Dual-hit hypothesis of aging-related DA dysfunction

描述（由申请人提供）：众所周知，老年大脑经历一系列微妙但渐进的变化，最终导致神经元功能改变，并最终改变个体的行为。与认知表现的年龄相关下降一起，还发现大多数老年人的运动功能经历稳定和进行性下降。中脑多巴胺能神经元，这是重要的运动活动的调节，似乎是特别容易受到年龄相关因素，导致一个特定的增加，在神经退行性疾病折磨这些神经元，如帕金森氏病（PD）与年龄。该计划项目资助的重点是了解为什么中脑多巴胺神经元选择性地易受环境和内源性因子的影响，导致衰老过程中功能和结构的丧失。我们将沿着一个整体的“双重打击”假说，提出这是一个综合的内源性无法科普氧化应激和外部因素使其变得更糟，导致这些神经元的选择性退化，在一些人，而不是其他人在衰老过程中。每个项目都致力于了解中脑多巴胺能系统的功能和形态与年龄相关的恶化，重点是特定的内在和外在损害事件后的运动障碍。为此，该项目（项目0001-0005）中的所有主要项目将提供对运动障碍的三种特定决定因素的不同水平的分析，即：生长因子减少（内在、遗传改变）、内毒素暴露（产前外在因素，LPS）和甲基苯丙胺暴露（年轻成年小鼠的外在因素）。动物核心将提供所有主题，以保证每个项目之间的一致性，从而促进将不同研究方法中出现的发现统一到可能影响该递质系统老化影响的因素的神经生物学基础的连贯理解中的能力。受试者将在多个分析层次进行检查，包括细胞（项目0001 - 0004），组织培养（项目0005）和行为（项目0001和2）。项目0003将从神经炎症的角度整合不同的治疗（GDNF/BDNF部分缺失，LPS治疗和甲基苯丙胺），项目0004将从深入分析神经传递本身的角度检查相同的三个因素。最后，项目0005将检查通过分离切片培养或移植中的脑区域（黑质和纹状体）观察到的改变的内在与外在决定因素。这种围绕动物模型（GDNF/BDNF敲除）与外部因素的主题整合将把研究活动的多个维度集中在一个问题上（与年龄相关的运动功能下降），目的是提供一个相对完整的描述与年龄相关的多巴胺神经元细胞功能障碍导致运动障碍的神经学基础。

DESCRIPTION (provided by applicant): It is well known that the aged brain undergoes a series of subtle but progressive alterations that eventually lead to altered neuronal function and, ultimately, altered behavior of the individual. Together with the well-described age related decline in cognitive performance, it has also been found that motor function undergoes a steady and progressive decline in most aged humans. The midbrain dopaminergic neurons, which are important for regulation of motor activity, appear to be especially vulnerable to age-related factors, leading to a specific increase in neurodegenerative disorders afflicting these neurons, such as Parkinson's disease (PD) with age. This program project grant is focused on understanding why midbrain dopamine neurons are selectively vulnerable to environmental and endogenous agents, leading to lost function and structure during aging. We will work along an overall "dual-hit" hypothesis, proposing that it is a combined endogenous inability to cope with oxidative stress and external factors making it worse that leads to a selective degeneration of these neurons in some individuals but not others during aging. Every project is devoted to the understanding of age-related deterioration in the function and morphology of the midbrain dopaminergic system, with a focus on motor impairment following specific intrinsic and extrinsic damaging events. To this end, all primary projects in the program (Project 0001-0005) will provide a distinct level of analysis of three specific determinants of motor impairment, namely: growth factor reduction (intrinsic, genetic alteration), endotoxin exposure (prenatal extrinsic factor, LPS), and methamphetamine exposure (extrinsic factor to young adult mice). The Animal Core will provide all subjects to guarantee consistency between each project, and thereby facilitate the capacity to unite discoveries emerging from different research approaches into a coherent understanding of the neurobiological basis of factors that might affect the impact of aging in this transmitter system. The subjects will be examined at many levels of analysis, including cellular (Projects 0001 - 0004), tissue culture (Project 0005) and behavioral (Project 0001 and 2). Project 0003 will integrate the different treatments (GDNF/BDNF partial deletion, LPS treatment, and methamphetamine) from the perspective of neuroinflammation, and Project 0004 will examine the same three factors from the perspective of in-depth analysis of neurotransmission itself. Finally, Project 0005 will examine intrinsic versus extrinsic determinants of the alterations observed by isolating the brain regions (substantia nigra and striatum) in slice cultures or transplants. This thematic integration around an animal model (GDNF/BDNF knockouts) with external factors will focus multiple dimensions of research activity on a single problem (age-related decreased motor function) with the goal of providing a relatively complete description of the neurological basis of age-related dopamine neuron cell dysfunction leading to motor impairment.