1: Serotonin-mediated inhibition of ventral hippocampus is required for sustained goal-directed behavior.
Science of the Month - June 2019
Nature Neuroscience
Keitaro Yoshida, Michael R. Drew, Masaru Mimura, Kenji F. Tanaka
Activity in the ventral hippocampus increases in situations that cause anxiety. This brain region, which can be called an anxiety sensor—the ventral hippocampus—projects densely to the ventral striatum, a central region of the reward system. This research began with the question of what significance this holds. Since goal-directed behavior is driven by obtaining rewards, we started by measuring the activity of the ventral hippocampus during such behavior. By combining a fluorescent calcium probe and a fiber photometry system, we built a system to record weak neural activity signals and discovered that the activity of the ventral hippocampus decreases during sustained goal-directed behavior. Through interventional experiments using optogenetics, we found that this decrease in ventral hippocampus activity is essential for sustaining the behavior. Furthermore, we discovered that the decrease in ventral hippocampus activity is brought about by the activation of serotonin neurons. Our interpretation is that to act persistently and not be derailed by anxiety, it is necessary to suppress the activity of the ventral hippocampus. This is the first work to show the relationship between seeing things through and emotional regulation.
(Kenji Tanaka, Department of Neuropsychiatry, 76th Graduating Class)
2: Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in Granule Cell Axons.
Neuron,
2019 Mar 21;10(1):1299. doi: 10.1038/s41467-019-09143-8.
Keiji Ibata, Maya Kono, Sakae Narumi, Junko Motohashi, Wataru Kakegawa, Kazuhisa Kohda, Michisuke Yuzaki
Our brains are composed of synapses that connect approximately 100 billion neurons. Synapses, formed based on genetic information, are reorganized throughout life by neural activity, but the molecular mechanisms responsible for this process are not well understood. We previously reported that Cbln1, which belongs to the same family as the "complement" of the innate immune system, is essential for synapse formation in the cerebellum. In this study, we discovered that Cbln1 is present in lysosomes within the axons of cerebellar granule cells and is secreted along with lysosomal enzymes in response to neural activity. This "scrap-and-build mechanism," in which the destruction of the extracellular environment by lysosomal enzymes and synapse formation by Cbln1 work in concert, is a new concept. Elucidating the process of synapse reorganization in response to neural activity is considered important for understanding the pathology of various synaptopathies—such as depression, schizophrenia, and autism spectrum disorder—where synaptic lesions exist, and for developing new therapeutic methods.
(Michisuke Yuzaki, Department of Physiology, equivalent to the 64th Graduating Class)
3: Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers.
Cell Stem Cell.
2019 Mar 21;10(1):1299. doi: 10.1038/s41467-019-09143-8.
Hisayuki Hashimoto, Zhaoning Wang, Glynnis A. Garry, Venkat S. Malladi, Giovanni A. Botten, Wenduo Ye, Huanyu Zhou, Marco Osterwalder, Diane E. Dickel, Axel Visel, Ning Liu, Rhonda Bassel-Duby, Eric N. Olson
It has been reported that fibroblasts can be directly reprogrammed into induced cardiomyocyte-like cells (iCMs) without passing through a pluripotent stem cell stage by forcing the expression of multiple factors important for heart development, such as Gata4, Mef2c, Tbx5, Hand2, and Akt1. However, because the expression of these reprogramming factors is not heart-specific, it was unclear why combining these factors could induce iCMs. Therefore, we used the ChIP-Seq method to analyze the DNA binding sites of reprogramming factors and enhancer activity based on the histone modification H3K27ac across the entire genome of mouse fibroblasts. As a result, we interestingly found that two completely different biological processes, reprogramming and heart development, share many common features in their gene transcriptional control mechanisms (epigenomic profiles). Based on this discovery, future research is expected to, conversely, utilize reprogramming to elucidate new transcriptional control mechanisms that govern heart development.
(Hisayuki Hashimoto, Department of Cardiology, 85th Graduating Class)
Other Publications
1: Cancer Immunoediting by Innate Lymphoid Cells
TRENDS IN IMMUNOLOGY,
2019 May;40(5):415-430. doi: 10.1016/j.it.2019.03.004. Epub 2019 Apr 14.
Wagner M, Koyasu S