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

基本信息

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
项目类别：
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

项目摘要

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。