Maternal separation disrupts noradrenergic control of adult coping behaviors

Abstract

Early life stress (ELS) in humans and preclinical rodent models profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Here we used repeated maternal separation stress (MSS) to investigate the impact of ELS on the LC and stress-related behaviors in adulthood. Using ex vivo cell-attached electrophysiology, we recorded spontaneous LC firing across the lifespan from early development, pre-adolescence, adolescence, through adulthood. MSS significantly increased LC firing during early development and adulthood compared to No MSS mice. We next examined potential changes in the expression of genes linked to LC function. MSS decreased mRNA levels for both the alpha-2A adrenergic receptor and dopamine beta-hydroxylase, the enzyme necessary for NE synthesis. At the behavioral level, MSS increased locomotion in approach-avoidance exploratory assays and increased immobility in the forced swim test. Forced swim increased LC cFos expression, a marker for neuronal excitation, in both No MSS and MSS mice. However, MSS mice had significantly less cFos than No MSS controls. We then sought to reverse this MSS-induced increase in immobility by inhibiting the LC during the forced swim test. In No MSS mice, LC inhibition increased immobility time, however, LC inhibition did not affect MSS immobility. Together, this study demonstrates that MSS dysregulates LC-NE activity across the lifespan and disrupts the role of the LC in regulating coping strategies during stressful events.