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

人类大脑能够深刻而快速地适应环境变化。这种能力是学习和记忆的组成部分，并由无数的结构和功能机制支撑，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，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，在生理稳定范围内保持神经稳定性。 尽管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来自体外研究。人类研究探索稳态可塑性的功能相关性是有限的。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然不清楚。疼痛是一个突出的，动态的和行为相关的环境压力源，提供了一个有用的模型，研究人类的压力和可塑性之间的相互作用。使用人类实验疼痛模型，本提案的短期目标是发展一个详细的理论理解，在长期疼痛的存在下，稳态可塑性如何维持人类初级运动皮层（M1）的神经稳定性。为了实现这一目标，我和我的学员将致力于五个目标：目标1）研究兴奋性启动方案在人类M1的皮层内抑制和易化网络中诱导的稳态可塑性，以响应长时间的疼痛;目标2）研究抑制性启动方案在人类M1的皮层内抑制和易化网络中诱导的稳态可塑性，以响应长时间的疼痛;目的3）检查稳态反应是否仅限于疼痛时肌肉的皮质表征;目的4）探索突触可塑性和稳态可塑性在对长时间疼痛的反应中的关系;目的5）探索疼痛严重程度和稳态反应之间的关系。 我研究的长期目标是了解突触和稳态可塑性如何在健康的大脑功能中相互作用。拟议研究的结果将推进我们对稳态可塑性的基本理解，提供关于当系统暴露于显著，动态和长期环境压力时，人脑如何平衡神经变化和神经稳定性的竞争需求的新数据。这些信息对于开发与学习和记忆相关的脑机接口和人工智能应用至关重要。

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.