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

伤害感受回路神经可塑性的基本星形胶质细胞-神经元耦合机制。

• 批准号: RGPIN-2020-04000
• 负责人: Descalzi, Giannina
• 金额: $ 2.4万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716761
• 关键词: Fundamental; astrocyte; neuronal; coupling; mechanisms

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.

神经可塑性是所有类型的经验驱动的长期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，如伤害性超敏反应。虽然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。星形胶质细胞是神经胶质细胞的一种，是中枢神经系统中最丰富的细胞，尽管经典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，伤害性超敏反应增加了中枢神经系统内的星形胶质细胞活性。我最近发现，在大鼠海马中，星形胶质细胞-神经元乳酸穿梭在联想学习过程中为神经元提供了能量底物，这些底物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。多方面的研究表明，伤害性超敏反应和长期记忆与许多类似的分子机制和神经元活动的变化相对应。 然而，伤害性感受诱导的神经可塑性是否涉及星形胶质细胞-神经元乳酸穿梭，以及它是否是伤害性超敏反应发展所必需的尚未得到测试。 我的研究计划将采用伤害性超敏反应作为经验诱导可塑性的模型。本研究的长期目标是描述星形胶质细胞-神经元相互作用在涉及伤害感受的脑网络内的神经可塑性变化中的特征。我们将首先测试的假设，星形胶质细胞神经元乳酸穿梭是至关重要的参与伤害性和伤害性超敏反应。本研究计划在未来五年内的具体目标是：1）证明伤害性超敏反应发展对星形胶质细胞-神经元乳酸穿梭的时间效应; 2）证明伤害性刺激期间星形胶质细胞-神经元乳酸穿梭于mPFC中是否是行为反应和伤害性脑回路中伤害性感受诱导的活动所必需的;（3）证明星形胶质细胞-神经元代谢偶联在伤害性超敏反应中的必要性。我们的实验室将伤害性超敏反应作为神经可塑性的模型，确定星形胶质细胞-神经元偶联在神经元功能长期变化中的关键作用。该研究计划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。