Central Noradrenergic Neuron Subtype Development and Function

脑干去肾上腺素能神经元由一个小而多样的细胞群组成，它们投射到中枢神经系统的几乎所有区域。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，去甲肾上腺素信号在一系列神经退行性和神经发育障碍中以及暴露于一些环境毒物后被破坏。有趣的是，已经观察到，去肾上腺素能神经元亚群对疾病和暴露于某些有毒物质后的易感性不同。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而找到。相反，这种表型的复杂性只有通过揭示发育和遗传因素才能理解，这些因素定义了去甲肾上腺素能神经元独特的功能亚型。为了实现这一目标，我们研究了小鼠中枢神经系统中遗传定义的去肾上腺素能神经元亚群的发育、组织和功能。我们的中心假设是，发育早期不同的去甲肾上腺素能神经元亚型的遗传和环境扰动导致以后生活中对认知和情感障碍的易感性增强。为了解决这一假设，我们在小鼠模型中生成并利用病毒和遗传学策略来：1)识别分子上不同的去肾上腺素能神经元亚群；2)确定其结构组织；3)确定其在调节压力相关行为和学习中的作用；4)干扰它们的功能，揭示去甲肾上腺素能神经元发育的关键时期以及这些干扰对结构和功能的长期影响。

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.