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

我们的研究项目旨在发现哺乳动物大脑的不同区域如何获得精确控制的不同类型的神经细胞（神经元）补体，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存活的能力。事实上，超过一半的产生的神经元死于一种被称为细胞凋亡的程序性细胞死亡。决定哪些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被称为神经营养因子的存活分子。为了获得正确的神经营养因子，神经细胞必须表达一种受体分子，该受体分子识别神经营养因子并为其生存作用提供便利。此外，更可取的是，神经细胞在其环境中对某种形式的活动作出反应而存活，从而允许激活的输入信号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。我们认为，神经营养因子脑源性神经营养因子（BDNF）是由被称为轴突终末的特定连接输入产生的，在细胞凋亡期间，当神经元还很不成熟时，轴突终末进入目标区域。这些轴突末端在脆弱神经元附近释放激活神经递质（如谷氨酸）和BDNF。激活（去极化）递质和BDNF的协同作用导致目标神经元的存活，只要它表达BDNF受体。一旦传入轴突末端与神经元之间的连接建立，BDNF和谷氨酸的协同作用就转变为生存之外的角色，包括神经元生长，最终参与正常的成人功能。我们关注的是这种新机制是如何在纹状体中起作用的，纹状体是大脑中对正常运动至关重要的部分。我们认为，从丘脑向纹状体的输入传递谷氨酸和BDNF，它们共同允许承载BDNF受体的神经元存活。最终，纹状体的不同输入取决于它们的化学组成，当它们到达时，可能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。

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.