Urocortin 3 Modulates the Neuroendocrine Stress Response and Is Regulated in Rat Amygdala and Hypothalamus by Stress and Glucocorticoids

The endogenous corticotropin-releasing factor (CRF) type 2 receptor (CRFR2)-selective ligand urocortin 3 is expressed in discrete subcortical brain regions with fibers distributed mainly to hypothalamic and limbic structures. Close anatomical association between major urocortin 3 terminal fields and CRFR2 in hypothalamus, lateral septum, and medial amygdala (MEA) suggest it is well placed to modulate behavioral and hormonal responses to stress. Urocortin 3 was administered intracerebroventricularly to male rats under basal conditions or before a restraint stress, and circulating ACTH, corticosterone, glucose, and insulin were measured. Urocortin 3 activated the hypothalamic-pituitary-adrenal axis under basal conditions and augmented ACTH responses to restraint stress. Elevated blood glucose with lowered insulin to glucose ratios in both groups suggested increased sympathetic activity. Circulating catecholamines were also increased by urocortin 3, providing additional evidence for sympathoadrenomedullary stimulation. Intracerebroventricular urocortin 3 increased vasopressin mRNA expression in the parvocellular division of the hypothalamic paraventricular nucleus, whereas CRF expression was unchanged, providing a possible mechanism by which urocortin 3 mediates its actions. Urocortin 3 mRNA expression was examined after exposure to stress-related paradigms. Restraint increased levels in MEA with a trend to increased expression in the rostral perifornical hypothalamic area, whereas hemorrhage and food deprivation decreased expression in MEA. Adrenalectomy markedly increased expression in the rostral perifornical hypothalamic area, and high-level corticosterone replacement restored this to control levels. The evidence that urocortin 3 has the potential to influence hormonal components of the stress response and the changes in its expression levels after stressors is consistent with a potential function for the endogenous peptide in modulating stress responses.

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Daily Limited Access to Sweetened Drink Attenuates Hypothalamic-Pituitary-Adrenocortical Axis Stress Responses

Endocrinology ◽

10.1210/en.2006-1241 ◽

2007 ◽

Vol 148 (4) ◽

pp. 1823-1834 ◽

Cited By ~ 94

Author(s):

Yvonne M. Ulrich-Lai ◽

Michelle M. Ostrander ◽

Ingrid M. Thomas ◽

Benjamin A. Packard ◽

Amy R. Furay ◽

...

Keyword(s):

Mrna Expression ◽

Chronic Stress ◽

Stress Responses ◽

Restraint Stress ◽

Basolateral Amygdala ◽

Physiological Stress ◽

Plasma Corticosterone ◽

Male Rats ◽

Free Access ◽

Acute And Chronic Stress

Stress can promote palatable food intake, and consumption of palatable foods may dampen psychological and physiological responses to stress. Here we develop a rat model of daily limited sweetened drink intake to further examine the linkage between consumption of preferred foods and hypothalamic-pituitary-adrenocortical axis responses to acute and chronic stress. Adult male rats with free access to water were given additional twice-daily access to 4 ml sucrose (30%), saccharin (0.1%; a noncaloric sweetener), or water. After 14 d of training, rats readily learned to drink sucrose and saccharin solutions. Half the rats were then given chronic variable stress (CVS) for 14 d immediately after each drink exposure; the remaining rats (nonhandled controls) consumed their appropriate drinking solution at the same time. On the morning after CVS, responses to a novel restraint stress were assessed in all rats. Multiple indices of chronic stress adaptation were effectively altered by CVS. Sucrose consumption decreased the plasma corticosterone response to restraint stress in CVS rats and nonhandled controls; these reductions were less pronounced in rats drinking saccharin. Sucrose or saccharin consumption decreased CRH mRNA expression in the paraventricular nucleus of the hypothalamus. Moreover, sucrose attenuated restraint-induced c-fos mRNA expression in the basolateral amygdala, infralimbic cortex, and claustrum. These data suggest that limited consumption of sweetened drink attenuates hypothalamic-pituitary-adrenocortical axis stress responses, and calories contribute but are not necessary for this effect. Collectively the results support the hypothesis that the intake of palatable substances represents an endogenous mechanism to dampen physiological stress responses.

