Central Noradrenergic Neuron Subtype Development and Function

中枢去甲肾上腺素能神经元亚型的发育和功能

• 批准号: 10253784
• 负责人: Patricia Jensen
• 金额: $ 332.55万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253784
• 关键词: Address; Area; Attention; Behavior; Behavioral; Brain Stem; Cells; Cognition Disorders; Desire for food; Development; Disease; Emotions; Exposure to; Functional disorder; Genetic; Goals; Investigation; Learning; Life; Long-Term Effects; Memory; Molecular; Mood Disorders; Mus; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Norepinephrine; Phenotype; Physiological; Population Heterogeneity; Predisposition; Role; Signal Transduction; Stress; Structure; System; Toxic Environmental Substances; critical period; developmental genetics; developmental neurobiology; genetic approach; insight; mouse model; neuron development; noradrenergic; organizational structure; response; toxicant; virtual; virus genetics

Brainstem noradrenergic neurons comprise a small yet diverse population of cells that project to virtually all areas of the central nervous system. Through the release of norepinephrine, these neurons modulate functions as diverse as attention, emotion, appetite, memory, and response to stress. Consistent with this functional diversity, norepinephrine signaling is disrupted in a spectrum of neurodegenerative and neurodevelopmental disorders, and following exposure to a number of environmental toxicants. Interestingly, it has been observed that subpopulations of noradrenergic neurons are differentially susceptible to disease and following exposure to certain toxicants. Given these observations, we suspect that the key to understanding noradrenergic system dysfunction will not be found by focusing on the system as a whole. Rather, this phenotypic complexity will only be understood by uncovering the developmental and genetic factors that define unique functional subtypes of noradrenergic neurons. In pursuit of this goal, we investigate the development, organization, and function of genetically defined subsets of noradrenergic neurons in the mouse central nervous system. Our central hypothesis is that genetic and environmental perturbation of distinct noradrenergic neuron subtypes early in development result in enhanced susceptibility to cognitive and affective disorders later in life. To address this hypothesis, we generate and utilize viral and genetics strategies in mouse models to: 1) identify molecularly distinct subsets of noradrenergic neurons; 2) determine their structural organization; 3) determine their role in modulating stress-related behaviors and learning; and 4) perturb their function to uncover critical periods of noradrenergic neuron development and the long-term effect of these perturbations on structure and function.

脑干去甲肾上腺素能神经元包括投射到中枢神经系统的几乎所有区域的小而多样的细胞群体。通过释放去甲肾上腺素，这些神经元调节各种功能，如注意力、情绪、食欲、记忆和对压力的反应。与这种功能多样性一致，去甲肾上腺素信号传导在神经退行性和神经发育障碍的范围内以及暴露于许多环境毒物后被破坏。有趣的是，已经观察到去甲肾上腺素能神经元的亚群对疾病和暴露于某些毒物后的易感性不同。鉴于这些观察结果，我们怀疑理解去甲肾上腺素能系统功能障碍的关键不会通过关注整个系统来找到。相反，这种表型的复杂性将只能通过揭示定义去甲肾上腺素能神经元的独特功能亚型的发育和遗传因素来理解。为了实现这一目标，我们研究了小鼠中枢神经系统中去甲肾上腺素能神经元的遗传定义子集的发育、组织和功能。我们的中心假设是，不同的去甲肾上腺素能神经元亚型的遗传和环境干扰早期发展的结果在认知和情感障碍的易感性增强以后的生活。为了解决这一假设，我们在小鼠模型中产生并利用病毒和遗传学策略：1）鉴定去甲肾上腺素能神经元的分子上不同的子集; 2）确定它们的结构组织; 3）确定它们在调节应激相关行为和学习中的作用;和4）扰乱它们的功能，以揭示去甲肾上腺素能神经元发育的关键时期和长-这些扰动对结构和功能的长期影响。