Neuropeptide Y mediates the initial hypothalamic–pituitary–adrenal response to maternal separation in the neonatal mouse

The function of the hypothalamic–pituitary–adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPY-deficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.

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Headliner in Physiology and Management of Childhood Asthma: Hypothalamic-Pituitary-Adrenal Axis

Current Pediatric Reviews ◽

10.2174/1573396315666191026100643 ◽

2020 ◽

Vol 16 (1) ◽

pp. 43-52 ◽

Cited By ~ 1

Author(s):

Nese Akcan ◽

Nerin N. Bahceciler

Keyword(s):

Side Effects ◽

Hpa Axis ◽

Inhaled Corticosteroids ◽

Cushing Syndrome ◽

Early Recognition ◽

Persistent Asthma ◽

Receptor Expression ◽

Hypothalamic Pituitary Adrenal

Asthma is the most common chronic inflammatory disease of children. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy which are the most effective, commonly used treatment of persistent asthma. Mostly, studies on the relationship between asthma and cortisol have focused on side effects of treatment. Recently, asthmatic patients not treated with ICS have been reported to have an attenuated activity and/or responsiveness of their Hypothalamic-Pituitary- Adrenal (HPA) axis. Moreover, it has been proposed that asthma worsening with stress may be due to a dysfunctional HPA axis, or cortisol insensitivity due to chronic psychological stress through impaired glucocorticoid receptor expression or function. Although long-term ICS treatment might produce adrenal suppression or iatrogenic Cushing syndrome, improvement of adrenal function has also been detected in some of asthmatic cases. Thus, the response scheme of HPA axis still contains undiscovered features in asthma. The management of asthma can be improved by increasing knowledge on the role of HPA axis in asthma pathophysiology. The risk for side effects of ICS can be minimized through increased awareness, early recognition of at-risk patients and regular patient follow-up. This review was written to draw attention to the role of HPA axis in both asthma and its treatment and to illustrate a follow up algorithm of HPA axis in the management of asthma.

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Hypothalamic-Pituitary-Adrenal Axis Activity of Newborn Mice Rapidly Desensitizes to Repeated Maternal Absence but Becomes Highly Responsive to Novelty

Endocrinology ◽

10.1210/en.2008-0238 ◽

2008 ◽

Vol 149 (12) ◽

pp. 6366-6377 ◽

Cited By ~ 39

Author(s):

L. Enthoven ◽

M. S. Oitzl ◽

N. Koning ◽

M. van der Mark ◽

E. R. de Kloet

Keyword(s):

Glucocorticoid Receptor ◽

Receptor Antagonist ◽

Hpa Axis ◽

Mineralocorticoid Receptor ◽

Maternal Separation ◽

Mineralocorticoid Receptor Antagonist ◽

Newborn Mice ◽

Hypothalamic Pituitary Adrenal ◽

The Third ◽

Corticosterone Response

In CD1 mice we investigated the hypothalamic-pituitary-adrenal (HPA) axis response to maternal separation for 8 h daily from postnatal d 3 to 5. At d 3 a slow separation-induced corticosterone response developed that peaked after 8 h, and the pups became responsive to stressors. On the second and third day, the response to 8 h separation rapidly attenuated, whereas the response to novelty did not, a pattern reflected by the hypothalamic c-fos mRNA response. If maternal separation and exposure to novelty were combined, then after the third such daily exposure, the sensitivity to the stressor was further enhanced. Meanwhile, basal corticosterone and ACTH levels were persistently suppressed 16 h after pups were reunited with their mothers. To explain the HPA axis desensitization after repeated separation, we found that circulating ghrelin levels increased and glucose levels decreased after all periods of maternal separation, ruling out a role of altered metabolism. Glucocorticoid feedback was not involved either because a glucocorticoid receptor antagonist amplified the corticosterone response after the first but became ineffective after the third separation. In contrast, a mineralocorticoid receptor antagonist decreased and increased corticosterone levels after the first and third period of separation, respectively. In conclusion, the newborn’s HPA axis readily desensitizes to repeated daily maternal separation, but continues to respond to novelty in a manner influenced by a central mineralocorticoid receptor- rather than glucocorticoid receptor-mediated mechanism.

