们对这一机制的理解主要是通过体外研究获得的。人类对内稳态可塑性功能相关性的研究是有限的。特别是，人类大脑如何在长时间的环境压力下保持神经稳定性仍不清楚。疼痛是一种显著的、动态的、与行为相关的环境压力源，为研究人类压力与可塑性之间的相互作用提供了一个有用的模型。利用人类实验疼痛模型，本研究的短期目标是建立一个详细的理论认识，了解在长期疼痛存在的情况下，人体初级运动皮层（M1）的稳态可塑性如何维持神经稳定性。为了实现这一目标，我的学员和我将解决五个目标：目标1)研究人类M1皮层内抑制和促进网络中兴奋性启动协议诱导的稳态可塑性对长时间疼痛的反应；目的2)研究人类M1皮层内抑制和促进网络中抑制启动协议诱导的稳态可塑性对长时间疼痛的反应；目的3)检验体内平衡反应是否局限于疼痛时肌肉的皮层表征；目的4)探讨长时间疼痛反应中突触可塑性与内稳态可塑性的关系；目的5)探讨疼痛严重程度与内稳态反应的关系。我研究的长期目标是了解突触和稳态可塑性如何相互作用，以服务于健康的大脑功能。本研究的结果将促进我们对稳态可塑性的基本理解，为人类大脑在暴露于显著的、动态的和长期的环境压力下如何平衡神经变化和神经稳定性的竞争需求提供新的数据。这些信息对于脑机接口和与学习和记忆相关的人工智能应用的发展至关重要。

The human brain is capable of profound and rapid adaptation in response to environmental change. This ability is integral to learning and memory and is underpinned by a myriad of structural and functional mechanisms, collectively known as synaptic plasticity. Importantly, synaptic plasticity relies on a positive feedback loop that, left unchecked, has the potential to destabilise neural networks through the induction of excessive neural firing (uncontrolled long-term potential [LTP] of synaptic efficacy) or complete neural silencing (uncontrolled long-term depression [LTD] of synaptic efficacy). To prevent destabilisation, a second type of plasticity, termed homeostatic plasticity, maintains neural stability within a physiologically stable range. Despite the importance of homeostatic plasticity to healthy brain function, our understanding of this mechanism has primarily been informed by studies performed in vitro. Human studies probing the functional relevance of homeostatic plasticity are limited. In particular, how the human brain maintains neural stability in the context of prolonged environmental stress remains unclear. Pain is a salient, dynamic and behaviourally relevant source of environmental stress that provides a useful model with which to study the interaction between stress and plasticity in humans. Using human experimental pain models, the short-term objective of this proposal is to develop a detailed theoretical understanding of how homeostatic plasticity maintains neural stability in the human primary motor cortex (M1) in the presence of prolonged pain. Toward this objective, my trainees and I will address five aims: aim 1) to investigate homeostatic plasticity induced by an excitatory priming protocol within intracortical inhibitory and facilitatory networks of the human M1 in response to prolonged pain; aim 2) to investigate homeostatic plasticity induced by an inhibitory priming protocol within intracortical inhibitory and facilitatory networks of the human M1 in response to prolonged pain; aim 3) to examine whether the homeostatic response is restricted to the cortical representation of the muscle in pain; aim 4) to explore the relationship between synaptic and homeostatic plasticity in response to prolonged pain and aim 5) to explore the relationship between pain severity and the homeostatic response. The long-term goal of my research is to understand how synaptic and homeostatic plasticity interact in the service of healthy brain function. The outcomes of the proposed research will advance our fundamental understanding of homeostatic plasticity, providing novel data on how the human brain balances competing demands of neural change and neural stability when the system is exposed to salient, dynamic and prolonged environmental stress. This information is essential for the development of brain-machine interfaces and artificial intelligence applications related to learning and memory.