Neurocircuit of Partner-seeking Following Social Loss

项目摘要/摘要 亲人的死亡是极其痛苦的，在美国每年影响800万人，是一个重要的 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痛。探索社会损失与大脑之间关系的研究 功能是稀疏的，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。这突出了以下需要 以合适的动物模型来反映社会损失的行为症状，探讨神经生物学 机械装置。最近，我们利用社会一夫一妻制建立了一个社会损失的动物模型。 草原田鼠(Microtus Ochrogaster)表现出与正常田鼠相似的行为症状和干扰 在人类的社会损失中出现的中脑边缘奖赏通路。我们的长期目标是剖析 社会损失的神经回路(包括中脑边缘奖赏通路和皮质边缘痛通路)，定义了基因 个体对社会损失的脆弱性和恢复力的生物标记物，并开发治疗干预措施 神经和行为症状似乎是持续性的。我们关于社会损失的理论神经回路集中在 边缘系统，从腹侧被盖区(VTA)接收多巴胺(DA)信号，以及 增强激励状态和情感效价。我们的具体目标将检验以下假设：(Aim 1)失去特定的关系类型可能会将持久的变化传播到功能和结构 (目标2)长期社会失落的行为症状是基于 光刺激和化学神经支配可减轻DA神经传递障碍 (AIM 3)特异性DA受体表达和活性的变化 在失去和寻找伴侣的过程中，中脑边缘区域与波动的动机状态相耦合 暗示。这一贡献意义重大，因为它将确立光刺激靶向的几条途径 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。这项拟议的研究具有创新性，因为这是第一次对 动物模型中伴侣丧失时中脑边缘系统的神经调节。洞察 社交缺失的神经调节是有影响的，因为它可能扩大新兴精神健康的诊断标准 超越症状群的疾病，并为新的治疗靶点确定神经化学底物。

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.