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Limbic Pathways to Stress Control

10.1093/med/9780190215422.003.0008 ◽

2016 ◽

Author(s):

James P. Herman

Keyword(s):

Neural Networks ◽

Prefrontal Cortex ◽

Stress Response ◽

Hpa Axis ◽

Stress Responses ◽

Physiological Stress ◽

Brain Regions ◽

Subcortical Structures ◽

Stress Control ◽

Stress Activation

Appropriate control of the HPA (hypothalamo-pituitary-adrenocortical axis) is required for adaptation to physiological and environmental challenges. Inadequate control is linked to numerous stress-related pathologies, including PTSD, highlighting its importance in linking physiological stress responses with behavioral coping strategies. This chapter highlights neurocircuit mechanisms underlying HPA axis adaptation and pathology. Control of the HPA stress response is mediated by the coordinated activity of numerous limbic brain regions, including the prefrontal cortex, hippocampus, and amygdala. In general, hippocampal output inhibits anticipatory HPA axis responses, whereas amygdala subnuclei participate in stress activation. The prefrontal cortex plays an important role in inhibition of context-dependent stress responses. These regions converge on subcortical structures that relay information to paraventricular nucleus corticotropin-releasing hormone neurons, controlling the magnitude and duration of HPA axis stress responses. The output of these neural networks determines the net effect on glucocorticoid secretion, both within the normal adaptive range and in pathological circumstances.

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Diurnal variation and left-right distribution of pyroglutamyl peptidase I activity in the rat brain and retina

Acta Endocrinologica ◽

10.1530/acta.0.1250570 ◽

1991 ◽

Vol 125 (5) ◽

pp. 570-573 ◽

Cited By ~ 4

Author(s):

M. Ramirez ◽

B. Sanchez ◽

G. Arechaga ◽

S. Garcia ◽

P. Lardelli ◽

...

Keyword(s):

Rat Brain ◽

Brain Regions ◽

Male Rats ◽

Hypothalamic Area ◽

Time Points ◽

Asymmetrical Distribution ◽

Cervical Ganglia ◽

Endogenous Substrates ◽

The Right ◽

Light:Dark Cycle

Abstract. The thyroliberin and luliberin contents exhibit a diurnal rhythm within the brain and an asymmetrical distribution of both neuropeptides has been demonstrated in the hypothalamus. Since they have been described as substrates of pyroglutamyl peptidase I, this activity was analysed in several rat brain regions and other structures, in order to investigate its putative diurnal variations and changes in relation to the distribution of these neuropeptides and/or other susceptible substrates. Fluorometric activity was assayed in the retina, pituitary gland, superior cervical ganglia, pineal gland, some selected brain regions, and serum of adult male rats at six different time points of a 12:12 h light:dark cycle, using pyroglutamyl-β-naphthylamide as substrate. A significant circadian rhythm was demonstrated in the retina, the hypothalamus, and the intermediate-posterior pituitary lobe. In addition, a small but significant asymmetrical distribution of this activity, at certain time points, was disclosed: The activity was higher in the left than in the right retina at 10 h of the light period, whereas it was predominant in the right side at 01 h of the dark period. Furthermore, the activity was higher in the left anterior than in the right hypothalamic area at 13 and 01 h. These results could be indicative of a role of this enzymatic activity in the control of the functional status of its endogenous substrates.

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Voluntary wheel running initially increases adrenal sensitivity to adrenocorticotrophic hormone, which is attenuated with long-term training

Journal of Applied Physiology ◽

10.1152/japplphysiol.91128.2008 ◽

2009 ◽

Vol 106 (1) ◽

pp. 66-72 ◽

Cited By ~ 43

Author(s):

Jonathan E. Campbell ◽

Nasimeh Rakhshani ◽

Sergiu Fediuc ◽

Silvio Bruni ◽

Michael C. Riddell

Keyword(s):

