The role of perineuronal nets in adult cognition

神经周围网在成人认知中的作用

• 批准号: RGPIN-2019-06102
• 负责人: Saksida, Lisa
• 金额: $ 5.68万
• 依托单位: University of Western Ontario
• 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=714604
• 关键词: role; perineuronal; nets; adult; cognition

An emerging concept in neuroscience is that brain plasticity is dependent not only on neurons and glia, but also on structures present outside of these cells. The extracellular matrixwhich comprises about 20% of the brain's volume (1) and contributes to neuronal and glial communication (2)is a prime candidate for this role. Indeed, recent evidence from my lab suggests that one extracellular matrix component called a perineuronal net (PNN) may go beyond it's established role in neurodevelopment and contribute to fundamental learning and memory processes in the adult brain. The overarching goal of this research program is to develop a comprehensive understanding of mechanisms by which PNNs are involved in adult cognition. PNNs are a component of the extracellular matrix that are primarily found wrapped around inhibitory, parvalbumin positive cortical neurons. PNNs form during development, and are central in the closure of critical periods of heightened synaptic plasticity during development to lower levels during adulthood(3). Enzymatic degradation of chondroitin sulphate proteoglycans (CSPGs), major components of PNNs, can re-open the juvenile critical period for ocular dominance plasticity in adult rats (3) and can facilitate recovery from spinal cord injury and other forms of damage to the nervous system(4,5). Synaptic plasticity is also essential for learning and memory across the lifespan(6-8), however, almost no work has investigated whether PNNs contribute to fundamental learning and memory processes in the adult brain. Recent work from my lab has shown that depletion of PNNs can enhance recognition memory in adult mice (9-11), suggesting that PNNs comprise a critical regulatory component in normal learning and memory. Moreover, recent evidence suggests that PNNs may also have an important role in neuroprotection(12). PV neurons without a surrounding PNN are more vulnerable to oxidative stress(13) which has a knock-on effect on learning and memory(14). My hypothesis is that PNNs contribute substantially to adult learning and memory processes via two primary mechanisms (i) regulation of neuroplasticity and (ii) neuroprotection. My short-term objective is to test this hypothesis by degrading PNNs in cortical regions critical for learning, memory and behavioural control, and/or manipulating levels of oxidative stress via diet, exercise, or environmental enrichment, and then assessing the mice on cognitive tests dependent on those brain regions. We predict that performance on the tests will reflect a trade-off between increased synaptic plasticity and reduced neuroprotection, so may be improved or impaired depending on how the two types of manipulation are combined. In the long term, this research program will provide valuable insight into the mechanistic underpinnings of adult learning and memory processes, and how lifestyle factors including diet, exercise, and environmental enrichment can fundamentally alter both brain and behaviour.

神经科学中的一个新兴概念是，大脑可塑性不仅依赖于神经元和神经胶质，而且还依赖于这些细胞外的结构。细胞外基质约占大脑体积的20%（1），并有助于神经元和神经胶质细胞的沟通（2），是这一作用的主要候选者。事实上，最近来自我实验室的证据表明，一种称为神经元周围网（PNN）的细胞外基质成分可能超出了它在神经发育中的既定作用，并有助于成人大脑的基本学习和记忆过程。这项研究计划的总体目标是全面了解PNN参与成人认知的机制。 PNN是细胞外基质的组分，其主要被发现包裹在抑制性的小白蛋白阳性皮质神经元周围。PNN在发育过程中形成，并且在发育期间提高突触可塑性的关键时期关闭到成年期的较低水平中起中心作用（3）。硫酸软骨素蛋白聚糖（CSPG）（PNN的主要成分）的酶促降解可重新开启成年大鼠眼优势可塑性的幼年关键期（3），并可促进脊髓损伤和其他形式的神经系统损伤的恢复（4，5）。 突触可塑性对于整个生命周期的学习和记忆也是必不可少的（6-8），然而，几乎没有研究PNN是否有助于成人大脑的基本学习和记忆过程。我的实验室最近的工作表明，PNN的耗尽可以增强成年小鼠的识别记忆（9-11），这表明PNN在正常的学习和记忆中是一个关键的调节成分。此外，最近的证据表明，PNN也可能在神经保护中发挥重要作用（12）。没有周围PNN的PV神经元更容易受到氧化应激的影响（13），这对学习和记忆具有连锁效应（14）。 我的假设是，PNNs通过两种主要机制（i）调节神经可塑性和（ii）神经保护作用对成人学习和记忆过程做出重大贡献。我的短期目标是通过降解对学习，记忆和行为控制至关重要的皮质区域中的PNN来测试这一假设，和/或通过饮食，运动或环境富集来操纵氧化应激水平，然后根据这些大脑区域评估小鼠的认知测试。我们预测，测试的表现将反映突触可塑性增加和神经保护减少之间的权衡，因此可能会改善或受损，这取决于如何将两种类型的操作相结合。 从长远来看，这项研究计划将为成人学习和记忆过程的机制基础提供有价值的见解，以及包括饮食，运动和环境丰富在内的生活方式因素如何从根本上改变大脑和行为。