CAREER: Noradrenergic Regulation of Hippocampal Interneurons

这项由CAREER奖支持的研究考察了自然产生的神经递质去甲肾上腺素（NE）在大脑中的作用及其对中间神经元生理功能的影响。高级大脑结构的兴奋性网络，如海马体，主要由中继神经元组成。这些细胞的活动受局部抑制性突触相互作用控制，由少数称为中间神经元的特化细胞介导。这些中间神经元是一组不同的细胞，每一组可能负责一种不同形式的突触抑制。海马接收大量含有ne的纤维输入，其中许多似乎与中间神经元形成接触，这表明去甲肾上腺素能系统可能通过直接作用于中间神经元来调节突触抑制。NE与睡眠、觉醒、学习和记忆的调节有关，但我们对NE反应的中间神经元的不同亚群如何调节这些神经过程的理解尚不完整。有证据表明，NE对抑制性海马中间神经元至少有两个离散的、功能明确的亚群进行差异调节。为了验证这一假设，本CAREER项目将采用跨学科的方法，结合电生理学、分子生物学和神经成像技术，在体外大鼠海马中(i)表征NE对不同中间神经元群体的影响，（ii）识别介导这些NE反应的受体，以及（iii）确定受NE影响的中间神经元的形态学特征。除了扩展我们对NE如何调节中间神经元功能的基本理解之外，来自该项目的信息可能会对某些认知和行为状态的潜在机制产生重要见解。该研究员将通过开发和教授本科和研究生水平的神经科学课程，并参与推广计划，鼓励更多的高中生和本科生（特别是女性和少数民族）考虑和追求科学事业，将教育与他的研究工作结合起来。作为持续指导的一部分，将培训一组学生进行拟议的研究。此外，有利于学生和其他教师，研究者将帮助建立和指导一个电生理学核心设施。因此，这个职业奖不仅将促进我们对NE如何影响海马体网络功能的理解，而且还将允许高质量的培训和研究设施，为现在和未来的神经科学家提供刺激的教育体验。

The research supported by this CAREER award examines the role of the naturally occurring neurotransmitter norepinephrine (NE) in the brain and its effects on the physiological functions of interneurons. The excitatory networks of higher brain structures, such as the hippocampus, consist primarily of relay neurons. The activity of these cells is controlled by local inhibitory synaptic interactions, mediated by a small number of specialized cells called interneurons. These interneurons are a diverse group of cells, each presumably responsible for a distinct form of synaptic inhibition. The hippocampus receives a large input of NE-containing fibers, many of which appear to form contacts with interneurons, suggesting that the noradrenergic system may regulate synaptic inhibition through direct actions on interneurons. NE has been implicated in the regulation of sleep, arousal, learning and memory, but our understanding of how different subsets of NE-responsive interneurons modulate these neural processes is incomplete.Evidence suggests that NE differentially regulates at least two discrete, functionally defined, subpopulations of inhibitory hippocampal interneurons. To test this hypothesis, this CAREER project will use an interdisciplinary approach combining electrophysiological, molecular-biological and neuroimaging techniques in the in-vitro rat hippocampus to (i) characterize the effects of NE on different populations of interneurons, (ii) identify the receptors mediating these NE responses, and (iii) determine the morphological profile of interneurons affected by NE. In addition to extending our basic understanding of how NE modulates interneuron function, the information derived from this project may yield important insights into the mechanisms underlying certain cognitive and behavioral states.This investigator will integrate education with his research efforts by developing and teaching in undergraduate- and graduate-level neuroscience courses, and participating in outreach programs to encourage more high-school and undergraduate students (especially women and minorities) to consider and pursue careers in science. As part of the continued mentoring, a team of students will be trained to conduct the proposed research. In addition, benefiting both students and other faculty, the investigator will help establish and direct an electrophysiology core facility. Thus, this CAREER award will not only advance our understanding of how NE affects hippocampal network function, but also allow for high-quality training and research facilities, providing stimulating educational experiences for both present and future generations of neuroscientists.