Neurocircuit of Partner-seeking Following Social Loss

社交损失后寻求伴侣的神经回路

• 批准号: 10651414
• 负责人: Adam Steven Smith
• 金额: $ 65.83万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651414
• 关键词: Anatomy; Animal Model; Animals; Anterior; Anxiety; Behavior; Behavioral; Behavioral Symptoms; Brain; Brain region; Breeding; Cells; Cessation of life; Chemicals; Corpus striatum structure; Coupled; Cues; DRD1 gene; DRD2 gene; Disease; Distress; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Emotional; Evaluation; Female; Fiber; Fiber Optics; G-Protein-Coupled Receptors; Genetic Markers; Goals; Grief reaction; Housing; Human; Implant; Individual; Label; Laboratory Animal Models; Lesion; Life; Limbic System; Literature; Medical; Mental Depression; Mental disorders; Microtus; Modeling; Molecular Abnormality; Morbidity - disease rate; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Odors; Outcome; Oxidopamine; Pain; Pair Bond; Partner in relationship; Pathway interactions; Periodicity; Pharmacology; Phenotype; Photometry; Research; Rewards; Rodent; Same-sex; Scanning; Signal Transduction; Social Behavior; Social isolation; Stress; Substance abuse problem; Synapses; Testing; Therapeutic Intervention; Time; Ventral Tegmental Area; Vulnerable Populations; awake; calcium indicator; cingulate cortex; diagnostic criteria; dopaminergic neuron; experience; in vivo; innovation; insight; loved ones; mRNA Expression; male; mesolimbic system; nerve supply; neural; neural circuit; neurobiological mechanism; neurochemistry; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; neuroregulation; neurotransmission; new therapeutic target; optical fiber; optogenetics; peer; pharmacologic; postsynaptic; prairie vole; preference; presynaptic; receptor; receptor binding; resilience; response; sensor; social; social separation; symptom cluster; targeted treatment; therapeutic target; tool; transmission process; yearning

PROJECT SUMMARY/ABSTRACT The death of a loved one is monumentally painful, impacting 8 million in the US annually, and is a significant cause of psychiatric and medical morbidity, including psychiatric sequelae such as depression, anxiety, substance abuse, and complicated grief. Research exploring the association between social loss and brain function are sparse, and diagnostic criteria for the emerging disorders are based on symptom clusters rather than neural or genetic abnormalities, hindering pursuits of new therapeutic targets. This highlights the need for proper animal models for social loss to mirror the behavioral symptomology to explore the neurobiological mechanisms. Recently, we have developed an animal model of social loss using the socially monogamous prairie vole (Microtus ochrogaster), which manifest similar behavioral symptomology and disruption to normal mesolimbic reward pathway that occurs in social loss in humans. Our long-term goals are to dissect the neurocircuitry of social loss (including the mesolimbic reward and corticolimbic pain pathways), define genetic biomarkers of individual vulnerability and resiliency to social loss, and develop therapeutic intervention of neural and behavioral symptoms that appear persistent. Our theoretical neurocircuit of social loss centers in the limbic system, which receives dopamine (DA) signaling from the ventral tegmental area (VTA) and augments motivational state and emotional valence. Our specific aims will test the following hypotheses: (AIM 1) Loss of specific relationship types can propagate persistent change to the functional and structural connectivity of mesolimbic circuits; (AIM 2) Behavioral symptoms of long-term social loss are based on disruption to DA neurotransmission and can be alleviated with photostimulation and chemical innervations along select mesolimbic pathways; (AIM 3) Changes to the expression and activity of specific DA receptors in mesolimbic regions are coupled to fluctuating motivational states during loss and seeking of partner-associated cues. This contribution is significant since it will establish that several pathways targeted by photostimulation and pharmacological approaches have the potential to regulate behavioral symptomology of social loss through mesolimbic activity. The proposed research is innovative as it is the first systematic evaluation of neuromodulation of the mesolimbic system during partner loss in an animal model. Insight into the neuromodulation of social loss is impactful as it may expand diagnostic criteria for the emerging mental health disorders beyond symptom clusters and identifies neurochemical substrates for new therapeutic targets.

项目摘要/摘要 亲人的死是有着痛苦的痛苦，每年在美国影响800万，这是一个重要的 精神病和医疗发病率的原因，包括抑郁症，焦虑，诸如抑郁症， 药物滥用和复杂的悲伤。研究探索社会损失与大脑之间的关联 功能很少，新兴疾病的诊断标准是基于症状簇的 比神经或遗传异常，阻碍了新的治疗靶标的追求。这突出了需求 对于适当的动物模型，以反映行为症状探索神经生物学的行为症状 机制。最近，我们使用社会一夫一妻制开发了一种社会损失的动物模型 草原Vole（Microtus ochrogaster），表现出相似的行为症状和正常干扰 中左右奖励途径发生在人类的社会损失中。我们的长期目标是剖析 社会损失的神经循环（包括中唇奖励和皮质唇痛途径），定义遗传 个人脆弱性和对社会损失的弹性的生物标志物，并发展的治疗干预措施 看起来持续存在的神经和行为症状。我们社会损失中心的理论神经回路 边缘系统，该系统从腹侧对段区域（VTA）接收多巴胺（DA）和 增强动机状态和情感价。我们的具体目标将检验以下假设：（目标 1）特定关系类型的丧失可以传播到功能和结构的持续变化 中边路电路的连通性； （AIM 2）长期社会损失的行为症状是基于 对DA神经传递的破坏，可以通过光刺激和化学神经来缓解 沿着精选的中脑途径； （AIM 3）改变特定DA受体在 中边缘区域与损失和寻求伴侣相关的动机状态耦合 提示。这种贡献很重要，因为它将确定光刺激针对的几种途径 药理学方法有可能调节社会损失的行为症状 通过中唇活性。拟议的研究具有创新性，因为它是对 在动物模型中，伴侣损失期间中溶液系统的神经调节。深入了解 神经调节社会损失具有影响力，因为它可能会扩大新兴心理健康的诊断标准 超出症状簇的疾病，并确定了新的治疗靶标的神经化学底物。