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Molecular Mechanisms Underlying Stress Response and Resilience

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 46757

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Dr. Kazunori Kageyama

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Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
Interests: Cushing’s disease; hypopituitarism; pituitary tumor; proopiomelanocortin; stress
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Dr. Takahiro Nemoto

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Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo, Japan
Interests: orchestration in stress response focused on the HPA-axis; inharmonious in post-growth stress response due to fetal malnutrition based on the DOHaD theory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A variety of stressors induce various physiological responses by stimulating sympathetic, neuroendocrine, and behavioral systems. While stress activates the hypothalamic-pituitary-adrenal (HPA) axis, it suppresses the hypothalamic-pituitary-gonadal axis. Stress also modulates the immune system. Corticotropin-releasing factor (CRF) in the hypothalamus plays a central role in regulating the stress response. CRF stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH stimulates the secretion of glucocorticoids from the adrenal glands. The activated HPA axis is suppressed by the negative feedback effect of glucocorticoids. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The stressed state may be relieved or reduced by an action, medicine, or therapy. The molecular mechanisms underlying stress response and resilience, however, are not fully understood. This Special Issue is focused on stress response and resilience, and will include original research articles and reviews on aspects related to their molecular mechanisms.

Dr. Kazunori Kageyama
Dr. Takahiro Nemoto
Guest Editors

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Keywords

stress
resilience
relaxant
hypothalamus
CRF
ACTH
glucocorticoid

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 183 KiB

Open AccessEditorial

Molecular Mechanisms Underlying Stress Response and Resilience

by Kazunori Kageyama and Takahiro Nemoto

Int. J. Mol. Sci. 2022, 23(16), 9007; https://doi.org/10.3390/ijms23169007 - 12 Aug 2022

Cited by 4 | Viewed by 1378

Abstract

A variety of stressors induce various physiological responses by modulating sympathetic, neuroendocrine, and behavioral systems [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

Research

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18 pages, 3522 KiB

Open AccessArticle

Knockout of the hsd11b2 Gene Extends the Cortisol Stress Response in Both Zebrafish Larvae and Adults

by Antonia Theodoridi, Alberto Dinarello, Lorenzo Badenetti, Michail Pavlidis, Luisa Dalla Valle and Aleka Tsalafouta

Int. J. Mol. Sci. 2021, 22(22), 12525; https://doi.org/10.3390/ijms222212525 - 20 Nov 2021

Cited by 10 | Viewed by 2534

Abstract

The Hsd11b2 enzyme converts cortisol into its inactive form, cortisone and regulates cortisol levels, in particular in response to stress. Taking advantage of CRISPR/Cas9 technology, we generated a hsd11b2 zebrafish mutant line to evaluate the involvement of this gene in stress response regulation. The absence of a functional Hsd11b2 affects survival of zebrafish, although homozygous hsd11b2^−/− mutants can reach adulthood. Reproductive capability of hsd11b2^−/− homozygous adult males is almost completely abrogated, while that of females is reduced. Interestingly, basal cortisol levels and glucocorticoid-dependent transcriptional activities are not affected by the mutation. In agreement with basal cortisol results, we also demonstrated that basal response to light (LMR-L/D) or mechanical (VSRA) stimuli is not significantly different in wild-type (hsd11b2^+/+) compared to mutant larvae. However, after exposure to an acute stressor, the cortisol temporal patterns of synthesis and release are prolonged in both 5 days post fertilization larvae and one-year-old adult hsd11b2^−/− zebrafish compared to wild-type siblings, showing at the same time, at 5 dpf, a higher magnitude in the stress response at 10 min post stress. All in all, this new zebrafish model represents a good tool for studying response to different stressors and to identify mechanisms that are induced by cortisol during stress response. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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12 pages, 2318 KiB

Open AccessArticle

Biphasic Roles of Clock Genes and Bone Morphogenetic Proteins in Gonadotropin Expression by Mouse Gonadotrope Cells

by Yoshiaki Soejima, Nahoko Iwata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada and Fumio Otsuka

