Rule Lowenna, Yang Jessica, Watkin Holly, Hall Jeremy, Brydges Nichola Marie
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
Mol Psychiatry. 2021 Jun;26(6):1898-1908. doi: 10.1038/s41380-020-0718-4. Epub 2020 Apr 14.
Adverse experiences early in life are associated with the development of psychiatric illnesses. The hippocampus is likely to play pivotal role in generating these effects: it undergoes significant development during childhood and is extremely reactive to stress. In rodent models, stress in the pre-pubertal period impairs adult hippocampal neurogenesis (AHN) and behaviours which rely on this process. In normal adult animals, environmental enrichment (EE) is a potent promoter of AHN and hippocampal function. Whether exposure to EE during adolescence can restore normal hippocampal function and AHN following pre-pubertal stress (PPS) is unknown. We investigated EE as a treatment for reduced AHN and hippocampal function following PPS in a rodent model. Stress was administered between post-natal days (PND) 25-27, EE from PND 35 to early adulthood, when behavioural testing and assessment of AHN took place. PPS enhanced fear reactions to a conditioned stimulus (CS) following a trace fear protocol and reduced the survival of 4-week-old adult-born neurons throughout the adult hippocampus. Furthermore, we show that fewer adult-born neurons were active during recall of the CS stimulus following PPS. All effects were reversed by EE. Our results demonstrate lasting effects of PPS on the hippocampus and highlight the utility of EE during adolescence for restoring normal hippocampal function. EE during adolescence is a promising method of enhancing impaired hippocampal function resulting from early life stress, and due to multiple benefits (low cost, few side effects, widespread availability) should be more thoroughly explored as a treatment option in human sufferers of childhood adversity.
生命早期的不良经历与精神疾病的发展有关。海马体可能在产生这些影响中起关键作用：它在童年时期经历显著发育，并且对压力极具反应性。在啮齿动物模型中，青春期前的压力会损害成年海马神经发生（AHN）以及依赖此过程的行为。在正常成年动物中，环境富集（EE）是AHN和海马体功能的有力促进因素。青春期暴露于EE是否能在青春期前应激（PPS）后恢复正常的海马体功能和AHN尚不清楚。我们在啮齿动物模型中研究了EE作为PPS后AHN减少和海马体功能降低的一种治疗方法。在出生后第25 - 27天给予应激，从出生后第35天到成年早期给予EE，此时进行行为测试和AHN评估。PPS增强了在痕迹恐惧实验中对条件刺激（CS）的恐惧反应，并减少了整个成年海马体中4周龄成年新生神经元的存活。此外，我们表明在PPS后CS刺激回忆期间，活跃的成年新生神经元较少。所有这些影响都被EE逆转。我们的结果证明了PPS对海马体的持久影响，并突出了青春期EE对恢复正常海马体功能的效用。青春期的EE是增强因早期生活压力导致的受损海马体功能的一种有前景的方法，并且由于其多种益处（低成本、副作用少、广泛可用），作为童年逆境人类患者的一种治疗选择应更深入地探索。
