Early Development of Social-Emotional Behaviors and Amygdala Function

社会关系和情感行为的破坏是精神分裂症最早发作的症状之一，通常始于青春期或有时儿童晚期。精神分裂症的这些终身社会行为障碍的神经生物学机制知之甚少，缺乏有效的治疗方法。然而，多方面的证据表明，杏仁核回路中的NMDA信号和表观遗传机制在早期社会行为发展中起着重要作用。项目II将测试的总体假设，即破坏基底外侧杏仁核（BLA）的NMDA受体信号将破坏社会情绪行为的早期发展，GABA信号或表观遗传标记的药理学调节将拯救社会性发展。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。使用NMDA NR 1亚型小鼠或杏仁核特异性缺失NMDA NR 1小鼠的行为研究，我们将测试以下假设：杏仁核中NMDA受体的破坏将导致社交选择测试中社交能力降低，恐惧条件反射受损，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亲和行为早期发展中的作用。使用双标记免疫组织化学（具有GABA能或谷氨酸能神经元标记物的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期间将显示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：确定发育早期NMDA NR 1突变体中BLA的生理激活。我们将测试的假设，NMDA NR 1亚型将显示减少抑制BLA活性的刺激BLA的多巴胺能传入，以及相关的传入将主要是丘脑-BLA青春期前和青春期后的前额-BLA。这些机制研究可能会导致精神分裂症阴性症状的新治疗方法的发展。

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.