Structural and Functional Plasticity in the Aging Brain.

在老化的大脑中，神经元发生了许多结构和功能的变化，然而其中许多变化还没有被很好地理解。在一定程度上，这是因为大脑是一个动态的结构，其结构和功能可以受到外部(即锻炼、社交)和内部(即氧化状态、钙调节)力量的调节。我的NSERC发现资助计划的主要目标将是更好地阐明这些力量如何改变老化大脑中n-甲基-D-天冬氨酸受体(NMDAR)的功能。NMDAR是一种参与多种形式突触可塑性的受体蛋白，已知对某些类型的学习和记忆至关重要。一些研究表明，NMDAR在突触活动中的作用随着年龄的增长而减弱，而L型电压门控钙通道(VGCC)的作用则增强。这种钙进入细胞的方式的改变导致细胞内钙的增加，从而更有效地激活钾通道，导致钾的外流，使细胞膜超极化。这降低了突触的可塑性，可能会使学习信息变得更加困难。我们最近有两项发现支持这一假设。首先，我们已经证明，通过调节NMDAR的氧化还原状态，可以在衰老的大脑中恢复NMDAR依赖的可塑性。其次，我们确定了结构可塑性与学习成绩之间的关系。我们的新数据表明，老化大脑中神经发生的速度与学习新信息所使用的策略类型密切相关，而不是与表现本身有关。我们希望确定，增强大脑处理氧化应激的能力是否会增加神经发生以及NMDA受体的作用，并导致学习策略转向年轻动物更常用的学习策略。这项工作将是非常新颖的，因为它将确定是否可以通过调节雄性和雌性动物大脑中的氧化状态来逆转与年龄相关的大脑功能变化。这项工作将使用最先进的行为学、电生理学、免疫组织化学和分子技术来研究老化的大脑。

There are a number of structural and functional changes in neurons that occur in the aging brain, however many of these changes are not well understood. In part, this is because the brain is a dynamic structure whose structure and function can be regulated by both external (i.e. exercise, social interactions) and internal (i.e. oxidative state, calcium regulation) forces. The main objective of my NSERC Discovery Grant program will be to better elucidate how these forces alter the function of n-methyl-D-aspartate receptors (NMDAr) in the aging brain. The NMDAr is a receptor protein involved in many forms of synaptic plasticity, and is known to be critical for certain types of learning and memory. Several studies have shown that the role of the NMDAr in synaptic events diminishes with age, while the role of L-type voltage gated calcium channels (VGCCs) increases. This shift in the way calcium enters the cell results in a rise in intracellular calcium that more potently activates potassium channels, resulting in an efflux of potassium that hyperpolarizes the cell membrane. This decreases synaptic plasticity and may make it harder to learn information. We have two recent findings supporting this hypothesis. First, we have shown that NMDAr dependent plasticity can be restored in aged brains by regulating the redox state of NMDArs. Second we have determined a relationship between structural plasticity and learning performance. Our new data shows that the rate of neurogenesis in the aging brain is tightly coupled to the types of strategies used to learn new information, but not to performance per se. We hope to determine if enhancing the capacity of the brain to handle oxidative stress will increase neurogenesis, as well as the role of NMDA receptors, and result in a shift to learning strategies to those that are more commonly employed by younger animals. This work will be extremely novel because it will determine if age-associated changes in brain function can be reversed by modulating the state of oxidation in the brain in both male and female animals. The work will employ state-of-the-art behavioural, electrophysiological, immunohistochemical and molecular techniques to study the aging brain.