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Monoaminergic signaling in cortical-limbic circuits regulate both normal physiology and responses to stress. Indeed, monoaminergic reuptake transporters, located on the pre-synaptic terminals of distal projections, are common pharmacological targets for mental disorders, like anxiety and depression. Early life adversity (ELA), which has an interaction with monoaminergic systems, increases vulnerability to mental disorders later in life. Despite this, we are yet to understand how ELA alters brain-wide patterns of neural activity. Here, we combine Manganese-enhanced MRI (MEMRI) with behavioral tracking and immunohistochemistry to investigate the effects of ELA on the modular neuroarchitecture and behavioral response to acute threat. ELA was administered from P2-P9 by depriving dams of adequate bedding. Mice (10 weeks, n=24) +/- ELA were subject to paired MEMRI and behavior longitudinally. Intraperitoneal injections of paramagnetic Mn(II) (0.3 mmol/kg) highlights brain activity in awake behaving mice. Behavior was recorded during Mn(II) uptake to assess avoidance and motility before, during and nine days after acute exposure to predator odor (TMT, 2,3,5-Trimethyl-3-thiazoine). Histochemical analysis was performed on serial brain sections from mice sacrificed and perfused at the conclusion of paired behavior-imaging experiments. MEMRI images were skull- stripped, spatially registered, and intensity normalized. To measure the degree of activity and relationships between brain regions we performed statistical parametric mapping (SPM), segmentation of 90 brain regions, cross-correlation analysis, and Louvain community detection. Predator stress increased avoidance behavior (percent of time in light) for both groups (p<0.05, Tukey-Adjusted), while only inter-subject variance was observed to be different between +/- ELA groups. Results suggest basal neural activity of ELA mice resembles that of acute fear in normally reared mice, with increased activity in the basal forebrain and hindbrain. Additionally, ELA disorganized network structure, increased modularity of basal brain networks and altered the dynamic response to acute threat. Staining for the norepinephrine transporter revealed lesser numbers of distal termini, suggesting alterations in neural activity could be due to an effect of ELA on the development of the noradrenergic system. Together our data find that ELA disrupts the arborization of noradrenergic projections, alters the coordination of basal neural activity and of neural activity in response to acute threat. Supported by NIMH RO1MH096093.


Poster presented at the Brain & Behavioral Health Research Day 2021



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