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.

项目概要/摘要 亲人的去世是巨大的痛苦，每年影响美国 800 万人，是一个重大事件 精神和医学发病的原因，包括精神后遗症，如抑郁、焦虑、 药物滥用和复杂的悲伤。研究探索社交损失与大脑之间的关系 功能稀疏，新出现疾病的诊断标准基于症状群而不是 而非神经或遗传异常，阻碍了对新治疗目标的追求。这凸显了需要 寻找适当的社会损失动物模型来反映行为症状学，探索神经生物学 机制。最近，我们利用社会一夫一妻制开发了一种社会损失动物模型 草原田鼠（Microtus ochrogaster），表现出类似的行为症状和对正常的破坏 人类社交损失中发生的中脑边缘奖励途径。我们的长期目标是剖析 社交损失的神经回路（包括中脑边缘奖励和皮质边缘疼痛通路），定义遗传 个人对社会损失的脆弱性和复原力的生物标志物，并制定治疗干预措施 神经和行为症状似乎持续存在。我们的社会损失理论神经回路中心在 边缘系统，接收来自腹侧被盖区 (VTA) 的多巴胺 (DA) 信号 增强动机状态和情绪效价。我们的具体目标将测试以下假设：（AIM 1) 特定关系类型的丢失可能会将持续的变化传播到功能和结构上 中脑边缘回路的连通性； (AIM 2) 长期社交丧失的行为症状基于 对 DA 神经传递的破坏可以通过光刺激和化学神经支配来缓解 沿着选定的中脑边缘通路； (AIM 3) 特定 DA 受体表达和活性的变化 在失去和寻求伴侣相关的过程中，中脑边缘区域与波动的动机状态相耦合 提示。这一贡献意义重大，因为它将确定光刺激针对的几种途径 和药理学方法有可能调节社会损失的行为症状 通过中脑边缘活动。所提出的研究具有创新性，因为它是第一个系统评估 动物模型中失去伴侣期间中脑边缘系统的神经调节。洞察 社交损失的神经调节是有影响力的，因为它可能会扩大新兴心理健康的诊断标准 超越症状群的疾病，并确定新治疗靶点的神经化学底物。