Reconfiguration of Brain-Wide Neural Activity After Early Life Adversity

Abstract

Early life adversity (ELA) predisposes individuals to physical and mental disorders lifelong. How ELA affects brain functions, leading to these vulnerabilities, is a mystery. To understand ELAs impacts, investigations into neural activity affected by ELA must go beyond localized areas toward simultaneous recordings from multiple widely distributed regions over time. Such studies will expose relative activity between regions and discover shifts in regional activity in response to different experiences. Here, we performed longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to measure degrees of brain-wide neural activity in ELA-exposed mice across a series of experiences in adulthood. To ascertain whether ELA resulted in atypical brain activity, results were compared to those of the standard mouse (Std). MEMRI captured activity in the freely moving home cage condition, and short- and long-term after exposure to TMT, a naturalistic predator threat. Images were normalized and aligned then analyzed with statistical mapping and automated segmentation. We found that neural activity in the home cage was greater in ELA compared to Std in multiple striatal-pallidal and hypothalamic regions. Upon acute threat, neural activity in Std increased in these regions to become more similar to that in ELA, while new hyperactive responses in ELA emerged in the midbrain and hindbrain. Nine days after acute threat, heightened neural activity in ELA persisted within locus coeruleus and increased within posterior amygdala, ventral hippocampus, and dorsomedial and ventromedial hypothalamus. These results reveal functional imbalances that arise between multiple brain-systems after ELA, which are dependent upon context and cumulative experiences into adulthood. Significance StatementEarly life adversity (ELA) is a crucial determinant of adult health. Yet the neurobiological basis for this remains elusive. Localized brain regions display atypical neural activity in rodents who experienced ELA, but how this contributes to overall brain state dynamics has been unknown. Here, we used longitudinal manganese-enhanced MRI to detect brain-wide activities altered by ELA in the adult across a series of conditions: freely moving, experiencing threat or its aftermath. Computational analyses revealed that ELA produced widespread dynamic reconfiguration of brain-wide neural activity in response to threat, shown here for the first time. Dynamic brain state remodeling after ELA provides critical insights into human mental health vulnerabilities associated with adverse childhood experiences (ACEs), and suggests plausible targets for intervention.