Reconfiguration of brain-wide neural activity after early life adversity.

ABSTRACT

Early life adversity (ELA) predisposes individuals to both physical and mental disorders lifelong. How ELA affects brain function leading to this vulnerability is under intense investigation. Research has begun to shed light on ELA effects on localized brain regions within defined circuits. However, investigations into brain-wide neural activity that includes multiple localized regions, determines relationships of activity between regions and identifies shifts of activity in response to experiential conditions is necessary. Here, we performed longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to image the brain in normally reared or ELA-exposed adults. Images were captured in the freely moving home cage condition, and short- and long-term after naturalistic threat. Images were analyzed with new computational methods, including automated segmentation and fractional activation or difference volumes. We found that neural activity was increased after ELA compared to normal rearing in multiple brain regions, some of which are involved in defensive and/or reward circuitry. Widely distributed patterns of neural activity, "brain states", and their dynamics after threat were altered with ELA. Upon acute threat, ELA-mice retained heightened neural activity within many of these regions, and new hyperactive responses emerged in monoaminergic centers of the mid- and hindbrain. Nine days after acute threat, heightened neural activity remained within locus coeruleus and increased within posterior amygdala, ventral hippocampus, and dorso- and ventromedial hypothalamus, while reduced activity emerged within medial prefrontal cortical regions (prelimbic, infralimbic, anterior cingulate). These results reveal that functional imbalances arise between multiple brain-systems which are dependent upon context and cumulative experiences after ELA.