Stress Response ◽

Hpa Axis ◽

Restraint Stress ◽

Acute Stress ◽

Wheel Running ◽

Male Rats ◽

Voluntary Wheel Running ◽

Acute Stress Response ◽

Voluntary Wheel

Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) voluntary wheel running on adrenal sensitivity to ACTH stimulation and the acute stress response to restraint in male rats. Diurnal glucocorticoid patterns were measured on days 7 (all groups) and 35 (8-wk groups). Rats were subjected to 20 min of restraint stress on either week 1 or on week 7 of treatment to assess HPA activation. One week later, exogenous ACTH (75 ng/kg) was administered to assess adrenal sensitivity to ACTH. Following this, adrenals were collected and analyzed for key proteins involved in corticosterone (CORT) synthesis. By the end of week 1, exercising (E) animals had twofold higher peak diurnal CORT levels compared with sedentary (S) animals ( P < 0.01). CORT values were not different between groups at week 8. In response to restraint stress at week 2, CORT values in E were approximately threefold greater than in S ( P < 0.05). No difference was found between E and S rats in the response to, or recovery from, restraint at week 8. During the ACTH challenge at week 2, E demonstrated a ∼2.5-fold increase in adrenal sensitivity compared with S, while no difference was found between E and S at week 8. The expression of steroidogenic acute regulatory protein was found to be ∼50% higher in the adrenals in E compared with S at week 2 ( P < 0.05), but no difference existed between groups at week 8. These results show that volitional wheel running initially causes hyperactivation of the HPA axis, due to enhanced adrenal sensitivity to ACTH, but that these alterations in HPA activity are completely restored by 8 wk of training.

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Intranasal Administration of Neuropeptide Y Significantly Antagonized Chronic Stress Responses via Central Gabaa Receptors in Male Rats

10.21203/rs.3.rs-364636/v1 ◽

2021 ◽

Author(s):

Yu Yang ◽

Haijie Yu ◽

Reji Babygirija ◽

Bei Shi ◽

Weinan Sun ◽

...

Keyword(s):

Neuropeptide Y ◽

Receptor Antagonist ◽

Mrna Expression ◽

Hpa Axis ◽

Stress Responses ◽

Intranasal Administration ◽

Male Rats ◽

Invasive Technique ◽

Motor Functions ◽

Colonic Motor

Abstract Stress is widely believed to play a major role in the pathogenesis of many diseases. Central neuropeptide Y (NPY) counteracts the biological actions of corticotropin-releasing factor (CRF), and in turn attenuates stress responses. Administration (intracerebroventricular, ICV) of NPY, significantly antagonized the inhibitory effects of chronic complicated stress (CCS) on gastrointestinal (GI) dysmotility in rats. However, ICV administration is an invasive technique. The effect of intranasal administration of NPY on the hypothalamus-pituitary-adrenal (HPA) axis and GI motility in CCS conditions have not been studied, and the inhibitory mechanism of NPY on CRF through the gamma-aminobutyric acid (GABA)A receptor needs to be further investigated. A CCS rat model was set up, NPY was intranasal administered every day prior to the stress loading. Further, a GABAA receptor antagonist was ICV injected daily. Central CRF and NPY expression were evaluated, serum corticosterone and NPY levels were analyzed, and colonic motor functions was assessed. CCS rats showed significantly increased CRF expression and corticosterone levels, which resulted in enhanced colonic motor functions. Intranasal NPY significantly increased central NPY mRNA expression and reduced central CRF mRNA expression as well as the plasma corticosterone level, helping to restore colonic motor functions. However, ICV administration of the GABAA receptor antagonist significantly abolished these effects. Intranasal administration of NPY upregulates the hypothalamic NPY system. NPY may, through the GABAA receptor, significantly antagonize the overexpressed central CRF and attenuate the HPA axis activities in CCS conditions, exerting influences and helping to restore colonic motor function.

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Chronic restraint stress induces changes in the cerebral Galpha 12/13 and Rho-GTPase signaling network

Pharmacological Reports ◽

10.1007/s43440-021-00294-4 ◽

2021 ◽

Author(s):

Katarzyna Rafa-Zabłocka ◽

Agnieszka Zelek-Molik ◽

Beata Tepper ◽

Piotr Chmielarz ◽

Grzegorz Kreiner ◽

...

