Functional Subsets of Serotonergic Neurones: Implications for Control of the Hypothalamic‐Pituitary‐Adrenal Axis

Abstract

Serotonergic systems play an important role in the regulation of behavioural, autonomic and endocrine responses to stressful stimuli. This includes modulation of both the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-spinal-adrenal (HSA) axis, which converge at the level of the adrenal cortex to regulate glucocorticoid secretion. Paradoxically, serotonin can either facilitate or inhibit HPA axis activity and stress-related physiological or behavioural responses. A detailed analysis of the brainstem raphé complex and its ascending projections reveals that facilitatory and inhibitory effects of serotonergic systems on glucocorticoid secretion may be due to influences of topographically organized and functionally diverse serotonergic systems. (i) A serotonergic system arising from the middle and caudal dorsal raphé nucleus and projecting to a distributed central autonomic control system and a lateral 'emotional motor system'. Evidence suggests that serotonin can sensitize this subcortical circuit associated with autonomic arousal, anxiety and conditioned fear. (ii) A serotonergic system arising from the median raphé nucleus and projecting extensively and selectively to a ventral subiculum projection system. Evidence suggests that serotonin facilitates this limbic circuit associated with inhibition of ultradian, circadian and stress-induced activity of both the HPA axis and the HSA axis. These new perspectives, based on functional anatomical considerations, provide a hypothetical framework for investigating the role of serotonergic systems in the modulation of ultradian, circadian and stress-induced neuroendocrine function.

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

“…18,64 In addition, collateral serotonergic projections arise from the DRN to target functionally related regions, such as those involved in stress response, anxiety and conditioned fear. 9,49 Introduction of rodents to stressful stimuli associated with increased anxiety and fear [65][66][67][68] or i.c.v. infusion of CRF, Ucn1 or Ucn2 14,22,48,69 is effective at increasing immediate-early gene expression within caudal regions of the DRN.…”

“…9 Serotonin (5-HT) was found to regulate the hypothalamic-pituitary-adrenal (HPA) axis activity [9][10][11] and a variety of behavioral responses 12 during stressful challenges. Disturbed 5-HT functioning has a key role in the etiology of depression, as evidenced by altered expression of 5-HT receptors, decreased cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) levels and the therapeutic efficacy of selective 5-HT reuptake inhibitors.…”

Freewheel Running Prevents Learned Helplessness/Behavioral Depression: Role of Dorsal Raphe Serotonergic Neurons

“…5-HT is clearly implicated in the modulation of motor activity (Jacobs and Fornal, 1997). The rostral-mid DRN projects to regions involved in motor control, such as the caudate putamen and substantia nigra (Imai et al, 1986;Lowry, 2002). Increases in central 5-HT during exercise coincide with the onset of fatigue (Blomstrand et al, 1988(Blomstrand et al, , 1989Davis and Bailey, 1997), and administration of a 5-HT2 receptor antagonist increases running time to exhaustion (Bailey et al, 1993), suggesting that decreasing 5-HT responses during exercise may delay fatigue.…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…There is further topographical organization within the DRN itself. Although the possible significance of this organization will not be discussed here, Lowry and colleagues among others have shown that certain DRN subregions appear to be preferentially involved in stress and anxiety (Abrams et al, 2004(Abrams et al, , 2005Lowry, 2002;Maier and Watkins, 2005;Silva et al, 2002).…”