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.

项目摘要/摘要 社会认知，特别是社会依恋，在与年龄相关的疾病中经常受到严重干扰 神经精神疾病。额颞性痴呆(FTD)的特征是社交依恋中断 在疾病早期的行为和同理心的丧失。我们目前缺乏机械性的理解 依恋行为的神经生物学或其在疾病中的破坏，并且没有对这些进行干预 严重损害症状，尽管它们有可能成为早期诊断和治疗的目标。候选人 本次K08指导职业发展奖获得者是加州大学的内科医生、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 疾病对社会行为的神经生物学的影响。拟议研究计划的总体目标是澄清 FTD中调节社会依恋变化的分子和神经回路通路。候选人提出了 草原田鼠是一种独特的模式生物，可以形成长期的成体配对纽带，用来理解 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 原颗粒蛋白(Grn)是田鼠FTD最常见的遗传原因之一。这部作品代表了一种 研究痴呆症患者依恋缺陷的创新方法。她建议首先研究 与社会行为和FTD、催产素受体(OXTR)和GRN相关的基因丢失的影响 随年龄增长的行为和转录特征分析。然后，她将测试OXtr和GRn丢失的假设 使用体内的钙，汇聚到负责社交缺陷表现的特定神经回路上 成像和病毒跟踪方法，以绘制神经活动和连接的模式。拟议的研究是 意义重大，因为它试图机械地将与神经退行性疾病相关的风险基因与 这些疾病的特点是神经回路改变和社会依恋中断。这项建议 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，高级测序和生物信息学方法，以及翻译神经退行性变 疾病研究。这些技能建立在应聘者先前在神经内分泌信号及其作用方面的经验基础上 在衰老生物学和神经退行性疾病方面。主要指导团队(马诺利博士、米勒博士和 Ingraham)在分子遗传学、系统神经生理学和翻译FTD研究方面拥有专业知识。其他 主要贡献者和合作者提供田鼠行为、转录和 生物信息学(威尔西博士)和比较基因组学(横山博士)。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。