Changes in Gene Expression in the Locus Coeruleus-Amygdala Circuitry in Inhibitory Avoidance PTSD Model

Abstract

The locus coeruleus (LC)-amygdala circuit is implicated in playing a key role in responses to emotionally arousing stimuli and in the manifestation of post-traumatic stress disorder (PTSD). Here, we examined changes in gene expression of a number of important mediators of the LC-amygdala circuitry in the inhibition avoidance model of PTSD. After testing for basal acoustic startle response (ASR), rats were exposed to a severe footshock (1.5 mA for 10 s) in the inhibitory avoidance apparatus. They were given contextual situational reminders every 5 day for 25 days. Controls were treated identically but with the footshock inactivated. Animals were re-tested on second ASR and decapitated 1 h later. The shock group had enhanced hyperarousal and several changes in gene expression compared to controls. In the LC, mRNA levels of norepinephrine (NE) biosynthetic enzymes (TH, DBH), NE transporter (NET), NPY receptors (Y1R, Y2R), and CB1 receptor of endocannabinoid system were elevated. In the basolateral amygdala (BLA), there were marked reductions in gene expression for CB1, and especially Y1R, with rise for corticotropin-releasing hormone (CRH) system (CRH, CRH receptor 1), and no significant changes in the central amygdala. Our results suggest a fast forward mechanism in the LC-amygdala circuitry in the shock group.

Persistent Stress-Induced Neuroplastic Changes in the Locus Coeruleus/Norepinephrine System

“…CREB is a transcriptional factor which regulates transcription of multiple downstream genes including c-Fos, brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and neuropeptides [ 130 , 131 ]. These observations corroborate other studies that have shown altered expression of trophic factors and NE synthetic enzymes [ 18 , 28 , 54 – 57 , 61 ].…”

“…These effects are of particular interest in LC, where the interaction of CRF with its receptor CRFR1 activates cAMP-dependent intracellular signaling cascades, increasing tonic discharge and promoting anxiety-like behavior [ 64 , 77 , 188 , 189 ]. Evidence suggests that chronic stressor exposure is able to alter LC gene expression [ 18 , 28 , 54 – 57 , 61 ], promote long-term changes in synaptic transmission and excitability [ 53 , 62 ] and receptor trafficking [ 58 – 60 , 185 ], and, importantly, induce morphological changes and dendritic remodeling ( Figure 1 ) [ 50 , 52 , 53 , 57 , 190 ]. These actions appear to be dependent on a number of kinases and GTPases and their associated signaling pathways [ 50 , 52 , 57 ] and potentially on AMPAR function [ 191 , 192 ] which is modulated by CRF in the short term [ 49 ] and stressor exposure in the long term [ 62 ].…”

“…These observations suggest that LC neurons may undergo many long-lasting stress-induced adaptations ( Figure 1 ). These changes include receptor trafficking [ 58 – 60 ], altered expression of genes necessary for transmitter synthesis and release [ 28 , 54 – 56 , 61 ], protein kinases that activate transcription factors [ 57 ] and growth factors [ 18 ], electrophysiological properties [ 53 , 62 ], and morphological changes [ 50 , 53 , 63 ], all of which would directly impact LC function at both immediate and chronic time point poststress.…”

Analysis of Psychological and Sleep Status and Exercise Rehabilitation of Front-Line Clinical Staff in the Fight Against COVID-19 in China

“…The results showed that the medical staff in the experimental group had higher somatization symptoms, depression symptoms, and symptoms related to post-traumatic stress disorder. Clinical studies have found that under stress, the neuroendocrine network regulated by the HPA axis in the patient's body is disordered, the level of corticotropin-releasing factor is increased, and the level of cortisol is low, leading to the continuous activation of the adrenergic pathway [16]. As a result, emotions such as anxiety, fear, irritability, and hypersensitivity are more likely to occur.…”

Significance of the Stress Research: “In Memoriam, Richard Kvetnansky”

“…Advances on the role of specific circuits during stress include a report on alterations in gene expression in the locus coeruleus-amygdala circuitry during stress (Sabban et al 2017) and the role of the nucleus of the solitary tract/ dorsal vagal complex (Herman 2017).…”