Int. J. Mol. Sci. 2021, 22(20), 11186; https://doi.org/10.3390/ijms222011186 - 17 Oct 2021

Cited by 5 | Viewed by 1817

Abstract

Roles of Clock genes and the bone morphogenetic protein (BMP) system in the regulation of gonadotropin secretion by gonadotropin-releasing hormone (GnRH) were investigated using mouse gonadotropin LβT2 cells. It was found that luteinizing hormone (LH)β mRNA expression level in LβT2 cells changed gradually over time, with LHβ expression being suppressed in the early phase up to 12 h and then elevated in the late phase 24 h after GnRH stimulation. In addition, the mRNA expression levels of Clock genes, including Bmal1, Clock, Per2, and Cry1, also showed temporal changes mimicking the pattern of LHβ expression in the presence and absence of GnRH. Notably, the expression levels of Bmal1 and Clock showed strong positive correlations with LHβ mRNA expression levels. Moreover, a functional link of the ERK signaling of mitogen-activated protein kinases (MAPKs) in the suppression of LHβ mRNA expression, as well as Bmal1 and Clock mRNA expression by GnRH at the early phase, was revealed. Inhibition of Bmal1 and Clock expression using siRNA was involved in the reduction in LHβ mRNA levels in the late phase 24 h after GnRH stimulation. Furthermore, in the presence of BMP-6 and -7, late-phase Bmal1 and LHβ mRNA expression after GnRH stimulation was significantly attenuated. Collectively, the results indicated that LH expression in gonadotrope cells exhibits Bmal1/Clock-dependent fluctuations under the influence of GnRH and that the fluctuations are regulated by ERK and BMPs in the early and late stages, respectively, in a phase-dependent manner after GnRH stimulation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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12 pages, 1037 KiB

Open AccessArticle

Prenatal and Postnatal Methyl-Modulator Intervention Corrects the Stress-Induced Glucocorticoid Response in Low-Birthweight Rats

by Takahiro Nemoto and Yoshihiko Kakinuma

Int. J. Mol. Sci. 2021, 22(18), 9767; https://doi.org/10.3390/ijms22189767 - 9 Sep 2021

Cited by 4 | Viewed by 1868

Abstract

Low body weight at birth has been shown to be a risk factor for future metabolic disorders, as well as stress response abnormalities and depression. We showed that low-birthweight rats had prolonged high blood corticosterone levels after stress exposure, and that an increase in Gas5 lncRNA, a decoy receptor for glucocorticoid receptors (GRs), reduces glucocorticoid responsiveness. Thus, we concluded that dampened pituitary glucocorticoid responsiveness disturbed the glucocorticoid feedback loop in low-birthweight rats. However, it remains unclear whether such glucocorticoid responsiveness is suppressed solely in the pituitary or systemically. The expression of Gas5 lncRNA increased only in the pituitary, and the intact induction of expression of the GR co-chaperone factor Fkbp5 against dexamethasone was seen in the liver, muscle, and adipose tissue. Intervention with a methyl-modulator diet (folate, VB₁₂, choline, betaine, and zinc) immediately before or one week after delivery reversed the expression level of Gas5 lncRNA in the pituitary of the offspring. Consequently, it partially normalized the blood corticosterone levels after restraint stress exposure. In conclusion, the mode of glucocorticoid response in low-birthweight rats is impaired solely in the pituitary, and intervention with methyl-modulators ameliorates the impairment, but with a narrow therapeutic time window. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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22 pages, 12349 KiB

Open AccessArticle

Immunoelectron Microscopic Characterization of Vasopressin-Producing Neurons in the Hypothalamo-Pituitary Axis of Non-Human Primates by Use of Formaldehyde-Fixed Tissues Stored at −25 °C for Several Years

by Akito Otubo, Sho Maejima, Takumi Oti, Keita Satoh, Yasumasa Ueda, John F. Morris, Tatsuya Sakamoto and Hirotaka Sakamoto

Int. J. Mol. Sci. 2021, 22(17), 9180; https://doi.org/10.3390/ijms22179180 - 25 Aug 2021

