Section on Light and Circadian Rhythms

2022财年的研究项目可分为以下三个主要领域： 1-杆和锥体如何通过ipRGC驱动行为 我们已经产生了转基因小鼠系，以揭示固有的光敏视网膜神经节细胞(IpRGC)和相应的大脑电路对内部生物钟与太阳日同步的贡献。我们有一些动物要么只有交叉上核(SCN)投射的ipRGCs(Chen等人，《自然》2011)，要么我们用病毒阻止来自非SCN区域的输入，保持投射到SCN的ipRGC完好无损。我们发现不同的ipRGC亚型对昼夜节律的光携带作用有不同的贡献。值得注意的是，棒/锥输入需要与SCN不同的区域来进行光携带。具体来说，Brn3b阴性的ipRGC不支持棒/锥输入，而Brn3b阳性的ipRGC对棒/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。 我们发现了一个令人震惊的发现，即ipRGC的一个亚群(200个M1-Brn3b阴性，我们称之为昼夜节律光感受器)对生物钟和视觉的发育至关重要，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等人，《自然》2011)代表着一个进化上古老的光感受器类别，因为它们对几种不同的行为(光携带、时钟和视觉的发育以及局部瞳孔的光反射)具有广泛的影响。因此，了解这一群体相对于其他ipRGC和常规神经节细胞的分子和功能特征是至关重要的。因此，我们与亚历克斯·科洛德金在约翰霍普金斯大学医学院的实验室合作，获得了这一人群的转录组数据。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，光疗可以用于治疗人类几种类型的严重抑郁症。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，该区域参与调节光对情绪的影响(Fernandez et。Al，Cell 2018)。在与雨果·特杰达博士的合作下，我们在了解这一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博士和Merikangas博士的实验室建立合作关系，以确定该区域是否在包括人类在内的灵长类动物中发现。此外，由于这个情绪中枢接受Brn3b阳性的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。 也许现代神经科学最令人兴奋的方面之一就是了解驱动行为的确切回路。我们最近使用基因技术只标记了一个ipRGC亚型，并确定了它在视觉调节中的作用。我们正在出版这部作品。 共同努力，我们将继续在环境光信号如何调节几种对人类福祉至关重要的功能方面开辟新的天地。

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.