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、长期的大脑功能变化的基础。这是一个促进行为持久变化的基本过程，例如伤害性超敏反应。尽管大多数关于大脑可塑性的研究都集中在神经元上，但其他几种细胞类型似乎也参与其中。星形胶质细胞是一种胶质细胞，是中枢神经系统中最丰富的细胞，虽然传统上被认为是支持细胞，但最近的证据表明它们是神经可塑性的动态参与者。令人兴奋的新发现表明，伤害性超敏反应会增加中枢神经系统内星形胶质细胞的活性。我最近的研究表明，在大鼠海马体中，联想学习期间星形胶质细胞-神经元乳酸穿梭为神经元提供了能量基质，这是参与记忆形成的神经元变化所必需的，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，伤害性超敏反应和长期记忆具有许多相似的分子机制和神经元活动的变化。然而，伤害感觉诱导的神经可塑性是否参与星形胶质细胞-神经元乳酸穿梭，以及它是否对伤害感觉超敏反应的发展是必要的，尚未得到证实。我的研究项目将使用伤害性超敏反应作为经验诱发可塑性的模型。这项研究的长期目标是表征星形胶质细胞-神经元的相互作用，在大脑网络中涉及伤害感觉的神经可塑性变化。我们将首先验证星形胶质细胞-神经元乳酸穿梭在伤害感觉和伤害性超敏反应中起关键作用的假设。我在未来五年的研究计划的具体目标是：1)证明伤害性超敏反应的发展对星形胶质细胞-神经元乳酸穿梭的时间效应；2)证明在有害刺激下，脑皮层星形胶质细胞-神经元乳酸穿梭是否对行为反应和伤害性脑回路中伤害性诱导的活动是必要的；3)阐明星形胶质细胞-神经元代谢耦合在痛觉性超敏反应中的必要性。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贡献。这个研究项目将使我们的实验室成为大脑可塑性基本机制研究的领导者。

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.