Adolescence, sex and timing of neural vulnerability

描述(由申请人提供)：青春期是一个独特的过渡期，长期以来一直以情绪动荡、更容易上瘾以及抑郁症和精神分裂症等精神障碍的发作而闻名。此时发生的神经重组可能导致对包括应激在内的环境的脆弱性增加。特别是，人类的前额叶皮质在青春期会随着不同的时间和性别的轨迹斜率而减小(Lenot等人，2007年)。这意味着，大小减小的细胞基础在男性和女性之间也一定不同。在人类和其他物种的青春期，神经元、树突、突触和受体的修剪发生在前额叶皮质(Huttenlocher，1979；Lewis，1997；Andersen等人，2000；Markham等人，2007)，而且在极少数情况下，修剪有性别差异的迹象。这里将在目标1中研究修剪的时机，在这个时机中性别差异的含义将在目标2中用压力进行测试。人类青春期的压力是一种已知的精神病理学倾向，可以引发症状(Grant等人，2004；Arnsten，2011)，这表明正常的剪枝被破坏。青少年对压力的行为反应存在性别差异(罗密欧；2010年；威尔金等人，2012年)。这可能导致青春期精神分裂症的发病率和严重程度(男性与女性之比为1.4：1)，以及抑郁障碍终生发病率(女性与男性之比为2：1)(Abel等人，2010年；Parker&Bronchie，2010年)。因此，性和压力在青春期潜在脆弱回路的塑造中相互作用。我们的长期目标是了解青春期的神经变化是如何出错的，从而在性二态模式中引发精神病态。这项建议的中心假设是，在青春期修剪的时间上存在性别差异，这导致了不同的应激易感性。

DESCRIPTION (provided by applicant): Adolescence is a unique transitional time, long noted for emotional turmoil, increased vulnerability to addiction and the onset of psychiatric disorders such as depression and schizophrenia. The neural restructuring that occurs at this time may result in increased vulnerability to the environment including stress. The prefrontal cortex of humans, in particular, decreases in size during adolescence with different timing and slope of trajectories in each sex (Lenroot et al, 2007). This means that the cellular basis for the size decrease must also differ between males and females. Pruning of neurons, dendrites, synapses and receptors occurs in the prefrontal cortex during adolescence in humans and other species (Huttenlocher, 1979; Lewis, 1997; Andersen et al, 2000; Markham et al, 2007), and there are indications of sex differences in pruning in the rare instances where they have been examined. The timing of pruning will be investigated here in Aim 1, and the implications of sex differences in this timing will be tested with stress in Aim 2. Stress during human adolescence is a known predisposition for psychopathology and can precipitate symptoms (Grant et al, 2004; Arnsten, 2011) which indicates a disruption of normal pruning. There are sex differences in the behavioral reaction to stress in adolescents (Romeo; 2010; Wilkin et al, 2012). This may contribute to the incidence and severity of schizophrenia during adolescent onset (1.4:1 male>female) as well as in the lifetime occurrence of depressive disorders (2:1 female>male) (Abel et al, 2010; Parker & Brotchie, 2010). Thus sex and stress interact in the sculpting of potentially vulnerable circuits during adolescence. Our long-term goal is to understand how the neural changes during adolescence can go awry to precipitate psychopathologies in a sexually dimorphic pattern. The central hypothesis of the present proposal is that there are sex differences in the timing of pruning during adolescence that result in differential vulnerabilitiesto stress.