Mechanisms Regulating Neuronal Survival in the Mammalian Basal Ganglia

哺乳动物基底神经节神经元存活的调节机制

• 批准号: RGPIN-2021-03853
• 负责人: Sadikot, Abbas
• 金额: $ 2.04万
• 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: 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=761355
• 关键词: Mechanisms; Regulating; Neuronal; Survival; Mammalian

Background. Our program focuses on how structure and function is determined in the mammalian basal ganglia, a key network of nuclei that modulate motor coordination, cognition and limbic related behaviour. Both cell autonomous and non-autonomous factors determine the complement of adult central nervous system (CNS) neurons. Despite significant advances in understanding the cellular machinery underlying developmental cell death, less is known of how connectivity networks determine neuronal subtypes in different brain nuclei. The classic neurotrophic hypothesis proposes that neurons faced with developmental or degenerative apoptotic stress compete for limiting concentrations of target-derived growth factors. The theory derives mainly from work in the peripheral nervous system (PNS), with less work in more complex CNS systems. However, increasing evidence suggests afferent inputs are also important determinants of survival in the CNS, matching activity to the final complement of neuronal subtypes. Our overarching goal is to determine how different afferent systems modulate the survival of highly heterogeneous striatal subpopulations that correspond to specific functional motor networks. Aims. In recent work, focused on two key basal ganglia components, the ventral midbrain and striatum, we discovered that neurotransmitter systems and neurotrophins cooperate to play a crucial anterograde trophic role, matching activity with survival of specific neuronal phenotypes. We now propose that glutamatergic thalamic (TS) or cortical (CS) striatal afferents play important developmental trophic roles, with distinct survival or differentiation effects on different neuronal subtypes (Aim #1). As a mechanism, we propose anterograde trophic signaling in the TS system by the neurotrophin brain derived neurotrophic factor (BDNF) enhances survival of specific TrkB-positive targets on a background of depolarizing glutamatergic activity (Aim #2). Furthermore, we propose the complement of TS-dependent striatal neurons is functionally relevant, modulating for example the balance between hyperkinetic/facilitatory or hypokinetic/inhibitory motor behaviour. Significance. We will help discover fundamental mechanisms by which afferents promote survival of specific neurons in the developing mammalian CNS, using the striatum as a model. Afferent-mediated rescue of TrkB-positive targets on a background of depolarizing activity may be an important mechanism for specifying the appropriate complement of striatal subtypes. The striatum is especially compelling as a model since its heterogeneous subtypes modulate different aspects of motor and non-motor behaviors. Matching target composition to afferent trophic activity may therefore represent a fundamental mechanism that determines motor function. Recapitulating similar mechanisms in the adult may implicate afferents in important maintenance roles, and also provide important insight into healthy ageing and neurodegeneration.

背景。我们的项目重点研究哺乳动物基底神经节的结构和功能是如何确定的，基底神经节是调节运动协调、认知和边缘相关行为的关键核网络。细胞自主和非自主因素决定了成人中枢神经系统（CNS）神经元的补体。尽管在理解发育性细胞死亡背后的细胞机制方面取得了重大进展，但对连接网络如何决定不同脑核中的神经元亚型知之甚少。经典的神经营养假说提出，面临发育或退行性凋亡应激的神经元会竞争靶源性生长因子的限制浓度。该理论主要来源于外周神经系统（PNS）的工作，而在更复杂的中枢神经系统中工作较少。然而，越来越多的证据表明传入输入也是中枢神经系统存活的重要决定因素，将活动与神经元亚型的最终补体相匹配。我们的首要目标是确定不同的传入系统如何调节高度异质纹状体亚群的生存，这些亚群对应于特定的功能运动网络。目标。在最近的研究中，我们主要关注两个关键的基底神经节组成部分，即腹侧中脑和纹状体，我们发现神经递质系统和神经营养因子合作发挥关键的顺行营养作用，将活性与特定神经元表型的存活相匹配。我们现在提出谷氨酸能丘脑（TS）或皮质（CS）纹状体传入事件在发育营养中起重要作用，对不同的神经元亚型具有不同的存活或分化作用（Aim #1）。作为一种机制，我们提出神经营养脑源性神经营养因子（BDNF）在TS系统中的顺行营养信号在去极化谷氨酸能活性的背景下提高特定trkb阳性靶标的存活（Aim #2）。此外，我们提出，依赖ts的纹状体神经元的补体在功能上是相关的，例如调节多动/促进或低动/抑制运动行为之间的平衡。的意义。我们将以纹状体为模型，帮助发现在发育中的哺乳动物中枢神经系统中，传入事件促进特定神经元存活的基本机制。在去极化活动的背景下，传入介导的trkb阳性靶点的拯救可能是指定纹状体亚型适当补体的重要机制。纹状体作为一个模型尤其引人注目，因为它的异质亚型调节着运动和非运动行为的不同方面。因此，将目标成分与传入营养活动相匹配可能是决定运动功能的基本机制。在成人中重述类似的机制可能涉及重要的维持作用的传入事件，也为健康衰老和神经退行性变提供了重要的见解。