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Leukemia inhibitory factor regulates glucocorticoid receptor expression in the hypothalamic-pituitary-adrenal axis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00577.2004 ◽

2005 ◽

Vol 289 (5) ◽

pp. E857-E863 ◽

Cited By ~ 12

Author(s):

Anastasia Kariagina ◽

Svetlana Zonis ◽

Mahta Afkhami ◽

Dmitry Romanenko ◽

Vera Chesnokova

Keyword(s):

Glucocorticoid Receptor ◽

Hpa Axis ◽

Leukemia Inhibitory Factor ◽

Dominant Negative ◽

Receptor Expression ◽

Inhibitory Factor ◽

Mrna Levels ◽

Hypothalamic Pituitary Adrenal ◽

Protein Levels

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 μg/mouse, ip) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.

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Stress and Critical Illness: The Integrated Immune/Hypothalamic-Pituitary-Adrenal Axis Response

Journal of Intensive Care Medicine ◽

10.1177/088506669701200503 ◽

1997 ◽

Vol 12 (5) ◽

pp. 225-238 ◽

Cited By ~ 9

Author(s):

David J. Torpy ◽

George P. Chrousos Md

Keyword(s):

Nervous System ◽

Critical Illness ◽

Sympathetic Nervous System ◽

Hpa Axis ◽

Stress System ◽

Cognitive Changes ◽

Conservation Of Energy ◽

Hypothalamic Pituitary Adrenal ◽

Immune Activity ◽

Sympathetic Nervous

Critical illness leads to a coordinated reaction that is categorized as the stress response; activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system leads to metabolic and cardiovascular changes that are generally directed toward maintenance of homeostasis. The HPA axis and the sympathetic nervous system are linked via reciprocally activating brainstem pathways. The immune system acts via cytokines, which are hormones, to activate the HPA axis. Glucocorticoid secretion suppresses immune activity, thus completing an immune-HPA feedback loop. Restraint of immune activity may be a major function of glucocorticoids during stress, thus averting the potential for immune-mediated damage to healthy tissues. Cortisol also acts to produce adaptive metabolic, cardiovascular, and cognitive changes. Activation of the stress system is also associated with inhibition of thyroid, gonadal, and growth axes through neuroendocrine and peripheral mechanisms; such effects can be seen as directed toward conservation of energy. There is growing evidence that hyperfunction and hypofunction of the integrated stress system may lead to a variety of previously unexplained disorders. Recently, a more detailed understanding of the stress system combined with astute clinical observation of critically ill patients has led to promising new avenues for therapeutic investigation.

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DEVELOPMENT OF HYPOTHALAMIC–PITUITARY–ADRENAL RESPONSE TO STRESS IN RATS MADE HYPOTHYROID BY EXPOSURE TO THIOURACIL FROM CONCEPTION

Journal of Endocrinology ◽

10.1677/joe.0.0900403 ◽

1981 ◽

Vol 90 (3) ◽

pp. 403-409 ◽

Cited By ~ 4

Author(s):

L. A. MESERVE ◽

J. H. LEATHEM

Keyword(s):

Hpa Axis ◽

Adrenal Glands ◽

Hypothalamic Pituitary Adrenal ◽

Serum Corticosterone ◽

Functional Maturation ◽

State Delays ◽

Corticosterone Secretion ◽

Response To Stress ◽

Adrenal Response

The functional maturation of the hypothalamic–pituitary–adrenal (HPA) axis has been studied in rats of 20–35 days of age made hypothyroid by the administration of thiouracil from conception. Basal concentrations of corticosterone in serum were normal in hypothyroid animals. Ether stress led to an increase in corticosterone content of the adrenal glands of hypothyroid and normal rats but not to a rise in serum corticosterone of hypothyroid rats until 30 days of age. Corticosterone secretion in response to ACTH administration was subnormal in hypothyroid rats. The hypothyroid state delays the development of the hypothalamic–pituitary–portion of the HPA axis until 30 days of age and causes a diminution in the adrenal response to ACTH beyond this time.

