Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Department of Psychology, The Ohio State University, Columbus, OH, USA.
Neuroscience. 2018 Oct 15;390:265-277. doi: 10.1016/j.neuroscience.2018.08.030. Epub 2018 Sep 1.
Adolescence is a window of vulnerability to environmental factors such as chronic stress that can disrupt brain development and cause long-lasting behavioral dysfunction, as seen in disorders like depression, anxiety, and schizophrenia. There are also sex differences in the prevalence of these disorders across the lifespan. However, the mechanisms of how adolescent stress contributes to neuropsychiatric phenotypes are not well understood, nor are the mediating effects of sex. We hypothesize that adolescent stress disrupts the γ-aminobutyric acid (GABA) system in the prefrontal cortex (PFC) in a sex-specific manner, as this system matures during adolescence and plays an important role in cognitive and emotional functioning. We exposed male and female mice to unpredictable chronic mild stress (UCMS) during adolescence (post-natal day [PND] 28-42). One cohort underwent testing for PFC-related behavioral and molecular changes 24 h following the cessation of stress (late adolescence); a separate cohort was tested approximately 2.5 weeks after the end of UCMS (adulthood). We observed an age-related decline in anxiety-like behaviors in control mice, while mice stressed in adolescence showed elevated anxiety-like behaviors in both adolescence and adulthood. PFC-dependent cognitive functioning was also impaired in adult males stressed in adolescence. Adolescent stress disrupted expression patterns of parvalbumin (PV) and perineuronal nets (PNNs) in the PFC, as well as NMDA receptor subunit composition, in a sex- and age-specific manner. The findings presented here contribute to understanding how adolescent stress may lead to neuropsychiatric disorders such as anxiety by disrupting the development of the PFC and emotional behaviors.
青春期是一个易受环境因素影响的脆弱窗口，例如慢性应激，这可能会破坏大脑发育并导致长期的行为功能障碍，如抑郁症、焦虑症和精神分裂症等疾病。在整个生命周期中，这些疾病的发生率也存在性别差异。然而，青春期应激如何导致神经精神表型的机制尚不清楚，性别也没有起到介导作用。我们假设青春期应激以性别特异性的方式破坏前额叶皮层（PFC）中的γ-氨基丁酸（GABA）系统，因为该系统在青春期成熟，并且在认知和情绪功能中发挥重要作用。我们在青春期（出生后第 28-42 天）期间使雄性和雌性小鼠暴露于不可预测的慢性轻度应激（UCMS）中。一组在应激结束后 24 小时（青春期晚期）进行与 PFC 相关的行为和分子变化测试；另一组在 UCMS 结束后大约 2.5 周（成年期）进行测试。我们观察到对照组小鼠的焦虑样行为随着年龄的增长而下降，而在青春期受到应激的小鼠在青春期和成年期都表现出焦虑样行为增加。青春期应激还破坏了成年雄性小鼠的 PFC 依赖的认知功能。青春期应激以性别和年龄特异性的方式破坏了 PFC 中的钙调蛋白结合蛋白 28k（PV）和周围神经网（PNNs）以及 NMDA 受体亚基组成的表达模式。这里提出的发现有助于理解青春期应激如何通过破坏 PFC 和情绪行为的发育导致焦虑等神经精神疾病。
