Project 2

目前建议的主要目标是确定年轻人的分子和神经行为异常， 与精神分裂症相关的微管相关基因的基因突变导致的成年 (SZ)，如PCM 1，DPYSL 2和16 p11拷贝数变异（CNVs），以及这些改变如何被 青少年的社会孤立加剧了这种情况，在年轻的成年期产生了全面的精神障碍。我们 假设具有微管相关基因突变的小鼠将显示应激相关分子， 青春期和/或青年期的改变和异常前额叶皮层（PFC）成熟， 导致类似于SZ的不同尺寸的成年行为表型。目标1将确定遗传 突变产生的神经行为异常，可因青少年的社会孤立而加剧， 小鼠我们将确定遗传危险因素对SZ相关行为的影响以及 GABA能中间神经元和锥体神经元的树突棘在PFC中。我们还将检查这些 青少年的社会孤立加剧了这种表型。目标2将确定基因突变- 产生了分子变化，这些变化可以通过青少年的社会孤立而加剧。具体来说，我们将 评估候选应激相关因子的表达和PFC中的总体转录组变化。目的 3将确定从两个人收集的外周血样本中与应激相关的分子的改变。 独立的前瞻性队列，并将人类结果与小鼠模型的结果进行比较。的 该项目将确定由基因突变引起的应激相关分子表达的改变， 在青春期PFC成熟受损和成年后的行为后果，这可能是 易受青少年社会孤立的不利影响。我们的项目将促进未来的发展 的预后措施和生物标志物，以帮助确定前驱症状的疾病。

The main goal of the current proposal is to identify the molecular and neurobehavioral abnormalities in young adulthood resulting from the genetic mutations of the microtubule-related genes associated with schizophrenia (SZ), such as PCM1, DPYSL2, and 16p11 copy number variations (CNVs), and how these alterations can be exacerbated by adolescent social isolation to produce a full-blown psychiatric disorder in young adulthood. We hypothesize that mice with the microtubule-associated genetic mutations will display stress-related molecular alterations and abnormal prefrontal cortex (PFC) maturation during adolescence and/or young adulthood, leading to adult behavioral phenotypes resembling different dimensions of SZ. Aim 1 will identify the genetic mutations-produced neurobehavioral abnormalities that can be exacerbated by adolescent social isolation in mice. We will identify the effects of the genetic risk factors on SZ-related behaviors as well as maturation of GABAergic interneurons and dendritic spines of pyramidal neurons in the PFC. We will also examine if these phenotypes are exacerbated by adolescent social isolation. Aim 2 will determine the genetic mutations- produced molecular changes that can be intensified by adolescent social isolation. Specifically, we will evaluate expression of the candidate stress-related factors and the global transcriptome changes in PFC. Aim 3 will identify alterations in stress-associated molecules in peripheral blood samples collected from two independent prospective cohorts and compare the human results with those from the mouse models. The project will determine alteration in stress-related molecular expression induced by genetic mutations, leading to impaired PFC maturation during adolescence and adult behavioral consequences, which may underlie susceptibility to detrimental effects of adolescent social isolation. Our project will facilitate future development of prognostic measures and biomarkers to help identify prodromal signs of the disease.