Cited by 3 | Viewed by 2417

Abstract

Translational research often requires the testing of experimental therapies in primates, but research in non-human primates is now stringently controlled by law around the world. Tissues fixed in formaldehyde without glutaraldehyde have been thought to be inappropriate for use in electron microscopic analysis, particularly those of the brain. Here we report the immunoelectron microscopic characterization of arginine vasopressin (AVP)-producing neurons in macaque hypothalamo-pituitary axis tissues fixed by perfusion with 4% formaldehyde and stored at −25 °C for several years (4–6 years). The size difference of dense-cored vesicles between magnocellular and parvocellular AVP neurons was detectable in their cell bodies and perivascular nerve endings located, respectively, in the posterior pituitary and median eminence. Furthermore, glutamate and the vesicular glutamate transporter 2 could be colocalized with AVP in perivascular nerve endings of both the posterior pituitary and the external layer of the median eminence, suggesting that both magnocellular and parvocellular AVP neurons are glutamatergic in primates. Both ultrastructure and immunoreactivity can therefore be sufficiently preserved in macaque brain tissues stored long-term, initially for light microscopy. Taken together, these results suggest that this methodology could be applied to the human post-mortem brain and be very useful in translational research. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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10 pages, 2223 KiB

Open AccessArticle

Differential Effects of Fkbp4 and Fkbp5 on Regulation of the Proopiomelanocortin Gene in Murine AtT-20 Corticotroph Cells

by Kazunori Kageyama, Yasumasa Iwasaki, Yutaka Watanuki, Kanako Niioka and Makoto Daimon

Int. J. Mol. Sci. 2021, 22(11), 5724; https://doi.org/10.3390/ijms22115724 - 27 May 2021

Cited by 10 | Viewed by 3586

Abstract

The hypothalamic-pituitary-adrenal axis is stimulated in response to stress. When activated, it is suppressed by the negative feedback effect of glucocorticoids. Glucocorticoids directly inhibit proopiomelanocortin (Pomc) gene expression in the pituitary. Glucocorticoid signaling is mediated via glucocorticoid receptors, 11β-hydroxysteroid dehydrogenases, and the FK506-binding immunophilins, Fkbp4 and Fkbp5. Fkbp4 and Fkbp5 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor, resulting in modulation of the glucocorticoid action. Here, we explored the regulation of Fkbp4 and Fkbp5 genes and their proteins with dexamethasone, a major synthetic glucocorticoid drug, in murine AtT-20 corticotroph cells. To elucidate further roles of Fkbp4 and Fkbp5, we examined their effects on Pomc mRNA levels in corticotroph cells. Dexamethasone decreased Pomc mRNA levels as well as Fkpb4 mRNA levels in mouse corticotroph cells. Dexamethasone tended to decrease Fkbp4 protein levels, while it increased Fkpb5 mRNA and its protein levels. The dexamethasone-induced decreases in Pomc mRNA levels were partially canceled by Fkbp4 knockdown. Alternatively, Pomc mRNA levels were further decreased by Fkbp5 knockdown. Thus, Fkbp4 contributes to the negative feedback of glucocorticoids, and Fkbp5 reduces the efficiency of the glucocorticoid effect on Pomc gene expression in pituitary corticotroph cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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10 pages, 700 KiB

Open AccessArticle

Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells

by Satoshi Fujisawa, Motoshi Komatsubara, Naoko Tsukamoto-Yamauchi, Nahoko Iwata, Takahiro Nada, Jun Wada and Fumio Otsuka

Int. J. Mol. Sci. 2021, 22(9), 4553; https://doi.org/10.3390/ijms22094553 - 27 Apr 2021

Cited by 6 | Viewed by 2732

Abstract

Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic–pituitary–adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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Review

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23 pages, 866 KiB

Open AccessReview

Roles of Oxytocin in Stress Responses, Allostasis and Resilience

by Yuki Takayanagi and Tatsushi Onaka

Int. J. Mol. Sci. 2022, 23(1), 150; https://doi.org/10.3390/ijms23010150 - 23 Dec 2021

