Basic Mechanisms of Neuronal Development, Maintenance and Function in the Basal Ganglia

基底神经节神经元发育、维持和功能的基本机制

• 批准号: 327117-2013
• 负责人: Sadikot, Abbas
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630997
• 关键词: Basic; Mechanisms; Neuronal; Development; Maintenance

Our research program aims at discovering how different areas of the mammalian brain acquire a precisely controlled complement of diverse types of nerve cells (neurons) and form the right connections. The developing nervous system generates far more neurons than can survive. Indeed, over half the neurons that are produced die by a form of programmed cell death known as apoptosis. A major factor determining which neuron subtypes survive is whether they are able to get adequate access to survival molecules known as neurotrophins. In order to acquire the correct neurotrophin, the nerve cell must express a receptor molecule, which recognizes the neurotrophin and facilities its survival action. Furthermore, it is preferable that nerve cells survive in response to some form of activity in their environment, allowing for a matching of activating input fivers, with the correct number and type of neurons to be ultimately available for healthy function of the adult nervous system.We propose that the neurotrophin brain-derived neurotrophic factor (BDNF) is produced by specific connecting inputs called axon terminals, which enter the target area of interest during the apoptosis period while neurons are still quite immature. These axons terminals release both activating neurotransmitters (e.g. glutamate) and BDNF in the vicinity of the vulnerable neurons. A cooperative action of the activating (depolarizing) transmsitter and BDNF results in survival of the target neurons provided it expresses the BDNF receptor. Once the connections between the incoming axon terminal and the neuron is established, the cooperative action of BDNF and glutamate is transformed into roles beyond survival, including neuron growth and finally participating of normal adult function. We focus of how this novel mechanism works in the striatum, a part of the brain that is crucial to normal movements. We propose that inputs to the striatum from the thalamus deliver glutamate and BDNF, which together allow BDNF receptor bearing neurons to survive. Ultimately, different inputs to the striatum depending on their chemical make-up, and when they arrive, may allow distinct subsets of neurons to survive. This input-mediated survival mechanism may be a major factor allowing for survival of precise subtypes of neurons which make up the adult brain.

我们的研究计划旨在发现哺乳动物大脑的不同区域如何获得精确控制的各种类型的神经细胞（神经元）并形成正确的连接。发育中的神经系统产生的神经元远远超过其生存能力。事实上，超过一半的神经元是通过一种被称为细胞凋亡的程序性细胞死亡而死亡的。决定神经元亚型存活的一个主要因素是它们是否能够获得足够的生存分子，即神经营养因子。为了获得正确的神经营养因子，神经细胞必须表达受体分子，该受体分子识别神经营养因子并促进其存活作用。此外，神经细胞最好能对环境中的某种形式的活动作出反应而存活，从而使激活的输入纤维与正确数量和类型的神经元相匹配，最终可用于成人神经系统的健康功能。我们提出，神经营养蛋白脑源性神经营养因子（BDNF）是由称为轴突终末的特定连接输入产生的，其在细胞凋亡期间进入感兴趣的靶区域，而神经元仍然非常不成熟。这些轴突末梢在脆弱神经元附近释放激活性神经递质（例如谷氨酸）和BDNF。激活（去极化）transmissitter和BDNF的协同作用导致靶神经元的存活，前提是它表达BDNF受体。一旦传入轴突终末和神经元之间的连接建立起来，BDNF和谷氨酸的合作作用就转变为超越生存的作用，包括神经元生长和最终参与正常的成人功能。我们专注于这种新机制如何在纹状体中工作，这是大脑的一部分，对正常运动至关重要。我们认为，从丘脑到纹状体的输入传递谷氨酸和BDNF，它们一起允许携带BDNF受体的神经元存活。最终，根据纹状体的化学组成以及它们到达的时间，不同的输入可能会允许不同的神经元子集存活。这种输入介导的存活机制可能是构成成人大脑的神经元精确亚型存活的主要因素。