Early Development of Social-Emotional Behaviors and Amygdala Function

社交关系和情绪行为的中断是最早出现的症状之一 精神分裂症，常始于青春期，有时在儿童期晚期。神经生物学 精神分裂症患者这些终生社会行为障碍的机制尚不清楚，而且 缺乏有效的治疗方法。然而，多条证据表明，NMDA信号和 杏仁核环路中的表观遗传机制在早期社会行为发育中起着重要作用。 项目二将测试杏仁基底外侧核内NMDA受体信号传导中断的总体假设 (BLA)将扰乱社会情绪行为的早期发展，以及药物对 GABA信号或表观遗传标记将挽救社交能力的发展。具体目标1：确定角色 杏仁核NMDA信号在社会情绪行为早期发育中的作用。使用行为研究 NMDANR1低畸形症小鼠或杏仁核特异性NMDNR1缺失的小鼠，我们将测试 假设孤束核中NMDA受体的破坏将导致社交能力的降低 选择测试，恐惧条件反射受损，以及青春期前开始的寻求奖励行为减少， GABA-B激动剂或HDAC抑制剂将挽救社交能力的发展。具体目标2： 确定BLA细胞类型和表观遗传机制在社会性附属关系早期发育中的作用 行为。用双标记免疫组织化学(Fos)标记GABA能或谷氨酸能 神经元)和芯片序列，我们将检验这样的假设，即社交能力降低的小鼠将表现为减少 社会互动中BLA-GABA能中间神经元的激活以及DNA甲基化的增加 BLA中组蛋白乙酰化程度降低。具体目标3：测定白血球的生理活性 在NMDANR1突变体的早期发育过程中。我们将检验这样的假设：NMDA NR1亚型 可通过刺激谷氨酸能传入血乳酸而减少对血乳酸活性的抑制。 相关的传入主要是青春期前的丘脑-BLA和青春期后的前额-BLA。这些 机制研究可能会导致开发新的治疗精神分裂症阴性症状的方法。 相关性(请参阅说明)： 社交和情绪行为障碍是最早发生的、最致残的和最多的 难以治疗的精神分裂症症状。为了更好地了解所涉及的大脑机制和开放 为治疗开辟新的途径，该项目将使用小鼠模型来测试谷氨酸信号转导在 杏仁核在早期发育的社会和情绪行为与精神分裂症有关。

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 earty 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 behaivors 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 activafion 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. RELEVANCE (See instructions): Disruptions of social and emotional behaviors are some of the earliest-onset, most disabling, and most difficult-to-treat symptoms of schizophrenia. To better understand the brain mechanisms involved and open up new avenues for treatment, this project will use mouse models to test the role of glutamate signaling in the amygdala in early development of social and emofional behaviors relevant to schizophrenia.