Neurophysiological links to depression probed by high-speed optical technologies

描述（由申请人提供）：这项工作的目标是使用高精度的生物工程工具来帮助解开现代精神病学的一个深层问题：情感的神经基础是什么？虽然许多大脑区域和神经调节剂都与情绪处理有关，但情绪的神经生理调节的清晰图景一直难以捉摸。在与神经信息处理相关的空间和时间尺度上对这种生理学的精确了解，将极大地提高我们设计和实施新的治疗策略的能力，从而可能彻底改变精神病学的实践。在涉及情绪调节的几个大脑区域中，海马体被认为扮演着特别重要的角色。为了深入了解海马体在情绪调节中的作用，人们正在开发新兴的高分辨率光学技术，可以在相关的空间和时间尺度上记录和刺激神经活动。通过利用动物模型显示情绪的行为相关性，用抗抑郁药和压力范式双向操纵这种行为，然后用强迫游泳测试分析这些行为改变的影响，本提案试图研究与该问题相关的三个具体目标：1)确定双向调节强迫游泳测试表现影响海马活动的时空模式，并确定这些活动模式是否与动物行为状态相关。2)通过使用高速成像识别的申请人通路的体内刺激，确定这些投影是否足以调节强迫游泳测试的表现。3)分离在海马突起调节强迫游泳测试表现中起主要作用的神经元群。全世界有超过1.21亿人患有抑郁症，而一线治疗的效果有限，而且可能产生严重的副作用。这项工作将对公众健康产生重大影响，因为它将确定和定量描述神经情绪调节机制的关键组成部分。由于神经刺激技术已经证明了缓解抑郁症的功效，这项研究可能会直接导致发现这种治疗的额外目标，因为它有助于形成情绪和抑郁的定量理论。

DESCRIPTION (provided by applicant): The goal of this work is to use the high-precision tools of bioengineering to help unravel one of the deep questions of modern psychiatry: what is the neural basis of emotion? While many brain regions and neuromodulators have been implicated in emotional processing, a clear picture of the neurophysiological regulation of mood has been elusive. Precise knowledge of this physiology, on the spatial and temporal scales relevant for neural information processing, would drastically improve our ability to design and implement novel therapeutic strategies and could thereby revolutionize psychiatric practice. Of the several brain regions implicated in mood regulation, the hippocampus is hypothesized to play a particularly strong role. To gain insight into the role of the hippocampus in mood regulation, development is underway of emergent high resolution optical technologies that enable recording and stimulation of neural activity on the relevant spatial and temporal scales. By utilizing animal models displaying behavioral correlates of mood, manipulating this behavior bidirectionally with antidepressants and stress paradigms, and then assaying effects of these behavioral modifications with the forced swim test, this proposal seeks to investigate three specific aims pertinent to this question: 1) Identify spatiotemporal patterns of evoked hippocampal activity that are affected by bidirectional modulation of forced swim test performance, and resolve whether these activity patterns correlate well with animal behavioral state. 2) Determine the sufficiency of these projections to modulate forced swim test performance via in vivo stimulation of applicant pathways identified using high-speed imaging. 3) Isolate neuronal populations that are primary in the role of these hippocampal projections in regulating forced swim test performance. Depression affects over 121 million people worldwide and frontline treatments show limited efficacy and the potential for developing serious side effects. This work will have great impact on public health as it will identify and quantitatively describe key components of the neural mood regulatory machinery. As neural stimulation techniques have already demonstrated efficacy in relieving depression, the proposed research may lead directly to discovering additional targets for such treatment as it contributes to the formation of a quantitative theory of mood and depression.