Junjie Guo, Ph.D., Assistant Professor of Neuroscience, Yale University School of Medicine, New Haven, CT

Mechanism and functions of repeat expansion self-exonization in C9orf72 ALS/FTD

As intricate as the DNA replication process is, sometimes errors happen. Some neurological diseases are linked to a particular type of error called nucleotide repeat expansion (NRE), in which a short DNA segment is repeated over and over in hundreds or more copies. Where these repeats occur in the genome matters: during a critical step in gene expression called RNA splicing, only certain pieces (exons) of the RNA transcribed from DNA are joined together to become the final messenger RNA, whereas the remaining RNA sequences (introns) between exons will be broken down.

However, in some cases, introns with NREs are not broken down, but manage to instruct the making of a variety of repeat proteins that are harmful to nerve cells. A well-known example is an intron NRE within a gene called C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and frontotemporal dementia (FTD). In his research, Dr. Guo hopes to uncover how this intron NRE disrupts RNA splicing and causes the production of toxic repeat proteins.

Guo and his team will first test a variety of NRE mutations to see which are able to change the splicing pattern so the intron can escape degradation. Their second aim will test the hypothesis that these changes in the splicing pattern are critical for the C9orf72 NRE RNA to increase its export out from the cell nucleus into the cytoplasm and instruct the making of toxic repeat proteins. Finally, their research will explore the possibility that differences between the ways in which each cell splices its RNAs may explain why certain types of nerve cells such as motor neurons are more vulnerable in ALS.

Juliet K. Knowles, MD, PhD, Assistant Professor of Neurology, Stanford University School of Medicine, Palo Alto, CA

Neuron-to-OPC synapses in adaptive and maladaptive myelination

In her role as a pediatric clinician specializing in epilepsy, Dr. Knowles sees firsthand how this neurological disorder (actually a collection of several related but distinct diseases) is experienced and how it progresses. As a neuroscientist, she has the opportunity to help uncover how and why. Knowles and her team are focusing their research on the role of neuronal activity in myelination in patients with generalized epilepsy, a common form of the disease that is characterized by the presence of seizures and absence seizures.

Myelination is the process by which the axons (projections) of neurons are encased in myelin, which enhances the speed of axon signal transmission, and makes neural networks more efficient. The process involves oligodendrocyte progenitor cells (OPCs) which can develop into oligodendrocytes, cells that produce myelin. In earlier research, Knowles uncovered that the neural activity of absence seizures promotes myelination of the seizure circuit, making it more efficient. This appears to lead to an increase in absence seizure frequency and severity; when Knowles and her team blocked the OPCs’ response to neural activity, seizure-induced myelination did not occur, and the seizures didn’t progress.

Knowles’ new research will now explore how this happens and identify possible approaches for future therapies. One aim will document the neuron to OPC synapses in both epileptic and healthy mouse models. A second aim will compare neuron-to-OPC synaptic activity and synaptic gene expression in healthy or epileptic mice – specifically focusing on how myelination promoted by a seizure differs from that promoted by learning. A third aim will explore how disrupting the post-synaptic receptors on oligodendrocytes affects the progression of epilepsy, not just in terms of seizures, but related symptoms such as disrupted sleep and cognitive impairment, both of which are common in individuals affected by epilepsy.

Akhila Rajan, 博士, Associate Professor, Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA

Adipocyte-brain mitochondrial signaling and its impacts on brain function

Communication between organs and the brain is critical to an animal’s survival and health. Signals tell the brain when the body needs more energy, is hungry, or needs to sleep, move or perform countless other tasks. But recent research has revealed that communication can include more than hormones – packets of material can also be passed to brain cells. Dr. Rajan’s research focuses on the phenomena of fat cells (adipocytes) sending bits of mitochondria – the organelles within cells that generate energy, among other roles – to the brain, and how that affects brain function.

Previous research has found that when these mitochondrial bits reach the brain, it makes the fly model Rajan’s team works with more hungry, specifically for high sugar foods, promoting a cycle of obesity and further sending of material. There is a known correlation between obesity and a range of neurological disorders, including sleep disorders and cognitive decline, and this new research hopes to shed light on these links and potentially identify targets for future therapies.

