Early Development of Social-Emotional Behaviors and Amygdala Function

社会关系和情感行为的中断是精神分裂症最早出现的症状之一，通常开始于青春期，有时开始于童年后期。精神分裂症终生社会行为障碍的神经生物学机制尚不清楚，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育中发挥重要作用。项目II将测试一个整体假设，即基底外侧杏仁核（BLA）中NMDA受体信号的破坏将破坏社会情感行为的早期发展，而GABA信号或表观遗传标记的药理调节将恢复社交能力的发展。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畸形小鼠或杏仁核特异性缺失NMDA NR1小鼠的行为研究，我们将验证以下假设：杏仁核中NMDA受体的破坏将导致社交选择测试中的社交能力降低，恐惧条件反射受损，从青春期前开始减少寻求奖励的行为，以及GABA-B受体兴奋剂或HDAC抑制剂将恢复社交能力的发展。特定目标2：确定BLA细胞类型和表观遗传机制在社会依恋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，我们将验证这样的假设：社交能力降低的小鼠在社交互动中会表现出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。特异性目的3：确定NMDA NR1突变体在早期发育过程中BLA的生理激活。我们将验证NMDA NR1低形态通过刺激谷氨酸能传入神经来降低BLA活性的假设，并且相关传入神经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.