Exercise and hippocampal bidirectional synaptic plasticity

运动与海马双向突触可塑性

• 批准号: RGPIN-2019-06104
• 负责人: Christie, Brian
• 金额: $ 2.91万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760797
• 关键词: Exercise; hippocampal; bidirectional; synaptic; plasticity

In 1999 we showed for the first time that voluntary exercise can enhance the production of new neurons in the adult hippocampus (called adult neurogenesis) and facilitate spatial memory, a cognitive function that the hippocampus is believed to support. My initial NSERC funding in 2001 allowed me to establish this research program in Canada, and using both mice and rats, we went on to show that exercise can alter the neuro-circuitry of the hippocampus, and enhance the capacity for neurons to communicate with one another (a process called long-term potentiation (LTP) of synaptic efficacy). We subsequently went on to show that exercise also benefited existing cells, helping neurons to grow and sprout more branches and synaptic spines, much like fertilizer can help plants grow and develop more. These structural improvements were also accompanied by functional changes, making these cells more capable of communicating with other cells, and also improving learning and memory performance in the animals that exercised. Thus far, there is considerable evidence to indicate that exercise makes for a more dynamic hippocampus and enhances learning capacity, while animals that do not engage in exercise have a hippocampus that is both morphologically and functionally more restricted and static. Our current work continues to be focused on examining the mechanisms that allow exercise to be beneficial for hippocampal structure and function, however we have expanded our focus to include peripheral signaling molecules. Most of the focus to date has been on how exercise enhances brain-derived neurotrophic factor (BDNF), a growth factor that plays an important role in the growth and differentiation of new neurons. While BDNF is a key factor in mediating the effects of exercise, we have new evidence that indicates that peripheral signalling mechanisms also can play a direct role, possibly by affecting BDNF. Our research program intends to explore two signalling cascades related to the effects of exercise on muscle and adipocytes (fat cells). It has recently been shown that exercise can induce BDNF expression by acting though a PGC-1alpha/FNDC5 pathway. FNDC5 is a small protein, or myokine, that is released from muscles during exercise. Myokines are secreted as glycosylated type 1 membrane proteins. The secreted form of FNDC5 is called irisin, and we have preliminary data that irisin can directly impact synaptic plasticity in the hippocampus. Adiponectin, is a protein-hormone that is secreted from adipocytes into the bloodstream after exercise. Adiponectin receptors are highly expressed in the hippocampus (i.e. ADIPOR1 and ADIPOR2) and their activation leads to the phosphorylation of AMPK (5' adenosine monophosphate-activated protein kinase). AMPK is involved in regulating BDNF expression, and we believe that BDNF induction may be related to the ability of AMPK to activate PGC1-alpha signaling, suggesting a link between adiponectin and irisin release during exercise.

1999年，我们首次表明，自愿锻炼可以促进成人海马区新神经元的产生(称为成人神经发生)，并促进空间记忆，这是海马体据信支持的一种认知功能。2001年，我最初获得NSERC的资助，这让我在加拿大建立了这个研究项目，我们使用小鼠和大鼠，继续证明运动可以改变海马体的神经电路，并增强神经元相互交流的能力(这一过程被称为突触功效的长期增强(LTP))。我们随后继续证明，锻炼也有利于现有的细胞，帮助神经元生长和萌发更多的分支和突触刺，就像肥料可以帮助植物生长和发育一样。这些结构的改进还伴随着功能的变化，使这些细胞更有能力与其他细胞交流，也改善了运动动物的学习和记忆表现。到目前为止，有相当多的证据表明，运动有助于形成更具活力的海马体，并增强学习能力，而不参加运动的动物的海马体在形态和功能上都更加受限和静止。我们目前的工作仍然集中在研究运动对海马体结构和功能有益的机制，但我们已经将重点扩大到包括外周信号分子。到目前为止，大多数关注的焦点是运动如何增强脑源性神经营养因子(BDNF)，这是一种在新神经元的生长和分化中发挥重要作用的生长因子。虽然BDNF是调节运动效果的关键因素，但我们有新的证据表明，外周信号机制也可以发挥直接作用，可能是通过影响BDNF。我们的研究计划打算探索与运动对肌肉和脂肪细胞(脂肪细胞)的影响有关的两个信号级联。最近的研究表明，运动通过PGC-1α/FNDC5途径诱导BDNF的表达。FNDC5是一种小蛋白或肌肉因子，在运动过程中从肌肉中释放出来。肌动蛋白是以糖基化的1型膜蛋白的形式分泌的。FNDC5的分泌形式被称为虹膜蛋白，我们有初步数据表明，虹膜蛋白可以直接影响海马区突触的可塑性。脂联素是一种蛋白质荷尔蒙，运动后从脂肪细胞分泌到血液中。脂联素受体在海马区高表达(即AdipoR1和AdipoR2)，它们的激活导致AMPK(5‘-腺苷一磷酸活化蛋白激酶)的磷酸化。AMPK参与调节BDNF的表达，我们认为BDNF的诱导可能与AMPK激活PGC1-α信号的能力有关，提示脂联素与运动中虹膜蛋白的释放有关。