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.

项目总结/摘要 亲人的死亡是巨大的痛苦，每年影响美国800万人，是一个重大的问题。 精神和医学疾病的原因，包括精神后遗症，如抑郁，焦虑， 滥用药物和复杂的悲伤探索社交损失与大脑之间关系的研究 功能稀疏，新出现的疾病的诊断标准是基于症状群，而不是 而不是神经或遗传异常，阻碍了对新治疗靶点的追求。这突出表明， 对于社会损失的适当动物模型，以反映行为神经学，以探索神经生物学， 机制等最近，我们已经开发了一种社会损失的动物模型， 草原田鼠（Microtus ochrogaster），表现出类似的行为学和破坏正常 中脑边缘奖励通路，发生在人类的社会损失。我们的长期目标是剖析 社会损失的神经回路（包括中脑边缘奖励和皮质边缘疼痛通路），定义遗传 生物标志物的个人脆弱性和弹性的社会损失，并制定治疗干预， 神经和行为症状持续存在我们理论上的社交损失神经回路集中在 边缘系统，其接收来自腹侧被盖区（VTA）的多巴胺（DA）信号， 增强动机状态和情感效价。我们的具体目标将测试以下假设：（目的 1)特定关系类型的丢失可能会将持久更改传播到功能和结构 中脑边缘回路的连接;（目的2）长期社会损失的行为症状是基于 破坏DA神经传递，并可通过光刺激和化学神经支配缓解 沿着选择的中脑边缘通路;（AIM 3）在大鼠海马中特异性DA受体的表达和活性的变化。 在失去和寻找伴侣的过程中，中脑边缘区与波动的动机状态相关联。 线索这一贡献是重要的，因为它将建立光刺激靶向的几种途径， 药理学方法有可能调节社会损失的行为神经学 通过中脑边缘活动。这项研究是创新的，因为它是第一个系统的评估， 在动物模型中伴侣丢失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，因为它可以扩展新兴心理健康的诊断标准。 疾病超越症状集群，并确定新的治疗靶点的神经化学底物。