Early-life stress impairs development of functional interactions and neuronal activity within prefrontal-amygdala...

Early-life stress (ELS), such as parental neglect or abuse, predisposes an individual to develop mental disorders. Disease hallmarks include heightened amygdala reactivity and impaired prefrontal cortex-amygdala functional interactions, already during childhood and adolescence. However, which cellular and circuit mechanisms underlie these hallmarks, as well as the altered developmental trajectory of prefrontal-amygdala networks, is poorly understood. Here we performed simultaneous in vivo local-field potential and multi-unit recordings under light urethane anaesthesia in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of male and female pre-juvenile or adolescent mice, exposed to a resource scarcity model of ELS. We find a developmentally transient low-theta (3-5 Hz) oscillatory hypercoupling within mPFC-BLA networks in pre-juvenile ELS males which seems to result from a precocious development of coupling strength after ELS. In the mPFC, neuronal spiking activity was decreased in pre-juvenile males and the local theta entrainment of spike firing disrupted. In BLA, both sexes showed an increase in firing activity in a subpopulation of neurons after ELS, also confirmed by an increase in ΔFosB-positive neurons in BLA, which we identified to be non-GABAergic. Directed interactions, i.e. the ability to entrain spike firing in mPFC to the theta rhythm in BLA and vice versa, were also impaired predominantly in pre-juvenile males after ELS, while females showed a milder phenotype. These early sex-dependent impairments in the functional development of prefrontal-amygdala circuits may promote aberrant development of emotional behaviours after ELS and may predispose to a disease phenotype later on.