Keyword(s):

Mrna Expression ◽

Neural Plasticity ◽

Intracellular Signaling ◽

Restraint Stress ◽

Molecular Mechanisms ◽

Rho Gtpase ◽

Brain Regions ◽

Neuronal Morphology ◽

Stress Effects ◽

Neuropsychiatric Diseases

Abstract Background Evidence indicates that Gα12, Gα13, and its downstream effectors, RhoA and Rac1, regulate neuronal morphology affected by stress. This study was aimed at investigating whether repeated stress influences the expression of proteins related to the Gα12/13 intracellular signaling pathway in selected brain regions sensitive to the effects of stress. Furthermore, the therapeutic impact of β(1)adrenergic receptors (β1AR) blockade was assessed. Methods Restraint stress (RS) model in mice (2 h/14 days) was used to assess prolonged stress effects on the mRNA expression of Gα12, Gα13, RhoA, Rac1 in the prefrontal cortex (PFC), hippocampus (HIP) and amygdala (AMY). In a separate study, applying RS model in rats (3–4 h/1 day or 14 days), we evaluated stress effects on the expression of Gα12, Gα11, Gαq, RhoA, RhoB, RhoC, Rac1/2/3 in the HIP. Betaxolol (BET), a selective β1AR antagonist, was introduced (5 mg/kg/p.o./8–14 days) in the rat RS model to assess the role of β1AR in stress effects. RT-qPCR and Western Blot were used for mRNA and protein assessments, respectively. Results Chronic RS decreased mRNA expression of Gα12 and increased mRNA for Rac1 in the PFC of mice. In the mice AMY, decreased mRNA expression of Gα12, Gα13 and RhoA was observed. Fourteen days of RS exposure increased RhoA protein level in the rats’ HIP in the manner dependent on β1AR activity. Conclusions Together, these results suggest that repeated RS affects the expression of genes and proteins known to be engaged in neural plasticity, providing potential targets for further studies aimed at unraveling the molecular mechanisms of stress-related neuropsychiatric diseases.

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EFFECTS OF HISTAMINE IMPLANTS IN SEVERAL BRAIN REGIONS ON THE RELEASE OF PROLACTIN IN CONSCIOUS ADULT MALE RATS

Journal of Endocrinology ◽

10.1677/joe.0.0880351 ◽

1981 ◽

Vol 88 (3) ◽

pp. 351-358 ◽

Cited By ~ 19

Author(s):

E. O. ALVAREZ ◽

A. O. DONOSO

Keyword(s):

Plasma Levels ◽

Anterior Part ◽

Central Area ◽

Brain Regions ◽

Prolactin Secretion ◽

Male Rats ◽

Male Rat ◽

Amygdaloid Nucleus ◽

Acute Administration ◽

Hypothalamic Area

The levels of prolactin in the plasma of conscious male rats were determined at various times after an acute administration of histamine or a histamine releasing agent, compound 48/80, in three brain regions. The brain structures that were examined were, the caudal part of the preoptic area and anterior part of the anterior hypothalamic area (POA–AHA), the arcuate nucleus–ventromedial nucleus region (ARC–VMN) and the medial–basal amygdaloid nucleus of the limbic system (AME). A marked increase in plasma levels of prolactin was observed when implants of histamine were in the POA–AHA region. A more consistent increase was found when 1 μg histamine was injected in the same region; values of prolactin were about 3·6 times greater than in their controls injected with 0·9% saline. Such increased hormone levels lasted up to 2 h. A similar rise in prolactin level was found when the implants of histamine were located in the ARC–VMN region. When compound 48/80 or empty cannulae were placed in those brain regions that were examined, no changes in plasma levels of prolactin were induced. Both histamine and compound 48/80 elicited a delayed and long-lasting decrease of the high plasma level of prolactin present in rats bearing cannulae in the AME region. The results suggest that in the male rat, histaminergic sites, located in rostral and mediobasal hypothalamus and in the central area of the amygdala, are involved in the mechanisms controlling prolactin secretion.

