Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
Center for Brain and Behavior Research, Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):136-154. doi: 10.1016/j.pnpbp.2017.06.015. Epub 2017 Jun 19.
Repeated exposure to stress during childhood is associated with increased risk for neuropsychiatric illness, substance use disorders and other behavioral problems in adulthood. However, it is not clear how chronic childhood stress can lead to emergence of such a wide range of symptoms and disorders in later life. One possible explanation lies in stress-induced disruption to the development of specific brain regions associated with executive function and reward processing, deficits in which are common to the disorders promoted by childhood stress. Evidence of aberrations in prefrontal cortex and nucleus accumbens function following repeated exposure of juvenile (pre- and adolescent) organisms to a variety of different stressors would account not only for the similarity in symptoms across the wide range of childhood stress-associated mental illnesses, but also their persistence into adulthood in the absence of further stress. Therefore, the goal of this review is to evaluate the current knowledge regarding disruption to executive function and reward processing in adult animals or humans exposed to chronic stress over the juvenile period, and the underlying neurobiology, with particular emphasis on the prefrontal cortex and nucleus accumbens. First, the role of these brain regions in mediating executive function and reward processing is highlighted. Second, the neurobehavioral development of these systems is discussed to illustrate how juvenile stress may exert long-lasting effects on prefrontal cortex-accumbal activity and related behavioral functions. Finally, a critical review of current animal and human findings is presented, which strongly supports the supposition that exposure to chronic stress (particularly social aggression and isolation in animal studies) in the juvenile period produces impairments in executive function in adulthood, especially in working memory and inhibitory control. Chronic juvenile stress also results in aberrations to reward processing and seeking, with increased sensitivity to drugs of abuse particularly noted in animal models, which is in line with greater incidence of substance use disorders seen in clinical studies. These consequences are potentially mediated by monoamine and glutamatergic dysfunction in the prefrontal cortex and nucleus accumbens, providing translatable therapeutic targets. However, the predominant use of male subjects and social-based stressors in preclinical studies points to a clear need for determining how both sex differences and stressor heterogeneity may differentially contribute to stress-induced changes to substrates mediating executive function and reward processing, before the impact of chronic juvenile stress in promoting adult psychopathology can be fully understood.
儿童时期反复承受压力与成年后患神经精神疾病、物质使用障碍和其他行为问题的风险增加有关。然而,目前尚不清楚慢性儿童期压力如何导致晚年出现如此广泛的症状和障碍。一种可能的解释在于压力对与执行功能和奖励处理相关的特定大脑区域发育的干扰,而这些缺陷在儿童期压力引起的各种障碍中很常见。在反复暴露于各种不同应激源的幼年(青春期前和青春期)生物体中,前额皮质和伏隔核功能的异常证据不仅可以解释与广泛的儿童期应激相关的精神疾病之间症状的相似性,而且可以解释在没有进一步应激的情况下,这些症状会持续到成年期。因此,本综述的目的是评估当前关于在青少年期经历慢性应激后暴露于慢性应激的成年动物或人类中执行功能和奖励处理中断的知识,以及潜在的神经生物学,特别强调前额皮质和伏隔核。首先,强调了这些大脑区域在介导执行功能和奖励处理中的作用。其次,讨论了这些系统的神经行为发育,以说明幼年压力如何对前额皮质-伏隔核活动和相关行为功能产生持久影响。最后,对当前的动物和人类研究结果进行了批判性回顾,这些研究结果强烈支持这样一种假设,即在青少年时期暴露于慢性应激(特别是动物研究中的社会攻击和隔离)会导致成年后执行功能障碍,特别是在工作记忆和抑制控制方面。慢性青少年应激也会导致奖励处理和寻求的异常,在动物模型中特别注意到对滥用药物的敏感性增加,这与临床研究中观察到的物质使用障碍发生率更高是一致的。这些后果可能是由前额皮质和伏隔核中的单胺能和谷氨酸能功能障碍介导的,为可转化的治疗靶点提供了依据。然而,在临床前研究中主要使用雄性动物和基于社会的应激源,这表明需要确定性别差异和应激源异质性如何不同地导致执行功能和奖励处理中介导物质的变化,然后才能充分理解慢性青少年应激在促进成年期精神病理学中的作用。
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