Section on Light and Circadian Rhythms

研究项目，2022财年，可以分为以下三个主要领域： 1-视杆细胞和视锥细胞如何通过ipRGC驱动行为 我们已经产生了转基因小鼠系，以揭示内在光敏视网膜神经节细胞（ipRGC）和相应的大脑回路对内部生物钟与太阳日同步的贡献。我们有只具有视交叉上核（SCN）投射ipRGC的动物（Chen et al.，Nature 2011），或者我们使用病毒阻断来自非SCN区域的输入，保持投射到SCN的ipRGC完整。我们发现不同亚型的ipRGC昼夜光夹带的贡献。值得注意的是，杆/锥输入需要不同于SCN的光夹带区域。具体地，Brn 3b阴性ipRGC不支持视杆/视锥输入，而Brn 3b阳性ipRGC对于视杆/视锥输入主要重要。我们目前正在为这一重要发现准备出版手稿。 我们做出了惊人的发现，ipRGC的亚群（200个M1-Brn 3b阴性，我们称之为昼夜光感受器）对于昼夜节律钟以及视觉的发育是至关重要的，尽管它们不投射到视觉中心（Chew等人，eLife 2017）。一个令人兴奋的假设是，这200个ipRGC（Chen et al.，Nature 2011）代表了一个进化上古老的感光器类别，因为它们对几种不同的行为（光诱导，时钟和视觉的发展以及局部瞳孔光反射）有广泛的影响。因此，了解该群体相对于其他ipRGC和常规神经节细胞的分子和功能特化是至关重要的。因此，我们与约翰霍普金斯大学医学院的Alex Kolodkin实验室合作获得了该人群转录组的数据。该项目将提供分子手柄，以了解200个M1 ipRGC相对于其他ipRGC和传统神经节细胞的个体发育和功能特化。 2-众所周知，光疗法可用于治疗人类的几种类型的重度抑郁症。然而，很难确定光的这些效应是否纯粹是安慰剂效应。我们最近发表了一个令人兴奋的大脑区域参与调解光对情绪的影响（费尔南德斯等。例如，Cell 2018）。在与Hugo Tejeda博士的合作中，我们在理解这个大脑区域如何与下游区域相互作用以影响情绪方面取得了进展。未来将与Chudasama和Merikangas博士的实验室建立合作，以确定该区域是否存在于灵长类动物中，包括人类。此外，由于该情绪中心接收来自Brn 3b阳性ipRGC的主要输入，我们将确定该区域的视杆/视锥输入是否对情绪调节重要。 3-也许现代神经科学最令人兴奋的方面之一是了解驱动行为的确切电路。我们最近使用遗传技术标记了一种ipRGC亚型，并确定了它在视觉调节中的作用。我们正在出版这项工作。 我们将继续开拓新的领域，了解来自环境的光信号如何调节对人类福祉至关重要的几种功能。

Research projects, Fiscal Year 2022, can be divided into three major areas listed below: 1- How rods and cones drive behaviors through ipRGCs We have generated genetically modified mouse lines to uncover the contribution of intrinsically photosensitive retinal ganglion cells (ipRGCs) and the corresponding brain circuits to the synchronization of the internal biological clock to the solar day. We have animals that either harbor only the suprachiasmatic nucleus (SCN)-projecting ipRGCs (Chen et al., Nature 2011) or we used viruses to block input from non-SCN regions keeping the ipRGCs that project to the SCN intact. We found different contributions of individual subtypes of ipRGCs to circadian photoentrainment. Remarkably, the rod/cone input requires areas distinct from the SCN for photoentrainment. Specifically, Brn3b-negative ipRGCs do not support rod/cone input, whereas Brn3b-positive ipRGCs are predominantly important for rod/cone input. We are currently preparing a manuscript for publication for this important discovery. We made a startling discovery that a subpopulation of ipRGCs (200 M1-Brn3b-negative, which we called circadian photoreceptors) is critical for the development of the circadian clock as well as vision, although they do not project to visual centers (Chew et al., eLife 2017). An exciting hypothesis is that these 200 ipRGCs (Chen et al., Nature 2011) represent an evolutionarily ancient photoreceptor class given their broad influence on several distinct behaviors (photoentrainment, development of the clock and vision as well as local pupillary light reflex). Therefore, it is critical to understand the molecular and functional specification of this population in relation to other ipRGCs and conventional ganglion cells. Thus, we obtained data in collaboration with Alex Kolodkin's lab at the Johns Hopkins University-School of Medicine for the transcriptome of this population. This project will provide the molecular handles to understand the ontogeny and the functional specialization of the 200 M1 ipRGCs in relation to other ipRGCs and conventional ganglion cells. 2- It is well established that light therapy can be used to treat several types of major depression in humans. However, it has been hard to ascertain whether these effects of light are purely placebo effects. We recently published an exciting brain region involved in mediating light effects on mood (Fernandez et. al., Cell 2018). In collaboration with Dr. Hugo Tejeda, we made progress in understanding how this brain region interacts with downstream regions to influence mood. Future collaborations are established with the labs of Drs. Chudasama and Merikangas to determine if this region is found in primates, including humans. In addition, since this mood center receives predominant input from Brn3b-positive ipRGCs, we will determine whether rod/cone input to this region is important for mood regulation. 3- Perhaps one of the most exciting aspects of modern neuroscience is to understand the exact circuits that drive behaviors. We recently used genetic techniques to label only a single ipRGC subtype and determine its role in vision regulation. We are in the process of publishing this work. Together, we will continue to break new ground about how light signaling from the environment regulates several functions that are essential for the well-being of humans.