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Metabolic Signals Modulate Hypothalamic-Pituitary-Adrenal Axis Activation During Maternal Separation of the Neonatal Mouse

Journal of Neuroendocrinology ◽

10.1111/j.1365-2826.2006.01482.x ◽

2006 ◽

Vol 18 (11) ◽

pp. 865-874 ◽

Cited By ~ 56

Author(s):

M. V. Schmidt ◽

S. Levine ◽

S. Alam ◽

D. Harbich ◽

V. Sterlemann ◽

...

Keyword(s):

Maternal Separation ◽

Hypothalamic Pituitary Adrenal Axis ◽

Neonatal Mouse ◽

Hypothalamic Pituitary Adrenal ◽

Adrenal Axis ◽

Pituitary Adrenal Axis

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Effect of vasopressin 1b receptor blockade on the hypothalamic–pituitary–adrenal response of chronically stressed rats to a heterotypic stressor

Journal of Endocrinology ◽

10.1677/joe-08-0425 ◽

2008 ◽

Vol 200 (3) ◽

pp. 285-291 ◽

Cited By ~ 22

Author(s):

Francesca Spiga ◽

Louise R Harrison ◽

Cliona P MacSweeney ◽

Fiona J Thomson ◽

Mark Craighead ◽

...

Keyword(s):

White Noise ◽

Chronic Stress ◽

Hpa Axis ◽

Home Cage ◽

Male Rats ◽

Receptor Blockade ◽

Hypothalamic Pituitary Adrenal ◽

Corticosterone Secretion ◽

Corticosterone Response ◽

Adrenal Response

Exposure to chronic restraint (CR) modifies the hypothalamic–pituitary–adrenal (HPA) axis response to subsequent acute stressors with adaptation of the response to a homotypic and sensitization of the response to a heterotypic stressor. Since vasopressin (AVP) activity has been reported to change during chronic stress, we investigated whether this was an important factor in HPA facilitation. We therefore tested whether vasopressin 1b receptor (AVPR1B) blockade altered the ACTH and corticosterone response to heterotypic stressors following CR stress. Adult male rats were exposed to CR, single restraint, or were left undisturbed in the home cage. Twenty-four hours after the last restraint, rats were injected with either a AVPR1B antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in saline, 0.2/kg, s.c.) and then exposed to either restraint, lipopolysaccharide (LPS) or white noise. CR resulted in the adaptation of the ACTH and corticosterone response to restraint and this effect was not prevented by pretreatment with Org. Although we found no effect of CR on LPS-induced ACTH and corticosterone secretion, both repeated and single episodes of restraint induced the sensitization of the ACTH, but not corticosterone response to acute noise. Pretreatment with Org reduced the exaggerated ACTH response to noise after both single and repeated exposure to restraint.

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Interactions between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis

Acta Endocrinologica ◽

10.1530/eje.0.1400130 ◽

1999 ◽

pp. 130-136 ◽

Cited By ~ 64

Author(s):

R Krysiak ◽

E Obuchowicz ◽

ZS Herman

Keyword(s):

Neuropeptide Y ◽

Hpa Axis ◽

Animal Species ◽

In Vivo Studies ◽

Hypothalamic Pituitary Adrenal ◽

Hpa Axis Activity ◽

Pituitary Adrenal Axis

The aim of this paper is to review the present knowledge of interactions between the neuropeptide Y (NPY) system and the hypothalamic-pituitary-adrenal (HPA) axis. On the basis of in vitro and in vivo studies of various animal species, we review the effects of NPY on all levels of HPA axis activity. We also describe the effects of glucocorticosteroids on the NPY system in the hypothalamus, including interactions between glucocorticosteroids and insulin. On the basis of available literature, we discuss the role of these interactions in the control of food intake and in the pathogenesis of obesity.

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