Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction

Abstract

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.

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress

“…In accordance with this, rats defeated in adolescence show enhanced preference for psychostimulantassociated cues even when the drug is no longer available (Burke et al, 2011;Rodriguez-Arias et al, 2017), along with greater alcohol and cocaine self-administration (Burke & Miczek, 2015;Rodriguez-Arias et al, 2017;Rodríguez-Arias et al, 2017). Findings from the current and previous studies suggest that targeting D2 autoreceptors along with DAT to restore dopamine availability in the mPFC could lead to more efficacious treatment of the cognitive deficits seen in adult neuropsychiatric disorders promoted by periadolescent stress (Watt et al, 2017). The adolescent social defeat model may therefore provide an effective preclinical means to test novel and repurposed therapeutics.…”

“…In particular, a decrease in dopamine D1 receptor activity would lead to excessive noise from competing non-relevant networks (Arnsten & Rubia, 2012;Robbins & Arnsten, 2009). Optimal dopaminergic activity in the mPFC is required for many other higher cognitive (executive) functions outside the domain of working memory, including top-down control of mesolimbic pathways that mediate goal-directed behavior (Floresco, 2013;Logue & Gould, 2014;Watt et al, 2017). For example, insufficient mPFC dopamine activity during reward processing is associated with both increased impulsive choice (Yates et al, 2014) and perseveration in conditioned response despite changes in reward contingency (Floresco, 2013).…”

“…The dopaminergic system of the medial prefrontal cortex (mPFC) appears to be particularly vulnerable to stress exposure during periadolescence (pre-through late adolescence, approximately postnatal day [P]21-50 in rats; Watt, Weber, Davies, & Forster, 2017), including experience of social aggression, with altered function noted in adulthood well after stressor cessation (reviewed in Watt et al, 2017). Importantly, cognitive functions reliant on optimal PFC dopamine signaling, such as working memory, impulse control, and behavioral flexibility (Floresco, 2013), are disrupted in bullying-associated disorders (Baune, Fuhr, Air, & Hering, 2014;Etkin, Gyurak, & O'Hara, 2013;Green, 2006;Lewandowski et al, 2016).…”

Peripubertal stress of male, but not female rats increases morphine‐induced conditioned place preference and locomotion in adulthood

“…Both social stressors (e.g., social defeat, isolation, change in peer group structure) and non‐social stressors (e.g., footshock, nutritional deprivation, environmental disturbance) are widely used in rodents studies. The majority of preclinical studies assessing the effects of peripubertal stress on later drug reward processing have been conducted using social stressors (Watt, Weber, Davies, & Forster, ). Evidence suggests that early‐life social stressors increase reward sensitivity to drugs of abuse in adulthood.…”

Effect of early life stress on anxiety and depressive behaviors in adolescent mice

“…Moreover, abused adolescents show significantly higher rates of depression and behavior problems (Pelcovitz et al, 1994). Early life stress may alter neuronal networks of mood and cognitive systems, predisposing adolescents to developing psychological and psychiatric disorders that may continue to adulthood (Bonnie & Nim, 2015;Watt et al, 2017). However, the psychopathology of adolescents to early life stress is still not well understood.…”