Brain-wide input and output wiring diagram of oxytocin neurons and its function in claustrum-endopiriform complex

全脑催产素神经元输入输出接线图及其在屏状核-内皮状复合体中的功能

• 批准号: 10356917
• 负责人: Yongsoo Kim
• 金额: $ 46.5万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356917
• 关键词: Address; Affect; Anatomy; Animals; Area; Axon; Behavior; Behavioral; Blood Circulation; Brain; Brain Diseases; Brain Stem; Brain region; Cell Nucleus; Cells; Claustral structure; Collaborations; Complex; Computing Methodologies; DNA Sequence Alteration; Data; Dependovirus; Disease; Foundations; Future; Health; Human; Hypothalamic structure; Image; Impairment; Internet; Knockout Mice; Knowledge; Label; Maps; Mediating; Mental disorders; Metabolism; Methods; Microscopic; Mus; Neurodevelopmental Disorder; Neurons; Neuropeptides; Noise; Online Systems; Output; Oxytocin; Oxytocin Receptor; Pattern; Pituitary Gland; Play; Population; Rabies; Resolution; Rest; Role; Signal Transduction; Social Behavior; Social Functioning; Stimulus; Structure; Synapses; Techniques; Testing; Visualization; Work; anatomic imaging; autism spectrum disorder; base; behavioral impairment; behavioral response; cell type; computerized data processing; experience; high resolution imaging; imaging modality; information processing; multimodality; multisensory; neural circuit; neuroregulation; novel; receptor; receptor expression; relating to nervous system; sensory input; sensory system; serial imaging; social; therapeutic development; tomography; tool; two-photon; virus genetics

Abstract Social behavior reflects highly complex, multimodal, internal/external stimuli integration and is critical to the survival of many animals, including humans. Impaired social behavior has been implicated in many different mental disorders. Despite its importance, we know relatively little about underlying neural circuit mechanisms to generate context appropriate social behavioral response. Oxytocin (OT) is a neuropeptide that plays an essential role in regulating social behavior. Genetic mutations that affect OT signaling have been heavily implicated in brain disorders with social behavioral impairments such as autism spectrum disorder. OT neurons predominately located in the hypothalamus receive input from the sensory system and other brain regions to integrate both external stimuli and internal information. In turn, hypothalamic OT neurons release OT to the bloodstream via the pituitary to affect body metabolism and provide central projection to other brain regions. To support OT function, OT receptor (OTR) is highly expressed in socially important brain areas. Particularly, OT signaling via OTR in different brain regions is known to increase social information processing while suppressing background noise to achieve circuit specific neural modulation. Despite prominent roles of OT signaling during social behavior, precise neuroanatomical connectivity and circuit specific effects of OT signaling remain unclear. Here, we propose to study the detailed anatomical organization of hypothalamic OT neurons and to investigate its function in a novel mouse brain area. It has been technically challenging to image and analyze microscopic structures (e.g., axons) throughout the entire mammalian brain. To overcome this barrier, we previously developed a novel method that combines serial two-photon tomography (STPT) imaging of whole mouse brains at cellular resolution with viral and genetic tools to achieve quantitative input and output maps of cell type specific populations. Using this approach, we will examine topographically segregated output (Aim1) and input (Aim2) maps of hypothalamic OT neurons and will develop web visualization platform to display high-resolution images for further analysis. Moreover, we will investigate OT signaling function in the claustrum-endopiriform complex to guide normal social behavior based on our preliminary results (Aim3). We believe these studies will establish a much-needed detailed anatomical wiring diagram of OT neurons and will provide a foundation to elucidate the neural circuit basis of mature social behavior in health and disease.

