Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring.

Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60). R-fMRI sessions were conducted under light anesthesia at both ages. Offspring reared with insufficient bedding (that is, maltreated) displayed enduring negative affective behaviors. Amygdala-prefrontal cortex (PFC) functional connectivity increased significantly from adolescence to adulthood in controls, but not in maltreated animals. We computed the fractional amplitude of low-frequency fluctuations (fALFF), an index of intrinsic brain activity, and found that fALFF in medial prefrontal cortex and anterior cingulate cortex (MPFC/ACC) increased significantly with age in controls but remained unchanged in maltreated animals during adolescence and adulthood. We used a seed-based analysis to explore changes in functional connectivity between this region and the whole brain. Compared with controls, maltreated animals demonstrated reduced functional connectivity between MPFC/ACC and left caudate/putamen across both ages. Functional connectivity between MPFC/ACC and right caudate/putamen showed a group by age interaction: decreased in controls but increased in maltreated animals. These data suggest that maltreatment induces vulnerability to psychopathology and is associated with differential developmental trajectories of prefrontal and subcortical circuits underlying affect regulation.

Emergence of social behavior deficit, blunted corticolimbic activity and adult depression-like behavior in a rodent model of maternal maltreatment.

Disrupted social behavior is a core symptom of multiple psychiatric and neurodevelopmental disorders. Many of these disorders are exacerbated by adverse infant experiences, including maltreatment and abuse, which negatively affect amygdala development. Although a link between impaired social behavior, abnormal amygdala function and depressive-like behavior following early adversity has been demonstrated in humans and animal models, the developmental emergence of maltreatment-related social deficits and associated amygdala neural activity are unknown. We used a naturalistic rodent model of maternal maltreatment during a sensitive period, postnatal days 8-12 (PN8-12), which produces social behavior deficits that precede adolescent depressive-like behavior and amygdala dysfunction, to examine social behavior in infancy, periweaning and adolescence. Neural activity in response to the social behavior test was assessed via c-Fos immunohistochemistry at these ages. A separate group of animals was tested for adult depressive-like behavior in the forced swim test. Maltreatment spared infant (PN16-18) social behavior but disrupted periweaning (PN20-22) and adolescent (PN42-48) social behavior. Maltreated rats exhibited blunted neural activation in the amygdala and other areas implicated in social functioning, including the medial prefrontal cortex and nucleus accumbens, at these ages and increased adult depressive-like behavior. These findings may suggest corticolimbic involvement in the emergence of maltreatment-induced social deficits that are linked to adult depressive-like behavior, thereby highlighting potential targets for therapeutic intervention. Understanding how infant experiences influence social behavior and age-specific expression across development may provide insights into basic neural mechanisms of social behaviors and disease-relevant social dysfunction exacerbated by early-life stress.