Tufts Medical School
Garrett Scarpa, Bradly Stone, Grant Weiss, Pantelis Antonoudiou, Jamie Maguire
Adverse childhood experiences (ACEs) increase the incidence of psychiatric illnesses, which have been shown to be driven by disrupted networks in sex-specific ways. A cohesive understanding of the specific mechanisms by which disrupted network states contribute to increased vulnerability in patients following ACEs, however, has not been established. Local field potentials (LFPs) in the basolateral amygdala (BLA) bias engagement of pro-fear networks during fear expression and pro-safety networks during extinction, and therefore likely contribute to this vulnerability. Animal models of early life stress (ELS) effectively reproduce behavioral and neuroendocrine features relevant to the study of ACEs and have been shown to impact the formation and extinction of fear memories, however it remains unclear if altered network states contribute to these effects. Here, we demonstrate that our model of ELS results in increased social interaction (p = 0.035, N = 6-10) and reduced time spent immobile in the forced swim test (p = 0.003, N = 9-13), which appears to correspond with reduced corticosterone levels following an acute stressor (p = 0.200, N = 3) in male, but not female, C57BL/6J mice. Furthermore, we demonstrate that ELS impacts network states (p = 0.0193, N = 10-11) corresponding with altered circuit recruitment following acute stress. Finally, these effects appear to be mediated by dysfunction of principal neurons (p = 0.021, n = 5-6, N = 2-3) and possibly fast-spiking, parvalbumin (PV)-expressing interneurons (p = 0.2617, n =3, N = 1-2) in the BLA. These findings support previous studies which demonstrate sex-specific effects of ELS, and they suggest a novel mechanism through which ACEs may contribute to increased risk for neuropsychiatric disorders, contributing to a cohesive model for the sex-specific increased risk for psychiatric illnesses resulting from ACEs, and may inform the development of novel, sex-specific treatments for these individuals.