The Brainstem Noradrenergic Systems in Stress, Anxiety and Depression

Abstract

The locus coeruleus (LC) is regarded as a part of the central ‘stress circuitry’ because robust activation of the LC has been reported after stressful stimuli in experimental animals. A considerable amount of clinical evidence also suggests the relationship between the central noradrenergic (NAergic) system and fear/anxiety states or depression. However, previous animal studies have not been able to demonstrate unequivocally the involvement of the NAergic system in mediating fear or anxiety. The forebrain structures, including the hypothalamus, receive massive inputs from the medullary NAergic nuclei via the ventral NAergic bundle (VNAB). The VNAB has been implicated in the neuroendocrine stress axis mainly through its action on the corticotrophin‐releasing factor neurones in the paraventricular nucleus of the hypothalamus. Novel tools were introduced that are capable of disrupting the NAergic system more selectively and/or thoroughly than the neurotoxins employed in previous studies: the anti‐dopamine‐β hydroxylase (DBH)‐saporin is an immunotoxin that is taken up from nerve endings and disrupt the NAergic neurones in a retrograde manner. The genetically DBH‐depleted mice were also introduced, which lack endogenous noradrenaline. Owing to the rapid development of functional imaging technique, visualisation of the emotional phenomena has become possible in human subjects. Along with the advent of these technologies, endeavors have been continued to unravel the functional relevance of the central NAergic system to stress, anxiety and depression.

Cardiorespiratory concerns shape brain responses during automatic panic-related scene processing in patients with panic disorder

“…Although limited resolution does not allow for specific localization of subregions, coordinates suggest an involvement of pontine nuclei and locus coeruleus, a carbon dioxide/H+-sensitive brain site involved in communication of respiratoryand stress-induced activation changes. 54,55 The present study adds to what is known about the association between the brainstem and respiratory symptoms by linking increased brainstem activation to the subjective fear of respiratory symptoms. In his "false suffocation alarms" hypothesis, Klein 56 postulated that patients with panic disorder have a pathologically altered suffocation alarm monitor that results in a carbon dioxide hypersensitivity, forming the basis for sudden panic attacks.…”

Central Autonomic System

“…The catecholaminergic A2 and C2 neurons in the NTS (also called NA2 and Ad2; Paxinos and Watson, 2014) project to many of the same targets mentioned above including the PAG, parabrachial nucleus, paraventricular nucleus, rostral ventrolateral medulla, amygdala and bed nucleus of the stria terminalis and median preoptic nucleus of the hypothalamus (Tucker et al, 1987;Riche et al, 1990;Reyes and Van Bockstaele, 2006;Campbell and Herbison, 2007;Gaykema et al, 2007;Itoi and Sugimoto, 2010) but not to the caudal ventrolateral medulla (Hermes et al, 2006). The A2/C2 neurons probably comprise a number of different functional pathways, e.g., hypoxia responsive A2/C2 neurons project to the paraventricular hypothalamic nucleus (King et al, 2012), while some A2/C2 neurons contain glucose transporters and may participate in glucose regulation (Balfour et al, 2006;Briski et al, 2009).…”

Repeated Immobilization Stress Increases Nur77 Expression in the Bed Nucleus of the Stria Terminalis

“…The noradrenergic system plays a key role in the central responses to stress (Morilak et al 2005;Itoi and Sugimoto 2010). The BNST is the nuclei with the highest noradrenaline (NA) concentration in the brain, located exclusively in axon terminals (Brownstein and Palkovits 1984;Fuentealba et al 2000;Phelix et al 1992).…”