Too much, too young? Altered corticolimbic axonal innervation and resting state functional connectivity suggests sex-dependent outcomes in a rat model of early life adversity

Adverse early experiences significantly alter behavioral and neural trajectories via aberrant brain maturation. Children with a history of early life stress (ELS) exhibit maladaptive behaviors and increased risk of mental illness later in life. Evidence in ELS-exposed humans identifies a role of atypical corticolimbic development; specifically, within amygdala-prefrontal cortex (PFC) circuits, and show precocially mature task-based corticolimbic functional connectivity (FC). However, the neurobiological substrates of such ELS-driven developmental changes remain unknown. Here, we identify putative neurobiological changes to determine the timeline of developmental perturbations following ELS in rats. Anterograde axonal tracing from basolateral amygdala (BLA) to pre- and infralimbic (PL, IL) PFC was quantified at postnatal days (PD)28, 38, and 48, along with anxiety-like behavior, in maternally separated (ELS) or control reared (CON) male and female rats. Resting state (rs)FC was assessed at PD28 and PD48 in a separate cohort. We report that ELS-exposed female rats show early maturation of BLA-PFC innervation at PD28, with ELS-related changes in males not appearing until PD38. ELS disrupted the maturation of rsFC from PD28 to PD48 in females, with enduring relationships between early rsFC and later anxiety-like behavior. Only transient ELS-related changes in rsFC were seen in male PL. Together, these data provide evidence that female rats may be more vulnerable to the effects of ELS via precocial BLA-PFC innervation, which may drive altered corticolimbic rsFC. These data also provide evidence that increased BLA-IL rsFC is associated with behavioral resiliency following ELS in female rats, providing mechanistic insight into the underlying etiology of adversity-induced vulnerability and resiliency.