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The transformation of hormonal stress responses throughout puberty and adolescence

Journal of Endocrinology ◽

10.1530/joe-11-0206 ◽

2011 ◽

Vol 210 (3) ◽

pp. 391-398 ◽

Cited By ~ 76

Author(s):

Allison R Foilb ◽

Patina Lui ◽

Russell D Romeo

Keyword(s):

Stress Response ◽

Adolescent Development ◽

Stress Responses ◽

Stress Reactivity ◽

Plasma Corticosterone ◽

Male Rats ◽

Before And After ◽

Corticosterone Response ◽

Acute Stressor ◽

Adrenal Corticosterone

Prepubertal rats display heightened hormonal stress reactivity compared with adults in that levels of ACTH and corticosterone take twice as long (i.e. 40–60 min) to return to baseline following an acute stressor. Despite this substantial change in stress responsiveness, and the critical nature of the adolescence period of development, the maturation of the hormonal stress response from the time of pubertal onset to adulthood has not been thoroughly investigated. To examine this, we measured ACTH, corticosterone, and testosterone in 30-, 40-, 50-, 60-, and 70-day-old (i.e. spanning pubertal and adolescent development) male rats before and after a 30 min session of restraint stress. We found that the adult-like ACTH stress response develops between 50 and 60 days of age, while the corticosterone response changes between 30 and 40 days of age. We also found that adrenal corticosterone concentrations paralleled the plasma corticosterone response following restraint, suggesting that stress-induced adrenal corticosterone synthesis decreases during adolescent development and may, at least in part, contribute to the differential stress response observed before and after puberty. Finally, stress leads to increases in testosterone secretion, but only after 50 days of age. Collectively, these results indicate that shifts in hormonal stress responses occur throughout adolescent maturation and that these responses show distinct developmental profiles.

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Dynamic Changes in Oxytocin Receptor Expression and Activation at Parturition in the Rat Brain

Endocrinology ◽

10.1210/en.2007-0615 ◽

2007 ◽

Vol 148 (10) ◽

pp. 5095-5104 ◽

Cited By ~ 102

Author(s):

Simone L. Meddle ◽

Valerie R. Bishop ◽

Effimia Gkoumassi ◽

Fred W. van Leeuwen ◽

Alison J. Douglas

Keyword(s):

Mrna Expression ◽

Paraventricular Nucleus ◽

Maternal Behavior ◽

Brain Regions ◽

Oxytocin Receptor ◽

Lateral Septum ◽

Receptor Expression ◽

Olfactory Bulbs ◽

Bed Nucleus ◽

The Brain

Oxytocin plays a pivotal role in rat parturition, acting within the brain to facilitate its own release in the supraoptic nucleus (SON) and paraventricular nucleus, and to stimulate maternal behavior. We investigated oxytocin receptor (OTR) expression and activation perinatally. Using a 35S-labeled riboprobe complementary to OTR mRNA, OTR expression was quantified in proestrus virgin, 21- and 22-day pregnant, parturient (90 min. from pup 1 birth), and postpartum (4–12 h from parturition) rats. Peak OTR mRNA expression was observed at parturition in the SON, brainstem regions, medial preoptic area (mPOA), bed nucleus of the stria terminalis (BnST), and olfactory bulbs, but there was no change in the paraventricular nucleus and lateral septum. OTR mRNA expression was increased on the day of expected parturition in the SON and brainstem, suggesting that oxytocin controls the pathway mediating input from uterine signals. Likewise, OTR mRNA expression was increased in the mPOA and BnST during labor/birth. In the olfactory bulbs and medial amygdala, parturition induced increased OTR mRNA expression compared with pre-parturition, reflecting their immediate response to new stimuli at birth. Postpartum OTR expression in all brain regions returned to levels observed in virgin rats. Parturition significantly increased the number of double-immunolabeled cells for Fos and OTR within the SON, brainstem, BnST, and mPOA regions compared with virgin rats. Thus, there are dynamic region-dependent changes in OTR-expressing cells at parturition. This altered OTR distribution pattern in the brain perinatally reflects the crucial role oxytocin plays in orchestrating both birth and maternal behavior.

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