Central Noradrenergic Neuron Subtype Development and Function

脑干去甲肾上腺素能神经元由一小群不同的细胞组成，这些细胞几乎投射到中枢神经系统的所有区域。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。与这种功能多样性相一致的是，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在暴露于一些环境毒物后受到干扰。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具有不同的易感性。鉴于这些观察，我们怀疑，通过将去甲肾上腺素系统作为一个整体来关注，并不能找到理解去甲肾上腺素系统功能障碍的关键。相反，只有通过揭示定义去甲肾上腺素能神经元独特功能亚型的发育和遗传因素，才能理解这种表型复杂性。为了追求这一目标，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亚群的发育、组织和功能。我们的中心假设是，发育早期不同去甲肾上腺素能神经元亚型的遗传和环境扰动导致 在以后的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，我们采用了一种基于重组酶的遗传策略，使用了一组独特的转基因小鼠来：1)确定去甲肾上腺素能神经元的分子亚群；2)确定它们的结构组织；3)揭示它们在焦虑背后的电路中的功能作用；以及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期，并确定这些扰动对焦虑的长期影响。

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 responseto 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 have adopted a recombinase-based genetic strategy using a unique set of genetically modified mice to: 1) identify molecularly distinct subsets of noradrenergic neurons; 2) determine their structural organization; 3) uncover their functional role in circuits underlying anxiety; and 4) perturb their function to uncover critical periods of noradrenergic neuron development and to determine the long-term effect of these perturbations on anxiety.