Gomes Felipe V, Grace Anthony A
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
Schizophr Bull. 2017 May 1;43(3):592-600. doi: 10.1093/schbul/sbw156.
Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper-responsivity as indicated by augmented locomotor response to amphetamine and increased number of spontaneously active DA neurons which was confined to the lateral VTA. Additionally, prelimbic (pl) mPFC lesions triggered a DA hyper-responsivity in animals exposed to FS alone during adolescence. Our results are consistent with previous studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on intense multiple stressors. Our data also suggest that plPFC dysfunction increases the vulnerability to stress in terms of changes in the DA system. Hence, stress during adolescence could be a precipitating factor for the transition to schizophrenia, and stress control at this vulnerable period may circumvent these changes to prevent the emergence of psychosis.
青春期的应激是精神分裂症的一个风险因素，内侧前额叶皮质（mPFC）功能障碍被认为会干扰应激控制，增加对压力的易感性。我们评估了青春期不同应激事件（束缚应激[RS]、足部电击[FS]或FS与RS的组合）对成年大鼠精神分裂症相关行为的影响。成年后，对动物进行焦虑反应（高架十字迷宫）、认知功能（新物体识别测试）和多巴胺（DA）系统反应性（对苯丙胺的运动反应以及使用体内电生理学检测腹侧被盖区（VTA）的DA神经元活动）测试。所有青春期应激源都会损害成年动物的体重增加并诱发类似焦虑的反应。FS和FS+RS还会破坏认知功能。有趣的是，只有FS和RS的组合会诱发DA高反应性，表现为对苯丙胺的运动反应增强以及自发活动的DA神经元数量增加，且这种增加局限于外侧VTA。此外，青春期仅暴露于FS的动物，其前额叶前边缘（pl）mPFC损伤会引发DA高反应性。我们的结果与之前的研究一致，即青春期应激事件会导致长期变化。然而，对DA系统活动的影响似乎取决于强烈的多重应激源。我们的数据还表明，plPFC功能障碍会增加DA系统变化方面对压力的易感性。因此，青春期的应激可能是向精神分裂症转变的一个促发因素，在这个脆弱时期进行应激控制可能会规避这些变化以防止精神病的出现。
