The neuromolecular basis of adaptation to bond loss

适应键损失的神经分子基础

• 批准号: 10565940
• 负责人: Zoe Rebecca Donaldson
• 金额: $ 57.25万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565940
• 关键词: Ablation; Address; Adult; Age; Aggressive behavior; Animal Model; Animals; Atlases; Behavior; Behavior assessment; Behavioral; Bereavement; Biological; Biological Process; Brain; Cells; Data; Disease; Distress; Emotional; Exhibits; Face; Failure; Future; Gene Activation; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Grief reaction; Health; Human; Immediate-Early Genes; Impaired health; Impairment; In Situ Hybridization; Individual; Intervention; Investigation; Maintenance; Maps; Mediating; Mental disorders; Microtus; Modeling; Molecular; Neurons; Nucleus Accumbens; Pain; Pair Bond; Partner in relationship; Pathologic; Pattern; Persons; Phenotype; Physiological; Play; Population; Process; Proxy; Risk; Rodent Model; Role; Series; Social Behavior; Social isolation; Spouses; Study models; Testing; Therapeutic; Time; biological adaptation to stress; daily functioning; diphtheria toxin fragment A; experience; experimental study; improved; insight; loved ones; neural; novel; pandemic disease; prairie vole; preference; repaired; response; selective expression; sex; single-cell RNA sequencing; social; societal costs; therapeutic target

Project Summary Loss of a loved one elevates the risk for physical and mental illness and leads to impaired daily function. For most people, the deleterious effects of loss improve with time. However, in a subset of bereaved individuals, the failure to adapt leads to pathological manifestations of loss and an extension of bereavement-associated health impairments. A lack of investigation into the neuronal and molecular processes that underlie healthy adaptation to loss has hampered our ability to ameliorate the negative consequences of loss. To address this gap in our understanding, we propose to use partner separation in monogamous prairie voles to operationally produce loss. Socially monogamous prairie voles form life-long pair bonds and exhibit distress upon partner separation. However, pairs bonds fade with time after partner separation, as evidenced by reduced bonding- related behaviors. To identify the key neural and molecular changes that underlie the adaptive processes engaged after loss of a partner, we will compare voles with intact partner bonds to those who have been separated from their partner. In Aim 1, we will comprehensively assess behavioral and transcriptional responses to partner separation over time. In Aim 2, we will ask how the molecular identity of the neurons responsive to partner interaction changes as a function of separation time. Finally, in Aim 3 we will test the hypothesis that ablation of partner-active neurons facilitates bond dissolution and enables the vole to form a new bond. Together, these experiments will provide the first insights into key neuromolecular changes that underlie adaptation to loss, thereby representing potential therapeutic targets for treating the negative aspects of grief and Prolonged Grief Disorder.

项目概要 失去亲人会增加身体和精神疾病的风险，并导致日常功能受损。为了 对大多数人来说，损失的有害影响会随着时间的推移而改善。然而，在一部分失去亲人的人中， 未能适应会导致丧失的病理表现以及与丧亲之痛相关的健康状况的延长 损伤。缺乏对健康背后的神经元和分子过程的研究 对损失的适应阻碍了我们改善损失负面后果的能力。为了解决这个问题 由于我们的理解存在差距，我们建议利用一夫一妻制草原田鼠的伴侣分离来操作 产生损失。实行一夫一妻制的草原田鼠会形成终生的伴侣关系，并对伴侣表现出痛苦 分离。然而，在伴侣分居后，夫妻关系会随着时间的推移而逐渐消失，这一点可以通过减少关系来证明—— 相关行为。识别适应性过程背后的关键神经和分子变化 在失去合伙人后订婚的田鼠，我们将把拥有完整合伙人关系的田鼠与那些已经订婚的田鼠进行比较 与他们的伴侣分开。在目标 1 中，我们将全面评估行为和转录 随着时间的推移，对伴侣分离的反应。在目标 2 中，我们将询问神经元的分子身份如何 响应伴侣交互变化作为分离时间的函数。最后，在目标 3 中我们将测试 假设消融伴侣活跃神经元会促进化学键溶解并使田鼠能够形成 新债券。总之，这些实验将提供对关键神经分子变化的初步见解，这些变化 是对损失的适应的基础，因此代表了治疗消极方面的潜在治疗目标 悲伤和长期悲伤障碍。