Lifetime Neural Circuit and Behavioral Disruptions in a Mouse Model of Childhood Abuse

Background Childhood and adolescent maltreatment is a key predictor of mental illness in adulthood and increases the risk of development of obesity, diabetes and heart disease. It presents a pressing public health crisis as nearly 20% of children are affected across the globe, independent of race or nationality. Animal models are needed in order to examine how maltreatment reshapes specific neural circuits and gene pathways to affect adult behavior. However, while multiple well-characterized rodent models of infant neglect and abuse exist, models that specifically target a window akin to childhood (i.e. in post weaning young animals before the onset of puberty) that can robustly affect adult behavior are nearly absent. Aims & Objectives We recently developed a model of childhood to early adolescent social defeat stress in male mice to allow us to determine the neural circuit and genetic components most critically affected in adulthood after the exposure to early life maltreatment. Method We used a combination of behavioral analysis and whole brain c-fos imaging to determine candidate regions of interest critical for impaired social interaction in adulthood following early adolescent maltreatment. We then used chemogenetics to validate the necessity of an identified candidate region, the anterior insula, to impaired social interaction after early life trauma and performed RNA sequencing on this region to identify affected genes. Finally, we performed a neuronal rescue of one of the dysregulated genes, Hnrnpa2b1, in the anterior insula in adult male mice to determine if restoration of Hnrnpa2b1 in adulthood after early adolescent maltreatment could restore normative social behavior. Results Whole brain c-fos imaging and chemogenetic manipulation identified anterior insula (AI) hyperactivation as causal to adulthood maladaptive social responding after early adolescent maltreatment. RNA sequencing of AI in adult male mice exposed to maltreatment in early adolescence revealed altered expression of a host of RNA binding proteins. AI-specific neuronal rescue of one of these targets, Hnrnpa2b1, in adulthood after early adolescent maltreatment significantly restored normative social behavior. Discussion & Conclusions Our findings support the notion that AI dysfunction after trauma underlies aberrant behavioral responding and raise the novel possibility that normalization of AI activity with targeted non-invasive neural circuit therapies such as transcranial magnetic stimulation (TMS) or focused ultrasound could potentially improve psychiatric symptoms. RNA binding proteins such as Hnrnpa2b1 have also come to the forefront as potential targets in PTSD treatment as they have been found to be reduced across military and civilian cohorts suffering from PTSD. Our study demonstrates that restoration of trauma-induced changes in RNA binding protein levels may ameliorate maladaptive trauma-induced behaviors in adulthood.