Early Development of Social-Emotional Behaviors and Amygdala Function

社会情感行为和杏仁核功能的早期发展

• 批准号: 8704386
• 负责人: EDWARD S BRODKIN
• 金额: $ 31.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704386
• 关键词: Acute; Adolescence; Adult; Age; Agonist; Amygdaloid structure; Antipsychotic Agents; Baclofen; Behavior; Behavioral; Bilateral; Brain; Cells; ChIP-seq; Childhood; Coupling; DNA Methylation; Data; Defect; Development; Dyes; Emotional; Epigenetic Process; FOS gene; Gene Expression; Glutamates; Histone Acetylation; Histone Deacetylase Inhibitor; Image; Immunohistochemistry; Infusion procedures; Injection of therapeutic agent; Instruction; Interneurons; Label; Lead; MS-275; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; NR1 gene; Neurons; Pathway interactions; Physiological; Play; Puberty; Receptor Signaling; Rewards; Risperidone; Role; Saline; Schizophrenia; Signal Transduction; Slice; Social Behavior; Social Development; Social Interaction; Sucrose; Symptoms; Testing; Thalamic structure; Tissues; affiliative behavior; calmodulin-dependent protein kinase II; cell type; cohort; conditioned fear; disability; early onset; effective therapy; gamma-Aminobutyric Acid; mind control; mouse model; mutant; neurobiological mechanism; novel; postnatal; preference; recombinase; relating to nervous system; research study; social; transcriptome sequencing; voltage

Disruptions of social affiliative and emotional behaviors are among the earliest-onset symptoms of schizophrenia, often beginning during adolescence or sometimes late childhood. The neurobiological mechanisms of these lifelong social behavior disabilities of schizophrenia are poorly understood, and effective treatments are lacking. However, multiple lines of evidence suggest that NMDA signaling and epigenetic mechanisms in amygdala circuits play important roles in early social behavior development. Project II will test the overall hypothesis that disruption of NMDA receptor signaling in basolateral amygdala (BLA) will disrupt early development of socioemotional behaviors, and that pharmacologic modulation of GABA signaling or epigenetic marks will rescue sociability development. Specific Aim 1: Determine the role of amygdala NMDA signaling in early development of socioemotional behaviors. Using behavioral studies of NMDA NR1 hypomorph mice or mice with amygdala-specific deletions of NMDA NR1, we will test the hypotheses that disruption of NMDA receptors in the amgydala will lead to reduced sociability in the social choice test, impaired fear conditioning, and reduced reward seeking behaviors starting in prepubescence, and that a GABA-B agonist or an HDAC inhibitor will rescue sociability development. Specific Aim 2: Determine the role of BLA cell types and epigenetic mechanisms in early development of social affiliative behaviors. Using double-labeling immunohistochemistry (Fos with markers of GABAergic or glutamatergic neurons) and Chip-Seq, we will test the hypothesis that mice with reduced sociability will show reduced activation of BLA GABAergic interneurons during social interactions, as well as increased DNA methylation and decreased histone acetylation in the BLA. Specific Aim 3: Determine the physiological activation of BLA in NMDA NR1 mutants across early development. We will test the hypothesis that NMDA NR1 hypomorphs will show decreased inhibition of BLA activity by stimulation of glutamatergic afferents to BLA, and that the relevant afferents will be primarily thalamus-BLA prior to puberty and prefrontal-BLA after puberty. These mechanistic studies may lead to development of novel treatments for negative symptoms of schizophrenia.

社会归属和情感行为的破坏是精神分裂症最早出现的症状之一，通常开始于青春期或有时在儿童晚期。人们对精神分裂症这些终生社会行为障碍的神经生物学机制知之甚少，也缺乏有效的治疗方法。然而，多种证据表明杏仁核回路中的 NMDA 信号传导和表观遗传机制在早期社会行为发展中发挥着重要作用。项目 II 将测试总体假设，即基底外侧杏仁核 (BLA) 中 NMDA 受体信号传导的破坏将破坏社会情感行为的早期发展，而 GABA 信号传导或表观遗传标记的药理调节将挽救社交能力的发展。具体目标 1：确定杏仁核 NMDA 信号在社会情绪行为早期发展中的作用。通过对 NMDA NR1 亚型小鼠或杏仁核特异性缺失 NMDA NR1 的小鼠进行行为研究，我们将检验这样的假设：杏仁核中 NMDA 受体的破坏将导致社会选择测试中的社交性降低、恐惧调节受损以及青春期前开始的奖励寻求行为减少，并且 GABA-B 激动剂或 HDAC 抑制剂将拯救社交能力的发展。具体目标 2：确定 BLA 细胞类型和表观遗传机制在社会亲和行为早期发展中的作用。使用双标记免疫组织化学（带有 GABA 能或谷氨酸能神经元标记的 Fos）和 Chip-Seq，我们将测试以下假设：社交能力降低的小鼠在社交互动过程中 BLA GABA 能中间神经元的激活减少，以及 BLA 中 DNA 甲基化增加和组蛋白乙酰化减少。具体目标 3：确定 NMDA NR1 突变体在早期发育过程中 BLA 的生理激活。我们将测试这样的假设：NMDA NR1 亚型将通过刺激 BLA 的谷氨酸传入神经来减少对 BLA 活性的抑制，并且相关传入神经将主要是青春期前的丘脑-BLA 和青春期后的前额叶-BLA。这些机制研究可能会导致开发出治疗精神分裂症阴性症状的新疗法。