Abstract
Early life maltreatment by the caregiver constitutes a major risk factor for the development of later-life psychopathologies, including fear-related pathologies. Here, we used an animal model of early life maltreatment induced by the Scarcity-Adversity Model of low bedding (LB) where the mother is given insufficient bedding for nest building while rat pups were postnatal days (PN) 8–12. To assess effects of maltreatment on the expression of threat-elicited defensive behaviors, animals underwent odor-shock threat conditioning at three developmental stages: late infancy (PN18), adolescence (PN45) or adulthood (>PN75) and tested the next day with odor only presentations (cue test). Results showed that in typically developing rats, the response to threat increases with maturation, although experience with maltreatment in early infancy produced enhanced responding to threat in infancy and adulthood, but a decrease in maltreated adolescents. To better understand the unique features of this decreased threat responding in adolescence, c-Fos expression was assessed within the amygdala and ventromedial prefrontal cortex (vmPFC) associated with the cued expression of threat learning. Fos counts across amygdala subregions were lower in LB rats compared to controls, while enhanced c-Fos expression was observed in the vmPFC prelimbic cortex (PL). Correlational analysis between freezing behavior and Fos revealed freezing levels were correlated with CeA in controls, although more global correlations were detected in LB-reared rats, including the BA, LA, and CeA. Functional connectivity analysis between brain regions showed that LB reared rats exhibited more diffuse interconnectivity across amygdala subnuclei, compared the more heterogeneous patterns observed in controls. In addition, functional connectivity between the IL and LA switched from positive to negative in abused adolescents. Overall, these results suggest that in adolescence, the unique developmental decrease in fear expression following trauma is associated with distinct changes in regional function and long-range connectivity, reminiscent of pathological brain function. These results suggest that early life maltreatment from the caregiver perturbs the developmental trajectory of threat-elicited behavior. Indeed, it is possible that this form of trauma, where the infant’s safety signal or “safe haven” (the caregiver) is actually the source of the threat, produces distinct outcomes across development.
Highlights
In altricial species, such as humans and rodents, the brain continues to develop after birth and is quite sensitive to environmental programming that permits adaptation to diverse environments and cultures
We focus on two brain areas critical for responses to threat, the amygdala and ventromedial prefrontal cortex, during adolescence to complement the existing literature on fear/threat development, amygdala and PFC function in infancy and adulthood (Rudy and Morledge, 1994; Fanselow and LeDoux, 1999; Sevelinges et al, 2007; Thompson et al, 2008; Moriceau et al, 2009a,b; Cowan et al, 2013; Marek et al, 2013; Maren et al, 2013; Spielberg et al, 2014; Takahashi, 2014; Almada et al, 2015; Do-Monte et al, 2015; Duits et al, 2015; Pattwell et al, 2016; Matsuda et al, 2018; Norrholm and Jovanovic, 2018)
Our lab has shown that early life maltreatment causes precocious incorporation of the amygdala into the threat learning circuit by a few days (PN7 rather than PN10) and the amygdala is hyperactive within a threat conditioning paradigm at PN18 to support enhanced learning shown in our previous rodent work (Moriceau et al, 2009a; Opendak et al, 2019)
Summary
In altricial species, such as humans and rodents, the brain continues to develop after birth and is quite sensitive to environmental programming that permits adaptation to diverse environments and cultures This open system leaves the brain vulnerable to programming by trauma, with programming that goes beyond adaptation to initiate a pathological developmental pathway. One challenge to understanding how maltreatment causes threatassociated pathologies is the protracted and dynamic maturation of the threat system, which morphs through childhood, adolescence and adulthood as life and environmental demands change to produce unique expression patterns across the lifespan (Anda et al, 2006; Moffitt et al, 2007; Gilbert et al, 2009; Green et al, 2010; Callaghan et al, 2019). We employ the Scarcity-Adversity Model of low bedding (LB, insufficient bedding for nest building to induce maltreatment of pups) from PN8-12 (Opendak and Sullivan, 2016; Walker et al, 2017; Perry et al, 2018; Watamura and Roth, 2018)
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