The significance of glucocorticoid pulsatility

Lightman, Stafford L.; Wiles, Crispin C.; Atkinson, Helen C.; Henley, David; Russell, Georgina; McKenna, Mervyn; Spiga, Francesca; Wood, Susan A.; Conway-Campbell, Becky

doi:10.1016/j.ejphar.2007.11.073

Cited by 203 publications

(159 citation statements)

References 62 publications

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“…Moreover, it has been shown that alterations in HPA axis modulation can be reversed by treatment with Lactobacillus and Bifidobacterium (28,29). However, caution is needed when extrapolating from single timepoint neuroendocrine studies (30). Nonetheless, these data clearly indicate that in the bidirectional communication between the brain and the gut, the HPA axis is a key component that can be affected by changes in the enteric microbiota.…”

Section: Discussionmentioning

confidence: 87%

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Bravo¹,

Forsythe

Chew

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

3,127

2,512

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There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA B1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA Aα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABA Aα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety-and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stressrelated disorders such as anxiety and depression.brain-gut axis | irritable bowel syndrome | probiotic | fear conditioning | cognition T here is increasing evidence suggesting an interaction between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is recognized as the microbiome-gut-brain axis (1-4). Studies in rodents have implicated dysregulation of this axis in functional bowel disorders, including irritable bowel syndrome. Indeed, visceral perception in rodents can be affected by alterations in gut microbiota (5). Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic-pituitary-adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10). In addition, pathogenic bacteria in rodents can induce anxiety-like behaviors, which are mediated via vagal afferents (9, 11).GABA is the main inhibitory neurotransmitter of the CNS, the effects of which are mediated through two major classes of receptors-the ionotropic GABA A receptors, which exist as a number of subtypes formed by the coassembly of different subunits (α, β, and γ subunits; ref. 12), and the GABA B receptors, which are G protein coupled and consist of a heterodi...

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Section: Discussionmentioning

confidence: 87%

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Bravo¹,

Forsythe

Chew

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

3,127

2,512

View full text Add to dashboard Cite

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“…If verified, this outcome would motivate investigation of the impact of pulsatile T-dependent signaling patterns on target-tissues of androgen action. In this regard, glucocorticoid pulsatility has recently been shown to mediate distinct central nervous system effects (25,38,46). Analogously, in the only such study available, pulsatile and continuous T feedback exerted distinct effects of LH secretion (58).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Veldhuis¹,

Liu

Takahashi

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade. Am J Physiol Regul Integr Comp Physiol 303: R994 -R1002, 2012. First published September 19, 2012 doi:10.1152/ajpregu.00314.2012.-Gonadotrophin-releasing hormone (GnRH) pulsatility is required for optimal luteinizing hormone (LH) secretion, but whether LH pulsatility is required for physiological testosterone (T) secretion is not known. To test the postulate that pulses of recombinant human (rh) LH stimulate greater T secretion than continuous infusion of the same dose, a potent selective GnRH antagonist was administered overnight to 19 healthy men ages 18 -49 yr. Subjects then received saline or rhLH intravenously continuously or as 6-min pulses intravenously every 1 or 2 h at the same total dose. Blood was sampled every 10 min for 10 h to quantify T responses. For the four interventions, the descending rank order of mean LH and mean T concentrations was 1-h ϭ 2-h rhLH pulses Ͼ continuous rhLH Ͼ saline (P Ͻ 10 Ϫ3 ). Plateau LH and T concentrations correlated positively (R 2 ϭ 0.943, P ϭ 0.029) as did LH concentrations and LH half-lives (R 2 ϭ 0.962, P ϭ 0.019). Percentage pulsatile T secretion assessed by deconvolution analysis (Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. Endocrinology 147: 2817-2828, 2006) was the highest (P ϭ 0.019), and half-time to attain peak T concentrations was the shortest (P Ͻ 10 Ϫ6 ), for 1-h rhLH pulses. Approximate entropy (a pattern-regularity measure) revealed more orderly T secretion for 1-than 2-h rhLH pulses (P ϭ 0.0076). Accordingly, a pulsatile LH signal, while not obligatory to maintain mean T concentrations, controls the mean plasma LH concentration and determines quantifiable patterns of T secretion. These data introduce the question whether blood T patterns in turn supervise distinctive target-tissue responses.pulse; gonadotropin; human; testis; testosterone LOW TESTOSTERONE (T) concentrations increase the clinical risk of sarcopenia, osteopenia, diminished libido and potentia, visceral adiposity, decreased aerobic capacity, and (possibly) impaired cognitive function (30). Reduced T availability may result from reduced gonadotrope stimulation by hypothalamic gonadotrophin-releasing hormone (GnRH), attenuated biosynthesis of luteinizing hormone (LH), heightened T clearance, greater T negative feedback, and/or blunted testicular responses to LH (32,33). In addition, hypoandrogenemia in some conditions such as aging is associated with disorderly LH secretion patterns (30 -32, 36, 51) and smaller more frequent circhoral LH pulses (18,32,36). Whether small frequent LH pulses or continuous LH delivery into the bloodstream is less effective than larger infrequent LH pulses in driving T secretion is not known. The issue is central to the broader theme of pulsatility regulation and action in endocrine systems (17,20,54). Indeed, growth hormone (GH), ACTH, parathyroid hormone (PTH), insulin, and oxytocin driv...

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“…Glucocorticoids have long been recognised to show diurnal rhythms of release (reviewed in [81,[87][88][89]). In diurnal animals, peak levels of glucocorticoids are encountered in the early morning, whereas nocturnal animals show a peak in the early night.…”

Section: Rhythms Of Glucocorticoidsmentioning

confidence: 99%

“…It appears that the lower glucocorticoid affinity of the GR, together with the rapid clearance of the activated receptor by a proteasomedependent mechanism, leads to a signalling activity that closely follows changes in glucocorticoid levels. In contrast, the high affinity MR already responds to low glucocorticoid levels and its signalling activity appears to be more sustained (reviewed in [88]). These dynamics have consequences for gene expression: For the M a n u s c r i p t GR, it has been shown that pulsatile glucocorticoid signals can lead to different induction levels and expression dynamics of GR target genes compared with those observed under continuous stimulation [149].…”

Section: Neurogenesis and Circadian Rhythms -Are Glucocorticoids Invomentioning

confidence: 99%

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

Dickmeis

Foulkes

2011

Molecular and Cellular Endocrinology

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The circadian clock, an endogenous timekeeper that regulates daily rhythms of physiology, also influences the dynamic release of glucocorticoids. The release of glucocorticoids is characteristically pulsatile and is further modulated in a circadian fashion. A circadian pacemaker in the brain regulates daily rhythms of hypothalamicpituitary-adrenal axis and autonomic nervous system activity that both influence glucocorticoid release from the adrenal gland. This systemic regulation interacts with rhythms in the adrenal gland itself that are driven by its own circadian clock. One function of glucocorticoids is the regulation of cell proliferation. Depending on the tissue, this can involve both negative and positive regulation of a variety of processes, including cell differentiation and cell death. Cell proliferation is also under circadian control, and recent evidence suggests that this regulation may involve glucocorticoid signalling. Here, we review the dynamic processes participating in the interplay between the circadian clock, glucocorticoids and cell proliferation, and we discuss the potential implications for therapy.

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The significance of glucocorticoid pulsatility

Cited by 203 publications

References 62 publications

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Analysis of the impact of intravenous LH pulses versus continuous LH infusion on testosterone secretion during GnRH-receptor blockade

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

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