Larivee Rachelle, Johnson Natalie, Freedgood Natalie R, Cameron Heather A, Schoenfeld Timothy J
Department of Psychological Science and Neuroscience, Belmont University, Nashville, TN, United States.
Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States.
Front Behav Neurosci. 2022 Jul 5;16:940125. doi: 10.3389/fnbeh.2022.940125. eCollection 2022.
Stressors during the adolescent period can affect development of the brain and have long-lasting impacts on behavior. Specifically, adolescent stress impairs hippocampal neurogenesis and can increase risk for anxiety, depression, and a dysregulated stress response in adulthood. In order to model the functional effects of reduced hippocampal neurogenesis during adolescence, a transgenic neurogenesis ablation rat model was used to suppress neurogenesis during the adolescent period and test anxiodepressive behaviors and stress physiology during adulthood. Wildtype and transgenic (TK) rats were given valganciclovir during the first two weeks of adolescence (4-6 weeks old) to knock down neurogenesis in TK rats. Starting in young adulthood (13 weeks old), blood was sampled for corticosterone at several time points following acute restraint stress to measure negative feedback of the stress response, and rats were tested on a battery of anxiodepressive tests at baseline and following acute restraint stress. Although TK rats had large reductions in both cell proliferation during adolescence, as measured by bromodeoxyuridine (BrdU), and ongoing neurogenesis in adulthood (by doublecortin), resulting in decreased volume of the dentate gyrus, negative feedback of the stress response following acute restraint was similar across all rats. Despite similar stress responses, TK rats showed higher anxiety-like behavior at baseline. In addition, only TK rats had increased depressive-like behavior when tested after acute stress. Together, these results suggest that long-term neurogenesis ablation starting in adolescence produces hippocampal atrophy and increases behavioral caution and despair amid stressful environments.
青春期的应激源会影响大脑发育，并对行为产生长期影响。具体而言，青春期应激会损害海马神经发生，并增加成年后患焦虑症、抑郁症以及应激反应失调的风险。为了模拟青春期海马神经发生减少的功能影响，使用转基因神经发生消融大鼠模型在青春期抑制神经发生，并测试成年期的焦虑抑郁行为和应激生理学。在青春期的前两周（4-6周龄）给野生型和转基因（TK）大鼠服用缬更昔洛韦，以抑制TK大鼠的神经发生。从成年早期（13周龄）开始，在急性束缚应激后的几个时间点采集血液样本以检测皮质酮，以测量应激反应的负反馈，并在基线和急性束缚应激后对大鼠进行一系列焦虑抑郁测试。尽管通过溴脱氧尿苷（BrdU）测量，TK大鼠在青春期的细胞增殖以及成年期的持续神经发生（通过双皮质素）均大幅减少，导致齿状回体积减小，但所有大鼠在急性束缚后的应激反应负反馈相似。尽管应激反应相似，但TK大鼠在基线时表现出更高的焦虑样行为。此外，仅TK大鼠在急性应激后测试时出现了增加的抑郁样行为。总之，这些结果表明，从青春期开始的长期神经发生消融会导致海马萎缩，并在压力环境中增加行为谨慎和绝望感。
