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.

项目概要/摘要 社会认知，尤其是社会依恋，在与年龄相关的人群中常常受到严重干扰。 神经精神疾病。额颞叶痴呆 (FTD) 的特点是社会依恋受损 疾病早期的行为和同理心丧失。我们目前缺乏机制理解 依恋行为的神经生物学或其对疾病的破坏，并且对这些没有干预措施 尽管它们具有作为早期诊断和治疗目标的潜力，但仍严重损害症状。候选人 获得 K08 指导职业发展奖的是英国大学的医学科学家和精神病学家 加利福尼亚州、旧金山。她的长期职业目标是了解衰老和神经退行性疾病的影响 疾病对社会行为神经生物学的影响。拟议研究计划的总体目标是阐明 介导 FTD 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（一种形成长期成年配对关系的独特模式生物）来了解 社会依恋的神经生物学。在她的前期工作中，她使用分子遗传工具来敲除 颗粒体蛋白前体 (Grn) 是田鼠 FTD 最常见的遗传原因之一。这项工作代表了一个 研究痴呆症依恋缺陷的创新方法。她建议首先检查 与社会行为和 FTD 相关的基因、催产素受体 (OxtR) 和 Grn 丢失的影响，使用两者 随年龄变化的行为和转录组分析。然后她将检验 OxtR 和 Grn 丢失的假设 使用体内钙集中于负责呈现社交缺陷的特定神经回路 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 意义重大，因为它试图将与神经退行性疾病相关的风险基因与 这些疾病的特征是神经回路的变化和社会依恋的破坏。这个提议 提出了一个为期五年的研究职业发展计划，旨在为独立的研究奠定基础 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、先进测序和生物信息学方法以及转化神经退行性疾病 疾病研究。这些技能建立在候选人之前在神经内分泌信号传导及其作用方面的经验基础上 衰老生物学和神经退行性疾病。主要导师团队（Manoli 博士、Miller 博士和 Ingraham）拥有分子遗传学、系统神经生理学和转化 FTD 研究方面的专业知识。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）。研究直接培训 方法论和职业支持将使候选人能够过渡到独立调查员的职业生涯 在衰老和大脑健康方面。