Neurophysiological links to depression probed by high-speed optical technologies

描述(申请人提供)：这项工作的目标是使用生物工程的高精度工具来帮助解开现代精神病学的一个深层次问题：情绪的神经基础是什么？虽然许多大脑区域和神经调节器都与情绪处理有关，但关于情绪的神经生理调节一直难以捉摸。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治疗策略的能力，从而可能彻底改变精神病学实践。在与情绪调节有关的几个大脑区域中，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，新兴的高分辨率光学技术正在开发中，这种技术能够在相关的空间和时间尺度上记录和刺激神经活动。通过利用显示情绪行为相关性的动物模型，用抗抑郁药物和应激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修改的效果，本建议试图探讨与这个问题相关的三个具体目标：1)确定受强迫游泳测试成绩双向调节影响的海马区诱发活动的时空模式，并解决这些活动模式是否与动物行为状态有很好的相关性。2)确定这些投射是否足以通过使用高速成像识别的适用路径的活体刺激来调节强迫游泳测试的表现。3)分离在这些海马区投射调节强迫游泳测试成绩中起主要作用的神经元群。抑郁症影响着全球超过1.21亿人，一线治疗显示出有限的疗效和产生严重副作用的潜力。这项工作将对公众健康产生重大影响，因为它将识别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的有效性，拟议中的研究可能直接导致发现此类治疗的更多靶点，因为它有助于形成情绪和抑郁的量化理论。

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.