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 noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the α2-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.Stress; Norepinephrine; Fast-Scan Cyclic Voltammetry; Optogenetics; Bed Nucleus of the Stria Terminalis; Corticosterone . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/335653 doi: bioRxiv preprint first posted online May. 31, 2018; Stress is an important physiologic response to potentially harmful environmental stimuli.Under some conditions, however, such as chronic stress exposure or especially traumatic events, persistent alterations in the stress response occur, leading to abnormal and potentially maladaptive responses. Previous research has shown a central role of the catecholamine neurotransmitter norepinephrine (NE) in the physiological and behavioral stress responses 1 . NE release, in key downstream nuclei following stress has been implicated in a number of psychological disorders including addiction 2-3 , affective disorders 1 , and PTSD 4 .Noradrenergic neurons project through two primary pathways in the brain: the dorsal noradrenergic bundle and ventral noradrenergic bundle. The pontine locus coeruleus (A6) gives rise to the dorsal noradrenergic bundle sending projections throughout the cortex, thalamus, hippocampus, cerebellum, and amygdala [5][6][7] . In contrast, the ventral noradrenergic bundle mainly arises from two nuclei, A1 of the rostral ventrolateral medulla and A2 of the nucleus of the solitary tract 6 , and projects mainly to hypothalamus, parabrachial nucleus, midbrain, and bed nucleus of the stria terminalis (BNST) 3,6,8 . Of particular interest is the projection from the medullary noradrenergic nuclei (i.e. A1/A2) to the BNST because it comprises the densest region of NE terminals in the brain 9-12 and serves as a critical nucleus for processing affective state 13 .Furthermore,...

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats

“…Interestingly, while repeated TMT did not elicit elevations in self-administration in Experiment 3, data from Experiments 3 and 4 show that neither the acute physiological (fecal boli) nor neuroendocrine (corticosterone) responses habituated across repeated TMT exposures. This is consistent with another study showing that corticosterone response of mice to repeated exposures to rat-bedding does not habituate (Finn et al, 2018), and stands in contrast to other modes of repeated stress such as restraint where corticosterone responses habituate (Schmidt et al, 2019). This data pattern highlights the unique nature of PO as a stressor evocative of an evolutionarily engrained response (Perez-Gomez et al, 2015).…”

An ensemble recruited by α2a-adrenergic receptors is engaged in a stressor-specific manner in mice

“…In both instances, we found a decrease in transient peaks per minute when compared to baseline activity suggesting that the inhibitory effects of prolonged stress/novelty may mask the excitatory effect of guanfacine on calcium transients (Figure 7J and 9B). We chose restraint stress in particular because it is known to stimulate noradrenaline release in the BNST (Cecchi et al, 2002;Schmidt et al, 2018). We recorded calcium activity in Guansembles during repeated days of restraint stress using our tethered fiber-compatible restraint device (RESTRAINT,…”

Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons

“…These results are consistent with the idea that activation of A2/PrRP inputs to the vlBNST participates in the expression of passive avoidance. Noradrenergic signaling in the vlBNST has been broadly implicated in avoidance and other anxiety-like behavioral responses to innate stressors (Cecchi et al, 2002; Schmidt et al, 2019; Zheng & Rinaman, 2013), and BNST circuits are implicated in the expression of conditioned fear responses when rats are re-exposed to relevant contextual stimuli (Poulos et al, 2010; Zimmerman & Maren, 2011). A particularly interesting example supporting a role of noradrenergic signaling within the vlBNST in contextual conditioning is opiate withdrawal, which produces a robust conditioned place avoidance in rats (Aston-Jones et al, 1999).…”