Stress-Induced Alterations of Norepinephrine Release in the Bed Nucleus of the Stria Terminalis of Mice

Abstract

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated norepinephrine release across multiple stimulation parameters, and reduced sensitivity to the α 2 -adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.

Modulation of behavioral and neurochemical responses of adult zebrafish by fluoxetine, eicosapentaenoic acid and lipopolysaccharide in the prolonged chronic unpredictable stress model

“…Here, PCUS significantly elevated only norepinephrine levels vs. controls. Given that stress increases the activity of the sympathetic nervous system, this observation parallels rodent data where stress also increases norepinephrine 52 , 53 . A widely used SSRI, fluoxetine, decreased 5-HIAA (the main metabolite of serotonin) in zebrafish brain, as well as the ratio of 5-HIAA/serotonin (vs. control group), reflecting lower serotonin turnover, a common biomarker of SSRI antidepressant action in zebrafish models 54 , 55 .…”

Oleuropein Reverses Repeated Corticosterone-Induced Depressive-Like Behavior in mice: Evidence of Modulating Effect on Biogenic Amines

“…This finding was supported by Fan et al, 2014 who reported that Cort treatment for 21 days induced a significant increase in dopamine-β-hydroxylase protein (DβH) and nor-epinephrine transporter protein expression (NET) in the brain, and that this effect was counteracted by concomitant treatment with a corticosteroid receptor antagonist (mifepristone), in addition to spironolactone 67 . The changes of NET and DβH expression that was induced by Cort is a normal response to stress and was accompanied by increased stressful behaviours 68 . The effect of Cort on norepinephrine was minimized by treatment with oleuropein or fluoxetine and maintained nor-epinephrine level compared to that of the control group.…”

Role of the Bed Nucleus of the Stria Terminalis in PTSD: Insights From Preclinical Models

“…Acute restraint also causes an increase in corticosterone release in mice, but this change is significantly attenuated in PACAP- and PAC1-deficient mice, suggesting that PACAP-PAC1 receptor binding in BNST may mediate central short-term effects of restraint stress (Mustafa et al, 2015). Relatedly, acute stress (i.e., a short, potent stressor) has been shown to elevate norepinephrine in the BNST: Schmidt et al (2018) showed, using optogenetic-assisted fast-scan cyclic voltammetry, elevated norepinephrine release across several stimulation parameters and reduced sensitivity to norepinephrine auto-receptors in mice exposed to 5 days restraint stress. In contrast to reports of acute restraint, chronic immobilization increases BNST (but not amygdala) dendritic branching (Vyas et al, 2003), suggesting a role of stress in remodeling neurons in stress-related brain regions after the traumatic event that underlies PTSD.…”