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.

Keywords: Adolescence; Chronic juvenile stress; Drug reward; Executive function; Nucleus accumbens; Prefrontal cortex.

Figure 1. Summary of behaviors related to executive function and motivation mediated by subregions of the prefrontal cortex (PFC) and nucleus accumbens (NAc) of both the primate (left) and rodent (right)

Colors denote functionally homologous subregions between primates and rodents. ACC: Anterior cingulate cortex (green), OFC: orbitofrontal cortex (purple), NAcC: NAc core (orange), NAcSh: NAc shell (red). Note that the rodent medial PFC (mPFC; right, blue) is functionally homologous to the primate dorsolateral PFC (dlPFC; left, blue), with some functional homology to the primate ACC (Seamans et al., 2008).

Figure 2. Summary of developmental changes to the prefrontal cortex and nucleus accumbens occurring in both humans and rats over the juvenile/adolescent period, along age-related changes to executive function and reward behaviors

Peak changes in measured neural variables are represented by enclosed text, with the length of the box corresponding to their approximate duration in relation to the developmental timeline, while short vertical lines denote span of ages tested in cited studies (see text for details).

Figure 3. Summary of major effects of juvenile stress on adult mesoaccumbocortical activity and cognitive/behavioral outcomes

Typically dopamine activity in the prefrontal cortex (PFC), as derived from the ventral tegmental area (VTA), inhibits glutamatergic input to the nucleus accumbens (NAc), thus reducing excitatory input to the NAc. The majority of animal and human studies demonstrate that chronic juvenile stress is associated with reduced PFC activity. Human studies also show accumbal hypofunction in anticipation of reward, with animal studies demonstrating increased dopaminergic activity in the NAc in response to drugs of abuse. Combined, this dysregulation of the mesoaccumbocortical system is thought to result in poorer executive functioning and increased sensitivity to drugs of abuse in adult individuals exposed to chronic juvenile stress, thus contributing to neuropsychiatric illness.