Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling

Acevedo-Rodriguez, Alexandra; Kauffman, Alexander S.; Cherrington, Brian D.; Borges, Cibele dos Santos; Roepke, Troy A.; Laconi, Myriam Raquel

doi:10.1111/jne.12590

Cited by 136 publications

(117 citation statements)

References 113 publications

(170 reference statements)

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“…GnRH neuronal processes, named “dendrons,” by Herbison group [3], form an interwoven network that receives direct synaptic and neuropeptide input from upstream regulatory neurons, most notably kisspeptin [4, 5]. This GnRH network integrates other signals that impinge on reproduction, such as stress [6, 7], endocrine disruptors [8], circadian rhythms [9, 10], metabolism [11, 12], and acute inflammation during infection [13-15]. …”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

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Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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“…Neurosteroids can bind to intracellular receptors, which are responsible for the classical genomic actions . They can also produce rapid effects (non‐genomic mechanisms) via ligand‐gated channels, such as GABA A and several other membrane receptors . The former have a response time in the order of minutes, hours or days, whereas the latter are faster (seconds to minutes) .…”

Section: Discussionmentioning

confidence: 99%

“…68 They can also produce rapid effects (non-genomic mechanisms) via ligand-gated channels, such as GABA A and several other membrane receptors. 13,16,69 The former have a response time in the order of minutes, hours or days, whereas the latter are faster (seconds to minutes). 17,70 For example, P 4 can act via different types of P 4 receptors.…”

Section: Discussionmentioning

confidence: 99%

“Rapid actions of the neurosteroid allopregnanolone on ovarian and hypothalamic steroidogenesis: Central and peripheral modulation”

Cáceres

Orozco

Cabrera

et al. 2020

J Neuroendocrinology

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The present study aimed to determine whether an i.c.v. administration of allopregnanolone (ALLO) rapidly modifies the hypothalamic and ovarian 3β‐hydroxysteroid dehydrogenase (3β‐HSD) enzymatic activity and gene expression in in vivo and ex vivo systems in pro‐oestrus (PE) and dioestrus I (DI) rats. Animals were injected with vehicle, ALLO, bicuculline or bicuculline plus ALLO and were then killed. In the in vivo experiment, the hypothalamus, ovaries and serum were extracted and analysed. In the ex vivo experiment, the superior mesenteric ganglion ‐ ovarian nerve plexus ‐ ovary system was extracted and incubated during 120 minutes at 37 ºC. The serum and ovarian compartment fluids were used to determine progesterone by radioimmunoanalysis. In the in vivo experiments, ALLO caused a decrease in hypothalamic and ovarian 3β‐HSD enzymatic activity during PE. During DI, ALLO increased hypothalamic and ovarian 3β‐HSD activity and gene expression. The ovarian 3β‐HSD activity increased in both stages in the ex vivo system; gene expression increased only during DI. ALLO induced an increase in serum progesterone only in D1 and in the ovarian incubation liquids in both stages. All findings were reversed by an injection of bicuculline before ALLO. Ovarian steroidogenic changes could be attributed to signals coming from ganglion neurones, which are affected by the acute central neurosteroid stimulation. The i.c.v. administration of ALLO via the GABAergic system altered 3β‐HSD activity and gene expression, modulating the neuroendocrine axis. The present study reveals the action that ALLO exerts on the GABAA receptor in both the central and peripheral nervous system and its relationship with hormonal variations. ALLO is involved in the “fine tuning” of neurosecretory functions as a potent modulator of reproductive processes in female rats.

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“…HSD17B11 plays a role in hormone metabolism, through which it may mediate endogenous estrogen levels [60]. Through feedback on the brain, estrogens control the pulsatile release of GnRH and can influence stress signaling [61] and enhance hypothalamicpituitary-adrenal (HPA) function [62]. HSD17B11 is also related to CEBPB (CCAAT/enhancer-binding protein beta), a transcription factor regulating the expression of genes involved in immune and inflammatory responses [63,64].…”

Section: Control Vs Stress Splicing Comparison: Genes Of Interestmentioning

confidence: 99%

Stress-mediated convergence of splicing landscapes in male and female rock doves

et al. 2020

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Background: The process of alternative splicing provides a unique mechanism by which eukaryotes are able to produce numerous protein products from the same gene. Heightened variability in the proteome has been thought to potentiate increased behavioral complexity and response flexibility to environmental stimuli, thus contributing to more refined traits on which natural and sexual selection can act. While it has been long known that various forms of environmental stress can negatively affect sexual behavior and reproduction, we know little of how stress can affect the alternative splicing associated with these events, and less still about how splicing may differ between sexes. Using the model of the rock dove (Columba livia), our team previously uncovered sexual dimorphism in the basal and stress-responsive gene transcription of a biological system necessary for facilitating sexual behavior and reproduction, the hypothalamic-pituitary-gonadal (HPG) axis. In this study, we delve further into understanding the mechanistic underpinnings of how changes in the environment can affect reproduction by testing the alternative splicing response of the HPG axis to an external stressor in both sexes. Results: This study reveals dramatic baseline differences in HPG alternative splicing between males and females. However, after subjecting subjects to a restraint stress paradigm, we found a significant reduction in these differences between the sexes. In both stress and control treatments, we identified a higher incidence of splicing activity in the pituitary in both sexes as compared to other tissues. Of these splicing events, the core exon event is the most abundant form of splicing and more frequently occurs in the coding regions of the gene. Overall, we observed less splicing activity in the 3'UTR (untranslated region) end of transcripts than the 5'UTR or coding regions. Conclusions: Our results provide vital new insight into sex-specific aspects of the stress response on the HPG axis at an unprecedented proximate level. Males and females uniquely respond to stress, yet exhibit splicing patterns suggesting a convergent, optimal splicing landscape for stress response. This information has the potential to inform evolutionary theory as well as the development of highly-specific drug targets for stressinduced reproductive dysfunction.

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Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling

Cited by 136 publications

References 113 publications

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

“Rapid actions of the neurosteroid allopregnanolone on ovarian and hypothalamic steroidogenesis: Central and peripheral modulation”

Stress-mediated convergence of splicing landscapes in male and female rock doves

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