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

Abstract

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.

Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure

“…Importantly, this reduction in vocalization in PAE pups occurred despite PAE and control pups receiving similar maternal care. Moreover, consistent with previous findings (Blaze et al, 2013; Raineki et al, 2010, 2012, 2015; Yan et al, 2017), exposure to early-life adversity increased pup vocalization across prenatal groups. However, this response to early-life adversity was significantly reduced in PAE compared to control pups, suggesting that even when exposed to an adverse environment, PAE pups show a deficit in perceiving and/or responding to environmental stimuli.…”

“…Interestingly, increased CRP levels following early-life adversity are more pronounced in individuals with current depression (Danese et al, 2008, 2011), suggesting that increased levels of CRP may be indicative of adversity-related mental health problems or may even mediate, at least in part, the negative outcomes. We suggest that, similar to the clinical findings, increased CRP levels may, at least in part, underlie the increased levels of offspring depressive-like behavior observed in our previous studies using this model of early-life adversity (Raineki et al, 2012; 2015; Yan et al, 2017). Additionally, in the present study, PAE animals showed increased CRP levels compared to control animals, and PAE pups exposed to early-life adversity showed even higher levels of serum CRP.…”

“…We have shown previously that pups exposed to the naturalistic early-life adversity model used here exhibit dysfunctional social attachment behaviors with the mother in infancy (Raineki et al, 2010). This dysfunctional social behavior with the mother is followed by deficits in social behavior with peers, as well as depressive-like behavior later in life (Raineki et al, 2012, 2015, Yan et al, 2017). As cytokines are potent neuromodulators during development (Bajetto et al, 2001; Bessis et al, 2005; Deverman and Patterson, 2009; Smith et al, 2007; Stephan et al, 2012), the short- and long-term effects of early-life adversity may have their origins in the altered serum cytokine levels during infancy.…”

“…This limited bedding environment decreases the mother’s ability to construct a nest, leading to increased negative maternal behaviors (Raineki et al, 2010, 2012, 2015). Exposure to this type of early-life adversity has been shown to induce dysfunctional social behavior with the mother and peers, as well as depressive-like behavior later in life (Raineki et al, 2010, 2012, 2015; Rincón-Cortés and Sullivan, 2016, Yan et al, 2017). These behavioral deficits are, at least in part, supported by amygdala dysregulation (Raineki et al, 2010, 2012; Rincón-Cortés and Sullivan, 2016; Yan et al, 2017), data that corroborate the clinical literature demonstrating that adversity during infancy is associated with greater amygdala reactivity when exposed to emotional stimuli later in life (McCrory et al, 2013; Tottenham et al, 2011).…”

Neurobiology of infant attachment: attachment despite adversity and parental programming of emotionality

“…One such model introduces adversity to the attachment system by exposing rodent mothers and pups to a scarce resource environment, which produces an increase in negative maltreatment caregiving behaviors. This model has identified the amygdala as being particularly vulnerable to effects of caregiving quality, as indicated by an increase in depressive-like symptoms and antisocial behaviors in adult offspring who experienced negative caregiving, as well as altered fear-related behaviors, via an amygdala-dependent mechanism [8,40,41] involving decreased amygdala-prefrontal cortex functional connectivity [42]. These infant rodent results mirror altered amygdala-prefrontal cortex connectivity found in orphanage reared human children and nonhuman primates reared with maltreating caregivers [33,43].…”