Fundamental astrocyte-neuronal coupling mechanisms in neuroplasticity of nociceptive circuits.

神经可塑性是所有类型的经验驱动的、长期改变大脑功能的基础。这是一个促进行为持久变化的基本过程，例如伤害性过敏症。虽然大多数关于大脑可塑性的研究都集中在神经元上，但似乎也有其他几种细胞类型参与其中。星形胶质细胞是一种胶质细胞，是中枢神经系统中含量最丰富的细胞，虽然经典地被认为是支持性细胞，但最近的证据表明，它们在神经可塑性中发挥着积极的作用。令人兴奋的新发现表明，伤害性超敏反应增加了中枢神经系统内的星形胶质细胞活动。我最近发现，在大鼠海马区，在联想学习过程中，星形胶质细胞-神经元乳酸的穿梭为神经元提供了与记忆形成有关的神经元变化所必需的能量底物，包括对长期记忆至关重要的几种蛋白质的翻译。多项研究表明，伤害性超敏和长时记忆与许多相似的分子机制和神经元活动的变化相对应。然而，伤害性诱导的神经可塑性是否参与星形胶质细胞-神经元乳酸的穿梭，以及它是否对伤害性超敏的发展是必要的，还没有得到测试。 我的研究项目将使用伤害性超敏反应作为经验诱导可塑性的模型。这项研究的长期目标是描述星形胶质细胞与神经元的相互作用在涉及伤害性感觉的大脑网络内的神经可塑性变化中的特征。我们将首先验证星形胶质细胞-神经元乳酸穿梭与伤害性感觉和伤害性超敏密切相关的假说。我未来五年的研究计划的具体目标是：1)展示伤害性高敏感性发展对星形胶质细胞-神经元乳酸穿梭的时间效应；2)论证伤害性刺激期间星形胶质细胞-神经元乳酸在mPFC中的穿梭是否是行为反应和伤害性感受脑回路中伤害性诱导的活动所必需的；3)论证星形胶质细胞-神经元代谢偶联在伤害性敏感中的必要性。使用伤害性超敏反应作为神经可塑性的模型，我们的实验室将确定星形胶质细胞-神经元耦合在神经元功能长期变化中的关键作用。这项研究计划将使我们的实验室在研究大脑可塑性的基本机制方面处于领先地位。

Neuroplasticity underlies all types of experience-driven, long-term changes brain function. It is a fundamental process that promotes lasting changes in behaviour, such as nociceptive hypersensitivity. Although most research on brain plasticity has focused on neurons, several other cell types also appear to be involved. Astrocytes, a type of glial cell, are the most abundant cells in the central nervous system, and although classically considered supportive cells, recent evidence indicates that they are dynamic players in neuroplasticity. Exciting new findings indicate that nociceptive hypersensitivity increases astrocytic activity within the central nervous system. I have recently shown that, in the rat hippocampus, astrocyte-neuronal lactate shuttling during associative learning provides neurons with energy substrates that are necessary for neuronal changes involved in memory formation, including translation of several proteins that are critical for long-term memory. Multiple lines of research indicate that nociceptive hypersensitivity and long-term memory correspond with many similar molecular mechanisms and changes in neuronal activity. However, whether nociception-induced neuroplasticity engages astrocyte-neuronal lactate shuttling, and whether it is necessary for the development of nociceptive hypersensitivity has not been tested. My research program will employ nociceptive hypersensitivity as a model of experience-induced plasticity. The long-term objective of this research is to characterize astrocyte-neuronal interactions in neuroplastic changes within brain networks involved in nociception. We will first test the hypothesis that astrocyte-neuronal lactate shuttling is critically involved in nociception and nociceptive hypersensitivity. The specific objectives of my research program over the next five years are, 1) to demonstrate temporal effects of nociceptive hypersensitivity development on astrocyte-neuronal lactate shuttling; 2) to demonstrate whether astrocyte-neuronal lactate shuttling in the mPFC during noxious stimulation is necessary for behavioural responses and nociception-induced activity in the nociceptive brain circuit; and 3) to demonstrate the necessity of astrocyte-neuronal metabolic coupling in nociceptive hypersensitivity. Using nociceptive hypersensitivity as a model of neuroplasticity, our laboratory will identify the critical contributions of astrocyte-neuronal coupling in long term changes in neuronal function. This research program will establish our lab as a leader in the study of basic mechanisms of brain plasticity.