Working with the fly model, Rajan and her team aim to identify how exactly these bits of mitochondria are gaining access to neurons in the brain without being degraded; what happens when these bits of fat cell mitochondria integrate with neuronal mitochondria, specifically how it alters an animal’s behavior in terms of sleep and feeding; and what effect this process has on neuronal health overall. The research will take advantage of very precise genetic manipulations at which Rajan’s lab excels, involve cross-disciplinary insights provided by lab team members, and use advanced insect physiology chambers that let the team document feeding and changes in behavior at a level unavailable to previous generations of researchers.

Humsa Venkatesh, 博士, Assistant Professor of Neurology, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA

The neurobiology of glioma: Understanding malignant neural circuits instructing tumor growth

Cancers, including brain tumors, have traditionally been studied at a cellular or molecular level. Researchers are addressing questions such as what subpopulation of cells are involved, how do they mutate, and what can we do to those malignant cells to get them to stop replicating? Dr. Venkatesh is interested in looking at how the nervous system is also involved in cancer progression and has already discovered that neurons form synaptic connections to cancer cells.

Venkatesh and her lab are studying both primary and secondary brain tumors but have evidence that these findings apply to cancers in other parts of the body. The insight that tumors are interacting with neurons, and not just killing off nerves as had once been thought, has opened many possibilities. These malignant growths are taking signals from the nervous system intended to pass information to other cells and instead reinterpreting them to instruct the cancer to grow. Now researchers can explore how to harness the nervous system to help treat or manage this malignant disease. In an exciting development, Venkatesh’s previous work in this space has already led to clinical trials that repurpose existing drugs targeting the nervous system and apply them to cancer treatment.

This new research goes even further into understanding the mechanisms governing neural circuit activity-driven glioma progression. Using advanced neuroscience technologies and patient-derived cell lines, Venkatesh will be able to modulate and study the malignant neural networks, encompassing both neurons and tumor cells, that influence cancer growth. Understanding this activity-dependent mechanism and how it can be targeted without disrupting healthy neuronal function could open new fields of cancer research and novel therapeutic opportunities.


丽莎·贝特勒, MD, Ph.D., 伊利诺伊州芝加哥市西北大学 Feinberg 医学院内分泌学助理教授



Beutler 博士旨在使用先进的神经观察和操作技术来剖析炎症相关性厌食症的潜在机制。 Beutler 的团队将使用钙成像来揭示个体细胞因子(炎症期间释放的信号)对特定进食相关神经元组的影响。她的小组还将使用尖端的遗传工具来尝试消除由严重炎症引起的不适当的“不要吃”信号。最后,她将研究炎症疾病的特定模型如何改变对营养摄入的神经反应。

Beutler 的研究将是第一个在生物体中以这种详细程度来研究这些特定过程的研究。通过确定细胞因子释放的精确神经学靶点,并破译它如何调节食欲,Beutler 希望确定与炎症性疾病相关的营养不良的治疗靶点。此外,她的实验室旨在创建肠道-大脑-免疫信号的路线图,这可能不仅对治疗炎症介导的厌食症具有重大意义,而且对未来的喂养和代谢研究也具有广泛意义。

杰里米·戴,博士, 阿拉巴马大学伯明翰分校 Heersink 医学院神经生物学系副教授;和 伊恩·马兹 博士, 教授 – 神经科学和药理学系,主任 – 纽约市西奈山伊坎医学院神经表观基因组工程中心


吸毒成瘾对个人和整个社会都是一个严重的问题。虽然对理解和治疗成瘾进行了大量研究,但接受治疗的 60% 会复发。事实上,对毒品的渴望实际上可能会随着时间的推移而增加,在那些即使没有进一步接触毒品的情况下也已经上瘾的人中潜伏着。 Day 博士和 Maze 博士的目标是在一个新的水平上研究成瘾——在单细胞水平上深入研究药物使用对特定细胞的表观遗传影响,以及这些如何使受试者容易复发。

