Variable Response of Norepinephrine Transporter to Traumatic Stress and Relationship to Hyperarousal.

Chiso Nwokafor,Esther L Sabban,Roxanna J Nahvi,Lidia I Serova,Arax Tanelian

doi:10.3389/fnbeh.2021.725091

Chiso Nwokafor, Esther L Sabban + Show 3 more

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https://doi.org/10.3389/fnbeh.2021.725091

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Abstract

The noradrenergic systems play a key role in stress triggered disorders such as post-traumatic stress disorder (PTSD). We hypothesized that traumatic stress will alter expression of norepinephrine transporter (NET) in locus coeruleus (LC) and its target brain regions which could be related to hyperarousal. Male Sprague-Dawley rats were subjected to single prolonged stress (SPS) and several weeks later the LC was isolated. NET mRNA levels in LC, determined by RT-PCR, displayed variable response with high and low responsive subgroups. In different cohort, acoustic startle response (ASR) was measured 2 weeks after SPS and levels of NET mRNA and protein in LC determined. The high NET responsive subgroup had greater hyperarousal. Nevertheless, NET protein levels, as determined by western blots, were lower than unstressed controls in LC, ventral hippocampus and medial prefrontal cortex and displayed considerable variability. Hypermethylation of specific CpG region in promoter of SLC6A2 gene, encoding NET, was present in the low, but not high, NET mRNA responsive subgroup. Taken together, the results demonstrate variability in stress elicited changes in NET gene expression and involvement of epigenetic changes. This may underlie mechanisms of susceptibility and resilience to traumatic stress triggered neuropsychiatric symptoms, especially hyperarousal.

Highlights

Compelling evidence demonstrates that the noradrenergic system plays a key role in stress triggered disorders such as Posttraumatic Stress Disorder (PTSD), depression, and Attentiondeficit/hyperactivity Disorder (ADHD; Krystal and Neumeister, 2009; Hendrickson and Raskind, 2016; Kelmendi et al, 2017; Borodovitsyna et al, 2018; Naegeli et al, 2018; Giustino et al, 2019)
The levels of norepinephrine transporter (NET) mRNA were determined in the locus coeruleus (LC) in two separate cohorts of animals 2 or 4 weeks after exposure to the traumatic stress of single prolonged stress (SPS) (Figure 1)
Since hyperarousal is associated with activation of the NE/LC system (Naegeli et al, 2018) and is elevated in PTSD (O’Donnell et al, 2004) as well as by SPS (Serova et al, 2013; Nwokafor et al, 2019), we examined the relationship between SPS triggered changes in acoustic startle response (ASR) and NET gene expression in the LC (Experiment 3)

Summary

Introduction

Compelling evidence demonstrates that the noradrenergic system plays a key role in stress triggered disorders such as Posttraumatic Stress Disorder (PTSD), depression, and Attentiondeficit/hyperactivity Disorder (ADHD; Krystal and Neumeister, 2009; Hendrickson and Raskind, 2016; Kelmendi et al, 2017; Borodovitsyna et al, 2018; Naegeli et al, 2018; Giustino et al, 2019) Both peripheral and central measures of norepinephrine (NE) activity are increased in PTSD patients (Pitman and Orr, 1990; Southwick et al, 1999). NE is synthesized primarily in the locus coeruleus (LC), which projects widely throughout the brain and receives inputs from a diverse array of brain regions It provides the sole source of NE in the mammalian forebrain mediating a variety of brain functions and behaviors such as arousal, memory acquisition, attention, vigilance, Traumatic Stress and NET Gene Expression and responses to stress (Aston-Jones et al, 1996; Valentino and Van Bockstaele, 2008; Sara, 2009)

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