Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

Abstract

The amygdala is an important center of fear learning and memory and plays a critical role in regulating stress disorders. Previous studies have shown that changes in the amygdala caused by stress are an important cause of mental disorders including anxiety, but the specific mechanism remains unclear. Therefore, the purpose of this study was to investigate whether mental disorders induced by stress are related to γ-aminobutyric acid (GABA)ergic neuron damage in the basolateral amygdala (BLA) and whether endoplasmic reticulum stress (ERS) is involved in the injury process. Rat models of different durations of stress were established by restraint and forced ice-water swimming. Behavioral tests and high-performance liquid chromatography (HPLC) were used to detect anxiety in rats and changes in neurotransmitter levels in the BLA. Morphological approaches and microscopy-based multicolor tissue cytometry (MMTC) were used to detect the damage-induced changes in GABAergic neurons in the BLA. Immunofluorescence double labeling was used to detect the expression of ERS-related proteins before and after the inhibition of protein kinase R-like endoplasmic reticulum kinase (PERK) pathway. Stress resulted in damage to GABAergic neurons in the BLA, decreased GABA and increased glutamic acid (GLU) levels, perturbation of the excitation/inhibition (E/I) ratio in the BLA, and obvious anxiety disorders in rats. Moreover, ERS-mediated GABAergic neuron injury was an important cause of neurotransmitter level changes in the BLA. These results suggested that ERS-mediated GABAergic neuron injury in the BLA may be an important cause of stress-induced mental disorders.

Mechanism of Chronic Stress-Induced Glutamatergic Neuronal Damage in the Basolateral Amygdaloid Nucleus

“…It could be because of the fact that FJB fluorescence staining is more sensitive than H&E staining. In agreement with the previous studies, our results provide morphological evidence that chronic stress can lead to degeneration and death of GABAergic neurons [15] and astrocytes [34], leading to the decrease of the amygdala volume and may be related to the degeneration and death of glutamatergic neurons in the BLA nucleus.…”

“…But, with increasing stress duration and intensity, p-eIF-2α activates the expression of transcription factor ATF4, further promoting the expression of CHOP, thereby leading to neuronal injury and death [39,40]. Previous studies have confirmed that ER stress plays an important role in neuronal injury and the pathogenesis of neurodegenerative diseases [15,18,19,41]. In order to confirm whether ER stress-associated PERK pathway plays a role in stress-induced degeneration and death of glutamatergic neurons, we used a specific inhibitor Sal.…”

“…BLA consists of 80% of excitatory neurons (glutamatergic neurons) and 20% of inhibitory neurons (GABAergic neurons) [ 14 ]. Previous studies have found that acute stressors can induce the high expressions of glutamate (Glu) receptors in the BLA nucleus, which then gradually get adjusted to low expression steady-state level in response to prolonged stress exposure through a yet unknown mechanism [ 15 ].…”

Endoplasmic Reticulum Stress Is Associated with the Mesencephalic Dopaminergic Neuron Injury in Stressed Rats

“…Previous studies indicated that stress could lead to anhedonia in animals [ 28 ] that has been associated with dysfunctions in the reward system, particularly in the dopamine system [ 29 ]. Stress also resulted in anxiety and depression disorders [ 30 ], and neuroimaging, pharmacological, and electrophysiological methods were employed by researchers in humans and animal models, providing support for the presence of dopamine dysfunctions [ 31 ]. Particularly, Tye and collaborators [ 32 ] indicated that stress-induced abnormal behaviors could be reversed by selective activation of the dopamine system.…”

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

“…More studies are required to understand how the mutant neuroligin3 induced UPR activation is related to ASD associated synaptic pathologies. PERK has also been linked to stress-induced anxiety, and reducing PERK was found to mitigate ER stress-induced GABAergic neuron damage in rat basolateral amygdala (Wang S. et al, 2019 ).…”