Cited by 48 | Viewed by 11154

Abstract

Oxytocin has been revealed to work for anxiety suppression and anti-stress as well as for psychosocial behavior and reproductive functions. Oxytocin neurons are activated by various stressful stimuli. The oxytocin receptor is widely distributed within the brain, and oxytocin that is released or diffused affects behavioral and neuroendocrine stress responses. On the other hand, there has been an increasing number of reports on the role of oxytocin in allostasis and resilience. It has been shown that oxytocin maintains homeostasis, shifts the set point for adaptation to a changing environment (allostasis) and contributes to recovery from the shifted set point by inducing active coping responses to stressful stimuli (resilience). Recent studies have suggested that oxytocin is also involved in stress-related disorders, and it has been shown in clinical trials that oxytocin provides therapeutic benefits for patients diagnosed with stress-related disorders. This review includes the latest information on the role of oxytocin in stress responses and adaptation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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13 pages, 1341 KiB

Open AccessReview

Hypothalamic Regulation of Corticotropin-Releasing Factor under Stress and Stress Resilience

by Kazunori Kageyama, Yasumasa Iwasaki and Makoto Daimon

Int. J. Mol. Sci. 2021, 22(22), 12242; https://doi.org/10.3390/ijms222212242 - 12 Nov 2021

Cited by 36 | Viewed by 7155

Abstract

This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated Crf promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent Crf gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates “stress coping” mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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14 pages, 3986 KiB

Open AccessReview

Involvement of Ghrelin Dynamics in Stress-Induced Eating Disorder: Effects of Sex and Aging

by Chihiro Yamada

Int. J. Mol. Sci. 2021, 22(21), 11695; https://doi.org/10.3390/ijms222111695 - 28 Oct 2021

Cited by 7 | Viewed by 4050

Abstract

Stress, a factor that affects appetite in our daily lives, enhances or suppresses appetite and changes palatability. However, so far, the mechanisms underlying the link between stress and eating have not been fully elucidated. Among the peripherally produced appetite-related peptides, ghrelin is the only orexigenic peptide, and abnormalities in the dynamics and reactivity of this peptide are involved in appetite abnormalities in various diseases and psychological states. This review presents an overview of the research results of studies evaluating the effects of various stresses on appetite. The first half of this review describes the relationship between appetite and stress, and the second half describes the relationship between the appetite-promoting peptide ghrelin and stress. The effects of sex differences and aging under stress on appetite are also described. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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21 pages, 1110 KiB

Open AccessReview

The Molecular Biology of Susceptibility to Post-Traumatic Stress Disorder: Highlights of Epigenetics and Epigenomics

by Ghazi I. Al Jowf, Clara Snijders, Bart P. F. Rutten, Laurence de Nijs and Lars M. T. Eijssen

Int. J. Mol. Sci. 2021, 22(19), 10743; https://doi.org/10.3390/ijms221910743 - 4 Oct 2021

Cited by 23 | Viewed by 6662

Abstract

Exposure to trauma is one of the most important and prevalent risk factors for mental and physical ill-health. Excessive or prolonged stress exposure increases the risk of a wide variety of mental and physical symptoms. However, people differ strikingly in their susceptibility to develop signs and symptoms of mental illness after traumatic stress. Post-traumatic stress disorder (PTSD) is a debilitating disorder affecting approximately 8% of the world’s population during their lifetime, and typically develops after exposure to a traumatic event. Despite that exposure to potentially traumatizing events occurs in a large proportion of the general population, about 80–90% of trauma-exposed individuals do not develop PTSD, suggesting an inter-individual difference in vulnerability to PTSD. While the biological mechanisms underlying this differential susceptibility are unknown, epigenetic changes have been proposed to underlie the relationship between exposure to traumatic stress and the susceptibility to develop PTSD. Epigenetic mechanisms refer to environmentally sensitive modifications to DNA and RNA molecules that regulate gene transcription without altering the genetic sequence itself. In this review, we provide an overview of various molecular biological, biochemical and physiological alterations in PTSD, focusing on changes at the genomic and epigenomic level. Finally, we will discuss how current knowledge may aid us in early detection and improved management of PTSD patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)

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