初步研究表明,随着时间的推移接触药物会改变基因的表达方式。从本质上讲,药物可以劫持被称为“增强子”的基因调控元件,当激活这些元件时,会导致某些基因在脑细胞中表达,从而促使受试者寻找这些药物。 Day 和 Maze 设计了一个项目,以特定细胞类型的方式识别这些由可卡因激活(或未沉默)的增强剂 - 一种众所周知和研究的兴奋剂 - 然后创建并将病毒载体插入细胞中,这些载体只会在那个未沉默的增强子的存在。使用这种策略,病毒载体将仅在受可卡因影响的细胞集合中表达其货物,并允许研究人员通过光遗传学或化学遗传学方法激活或停用受影响的细胞。




大脑沉迷于寻找和食用食物。当发现热量密集的食物时——在野外很少见——动物会本能地迅速食用它。对于容易获得高热量食物的人类来说,本能有时会导致暴饮暴食、肥胖和相关的健康问题。但研究也表明,在某些情况下,当这种食物总是可用时,以高热量食物为食的动力可能会减弱。 Lammel 博士试图确定参与这种进食行为及其调节的神经过程和大脑区域。

多年来的研究将进食与下丘脑联系起来,下丘脑是大脑的一个古老而深部的部分。然而,证据也表明大脑的奖赏和愉悦中心的作用。 Lammel 的初步研究发现,从外侧伏隔核 (NAcLat) 到腹侧被盖区 (VTA) 的联系是享乐喂养的核心——激活这种联系光遗传学导致增加富含卡路里的食物的喂养,但不是普通食物。其他研究确定氨基酸神经降压素 (NTS) 除了其他作用外,还参与调节进食。

Lammel 的研究旨在描绘出导致动物享乐进食的大脑各个部分的回路和作用,以及 NTS 的作用,这在 NAcLat 中表达。受试者接受正常饮食或富含卡路里的果冻饮食,NAcLat-to-VTA 通路的活动被记录并映射到喂养行为。他还将跟踪长期暴露于享乐主义食物的变化。进一步的研究将着眼于细胞中 NTS 存在的变化,以及它的不同含量如何影响细胞功能。通过了解喂养和肥胖所涉及的途径和分子机制,这项工作可能有助于未来帮助管理肥胖的努力。

林赛·施瓦茨, 博士, 田纳西州孟菲斯圣裘德儿童研究医院发育神经生物学助理教授


动物的呼吸是自动的,但与其他基本功能不同——心跳、消化等——动物可以有意识地控制呼吸。呼吸也以两种方式与情绪和精神状态相关:情绪触发会导致呼吸变化,但有意识地改变呼吸也已被证明会影响精神状态。在她的研究中,Schwarz 博士的目标是确定哪些与呼吸相关的神经元被生理和认知线索选择性激活,并绘制出它们连接的大脑区域。这项研究可能有助于研究影响呼吸的各种神经系统疾病,例如婴儿猝死综合征 (SIDS)、中枢性睡眠呼吸暂停和焦虑症。

Schwarz 旨在利用神经标记技术的进步来研究这些位于脑干深处的神经元,这些神经元传统上难以在体内分离和记录。但是通过活动标记,Schwarz 可以识别先天与主动呼吸期间激活的神经元。对于后者,受试者会受到压力刺激的影响,导致他们冻结并改变他们的呼吸。然后,研究人员可以检查标记的神经元以确定哪些在受调节的受试者中处于活动状态,并确定这些神经元是否与先天呼吸期间处于活动状态的神经元重叠。




斯里甘加·钱德拉(Sreeganga Chandra)博士耶鲁大学医学院神经病学和神经科学系副教授







偏头痛是一种普遍的,常常使人衰弱的疾病。它很复杂,而且很难治疗。病人有不同的症状,通常是由感觉过敏引起的,可能包括疼痛,恶心,视力障碍和其他影响。偏头痛会影响大脑的多个相互连接的部分,但并不总是以相同的方式发生,而且治疗在人与人之间通常不会具有相同的效果。 Hultman博士的研究建议使用新工具检查偏头痛,以阐明治疗的新途径。