抽象的 社会行为反映了高度复杂、多模式、内部/外部刺激的整合，对于社会行为至关重要 包括人类在内的许多动物的生存。社会行为受损与许多不同的方面有关 精神障碍。尽管它很重要，但我们对潜在的神经回路机制知之甚少 产生适合情境的社会行为反应。催产素 (OT) 是一种神经肽，具有 对调节社会行为具有重要作用。影响 OT 信号传导的基因突变已被严重 与患有社会行为障碍的大脑疾病有关，例如自闭症谱系障碍。 OT神经元 主要位于下丘脑，接收来自感觉系统和其他大脑区域的输入， 整合外部刺激和内部信息。反过来，下丘脑 OT 神经元将 OT 释放到 血液通过垂体影响身体新陈代谢，并向其他大脑区域提供中枢投射。到 支持 OT 功能，OT 受体 (OTR) 在具有社会重要性的大脑区域高度表达。特别是，加班 众所周知，不同大脑区域通过 OTR 发出的信号可以增加社交信息处理，同时 抑制背景噪声以实现电路特定的神经调制。尽管 OT 发挥着重要作用 社交行为期间的信号传导、精确的神经解剖学连接以及 OT 的电路特定影响 信号传导仍不清楚。在这里，我们建议研究下丘脑 OT 的详细解剖结构 神经元并研究其在新的小鼠大脑区域中的功能。成像在技术上具有挑战性 并分析整个哺乳动物大脑的微观结构（例如轴突）。为了克服这个 障碍，我们之前开发了一种结合串行双光子断层扫描（STPT）成像的新方法 使用病毒和遗传工具以细胞分辨率对整个小鼠大脑进行定量输入和输出 细胞类型特定群体的图谱。使用这种方法，我们将检查地形隔离的输出 下丘脑 OT 神经元的（目标 1）和输入（目标 2）图，并将开发网络可视化平台 显示高分辨率图像以供进一步分析。此外，我们将研究 OT 信号传导功能 根据我们的初步结果（目标3），屏状核-内皮状复合体指导正常的社会行为。我们 相信这些研究将建立一个急需的详细的 OT 神经元解剖接线图，并将 为阐明健康和疾病中成熟社会行为的神经回路基础提供了基础。

项目成果

Disinhibition of somatostatin interneurons confers resilience to stress in male but not female mice.

生长抑素中间神经元的去抑制可以赋予雄性小鼠而非雌性小鼠的压力恢复能力。

• DOI: 10.1016/j.ynstr.2020.100238
• 发表时间: 2020-11
• 期刊: Neurobiology of stress
• 影响因子: 5
• 作者: Jefferson SJ;Feng M;Chon U;Guo Y;Kim Y;Luscher B
• 通讯作者: Luscher B

Seeing the Forest and Its Trees Together: Implementing 3D Light Microscopy Pipelines for Cell Type Mapping in the Mouse Brain.

• DOI: 10.3389/fnana.2021.787601
• 发表时间: 2021
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Newmaster KT;Kronman FA;Wu YT;Kim Y
• 通讯作者: Kim Y

Advances in studying whole mouse brain vasculature using high-resolution 3D light microscopy imaging.

• DOI: 10.1117/1.nph.9.2.021902
• 发表时间: 2022-04
• 期刊: Neurophotonics
• 影响因子: 5.3
• 作者: Bennett HC;Kim Y
• 通讯作者: Kim Y

Whole-Brain Wiring Diagram of Oxytocin System in Adult Mice.

• DOI: 10.1523/jneurosci.0307-22.2022
• 发表时间: 2022-06-22
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Son, Seoyoung;Manjila, Steffy B.;Newmaster, Kyra T.;Wu, Yuan-ting;Vanselow, Daniel J.;Ciarletta, Matt;Anthony, Todd E.;Cheng, Keith C.;Kim, Yongsoo
• 通讯作者: Kim, Yongsoo

Protocol for using serial two-photon tomography to map cell types and cerebrovasculature at single-cell resolution in the whole adult mouse brain.

• DOI: 10.1016/j.xpro.2023.102048
• 发表时间: 2023-03-17
• 期刊: STAR PROTOCOLS
• 作者: Liwang, Josephine K.;Bennett, Hannah C.;Pi, Hyun-Jae;Kim, Yongsoo
• 通讯作者: Kim, Yongsoo