Neural mechanisms of social attachment disruption in frontotemporal dementia

额颞叶痴呆社会依恋破坏的神经机制

• 批准号: 10591810
• 负责人: Kristen Berendzen
• 金额: $ 16.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591810
• 关键词: Adult; Affect; Age; Aging; Animal Model; Behavior; Behavior Therapy; Behavioral; Bioinformatics; Biological Models; Biology of Aging; Brain; Brain region; California; Cells; Characteristics; Clinical; Dementia; Diagnostic; Disease; Disease model; Doctor of Philosophy; Elderly; Empathy; Endocrine; Exhibits; Fiber; Foundations; Frontotemporal Dementia; Funding; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Image; Immunohistochemistry; Impairment; Incidence; Intervention; K-Series Research Career Programs; Knock-out; Lead; Link; Maintenance; Maps; Mediating; Mediator; Mentors; Mentorship; Methods; Microtus; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; Monitor; Motivation; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Neurosecretory Systems; Nucleus Accumbens; Oxytocin; Oxytocin Receptor; PGRN gene; Pair Bond; Pathology; Pathway interactions; Patient-Focused Outcomes; Pattern; Photometry; Physicians; Physiology; Population; Positioning Attribute; Program Development; Psychiatrist; Receptor Signaling; Research; Research Methodology; Research Personnel; Rodent; Role; San Francisco; Scientist; Signal Transduction; Social Behavior; Social isolation; Symptoms; System; Testing; Tissues; Training; Universities; Viral; Work; age related; aged; behavior change; brain health; burden of illness; career; career development; cell type; comparative genomics; dementia risk; design; effective therapy; experience; gene conservation; genetic signature; in vivo calcium imaging; innovation; interest; learning strategy; model organism; mutant; neural; neural circuit; neural patterning; neuromechanism; neuropathology; neurophysiology; neuropsychiatric disorder; neuropsychiatry; new therapeutic target; novel; novel strategies; prairie vole; programs; risk variant; single nucleus RNA-sequencing; skills; social; social attachment; social cognition; social deficits; social vulnerability; therapeutic target; tool; transcriptome sequencing; transcriptomic profiling; transcriptomics

PROJECT SUMMARY/ABSTRACT Social cognition, and social attachment in particular, is often significantly disrupted in age-related neuropsychiatric disease. Frontotemporal dementia (FTD) is characterized by disruptions in social attachment behavior and loss of empathy early in the course of the disease. We currently lack a mechanistic understanding of the neurobiology of attachment behavior or its disruption in disease and have no interventions for these profoundly impairing symptoms, despite their potential as early diagnostic and therapeutic targets. The candidate for this K08 Mentored Career Development Award is a physician scientist and psychiatrist at the University of California, San Francisco. Her long-term career goal is to understand the impact of aging and neurodegenerative disease on the neurobiology of social behavior. The overall objective of the proposed research plan is to elucidate the molecular and neural circuit pathways mediating social attachment changes in FTD. The candidate proposes to use the prairie vole, a unique model organism that forms long-term adult pair bonds, to understand the neurobiology of social attachment. In her preliminary work, she has used molecular genetic tools to knock out progranulin (Grn), one of the most common genetic causes of FTD, in the vole. This work represents an innovative and novel approach to studying attachment deficits in dementia. She proposes to first examine the effects of loss of genes relevant to social behavior and to FTD, the oxytocin receptor (OxtR) and Grn, using both behavioral and transcriptomic profiling with age. She will then test the hypothesis that loss of OxtR and Grn converge on specific neural circuits responsible for the presentation of social deficits, using in vivo calcium imaging and viral tracing methods to map patterns of neural activity and connectivity. The proposed research is significant because it seeks to mechanistically link the risk genes associated with neurodegenerative disease to the neural circuit changes and social attachment disruptions characteristic of these diseases. This proposal presents a five-year research career development program designed to provide a foundation for an independent research program. The specific career development goals outlined in this application include training in systems neuroscience, advanced sequencing and bioinformatics methods, and in translational neurodegenerative disease research. These skills build on the candidate's prior experience in neuroendocrine signaling and its role in aging biology and neurodegenerative disease. The primary mentorship team (Drs. Manoli, Miller, and Ingraham) has expertise in molecular genetics, systems neurophysiology, and translational FTD research. Other key contributors and collaborators provide expertise in vole behavior (Dr. Bales), transcriptomics and bioinformatics (Dr. Willsey), and comparative genomics (Dr. Yokoyama). The direct training in research methodology and career support will allow the candidate to transition to a career as an independent investigator in aging and brain health.

项目总结/摘要 社会认知，特别是社会依恋，在与年龄相关的疾病中往往会受到严重干扰。 神经精神疾病额颞叶痴呆（FTD）的特征是社会依恋的破坏 行为和同情心的丧失。我们目前缺乏一种机械的理解 依恋行为的神经生物学或其在疾病中的破坏，并没有干预这些 严重损害症状，尽管它们作为早期诊断和治疗靶点的潜力。候选 获得K 08职业发展指导奖的是密歇根大学的一位医生、科学家和精神病学家。 加州，旧金山弗朗西斯科。她的长期职业目标是了解衰老和神经变性的影响 疾病对社会行为的神经生物学影响。拟议研究计划的总体目标是阐明 介导FTD中社会依恋变化的分子和神经回路通路。候选人提议 使用草原田鼠（一种独特的模式生物，可以形成长期的成年配对纽带）来了解 社会依恋的神经生物学在她的初步工作中，她使用分子遗传工具敲除了 颗粒蛋白前体（Grn）是田鼠中FTD最常见的遗传原因之一。这项工作代表了一个 创新和新颖的方法来研究痴呆症的依恋缺陷。她建议首先审查 与社会行为和FTD、催产素受体（OxtR）和Grn相关的基因缺失的影响， 行为和转录组学分析随年龄的变化。然后，她将测试假设， 使用体内钙离子，集中在负责社交缺陷呈现的特定神经回路上 成像和病毒追踪方法来绘制神经活动和连接的模式。拟议的研究是 重要的是，它试图将与神经退行性疾病相关的风险基因与 神经回路的改变和社会依恋的破坏是这些疾病的特征。这项建议 提出了一个为期五年的研究职业发展计划，旨在提供一个独立的基础 研究计划。本申请中概述的具体职业发展目标包括系统培训 神经科学，先进的测序和生物信息学方法，并在翻译神经退行性疾病 疾病研究。这些技能建立在候选人在神经内分泌信号及其作用方面的经验之上 衰老生物学和神经退行性疾病。主要指导团队（马诺利博士、米勒博士和 英格拉哈姆）在分子遗传学、系统神经生理学和FTD转化研究方面具有专长。其他 主要贡献者和合作者提供田鼠行为（贝尔斯博士），转录组学和 生物信息学（Willsey博士）和比较基因组学（Yokoyama博士）。研究中的直接培训 方法和职业支持将使候选人能够过渡到作为独立调查员的职业生涯 在衰老和大脑健康方面。