Ultrasonographic Tissue Perfusion in Peri-implant Health and Disease.

Color flow ultrasonography has played a crucial role in medicine for its ability to assess dynamic tissue perfusion and blood flow variations as an indicator of a pathologic condition. While this feature of ultrasound is routinely employed in various medical fields, its intraoral application for the assessment of tissue perfusion at diseased versus healthy dental implants has never been explored. We tested the hypothesis that quantified tissue perfusion of power Doppler ultrasonography correlates with the clinically assessed inflammation of dental implants. Specifically, we designed a discordant-matched case-control study in which patients with nonadjacent dental implants with different clinical diagnoses (healthy, peri-implant mucositis, or peri-implantitis) were scanned and analyzed with real-time ultrasonography. Forty-two posterior implants in 21 patients were included. Ultrasound scans were obtained at the implant regions of midbuccal, mesial/distal (averaged as interproximal), and transverse to compute the velocity- and power-weighted color pixel density from color velocity (CV) and color power (CP), respectively. Linear mixed effect models were then used to assess the relationship between the clinical diagnoses and ultrasound CV and CP. Overall, the results strongly suggested that ultrasound's quantified CV and CP directly correlate with the clinical diagnosis of dental implants at health, peri-implant mucositis, and peri-implantitis. This study showed for the first time that ultrasound color flow can be applicable in the diagnosis of peri-implant disease and can act as a valuable tool for evaluating the degree of clinical inflammation at implant sites.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

Maternal first trimester serum levels of free-beta human chorionic gonadotrophin and male genital anomalies.

STUDY QUESTION: Are maternal first trimester levels of serum free-beta hCG associated with the development of hypospadias or undescended testis (UDT) in boys? SUMMARY ANSWER: Overall, first trimester maternal levels of serum free-beta hCG are not associated with hypospadias or UDT. However, elevated levels were found in severe phenotypes (proximal hypospadias and bilateral UDT) suggesting an altered pathway of hormonal release in early pregnancy. WHAT IS KNOWN ALREADY: Human chorionic gonadotrophin peaks in first trimester of pregnancy stimulating fetal testosterone production, which is key to normal male genital development. Endocrine-disrupting insults early in pregnancy have been associated with increased risk of common genital anomalies in males such as hypospadias and UDT. One plausible etiological pathway is altered release of hCG. STUDY DESIGN, SIZE, DURATION: We conducted a record-linkage study of two separate populations of women attending first trimester aneuploidy screening in two Australian states, New South Wales (NSW) and Western Australia (WA), in 2006-2009 and 2001-2003, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were women who gave birth to a singleton live born male infant. There were 12 099 boys from NSW and 10 518 from WA included, of whom 90 and 77 had hypospadias; and 107 and 109 UDT, respectively. Serum levels of free-beta hCG were ascertained from laboratory databases and combined with relevant birth outcomes and congenital anomalies via record linkage of laboratory, birth, congenital anomalies and hospital data. Median and quartile levels of gestational age specific free-beta hCG multiple of the median (MoM) were compared between affected and unaffected boys. Logistic regression was used to evaluate the association between levels of free-beta hCG MoM and hypospadias or UDT, stratified by suspected placental dysfunction and co-existing anomalies. Where relevant, pooled analysis was conducted. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference in median hCG levels amongst women with an infant with hypospadias (NSW = 0.88 MoM, P = 0.83; WA = 0.84 MoM, P = 0.76) or UDT (NSW = 0.89 MoM, P = 0.54; WA = 0.95 MoM, P = 0.95), compared with women with an unaffected boy (NSW = 0.92 MoM; WA = 0.88 MoM). Low (<25th centile) or high (>75th centile) hCG levels were not associated with hypospadias or UDT, nor when stratifying by suspected placental dysfunction and co-existing anomalies. However, there was a tendency towards high levels for severe types, although confidence intervals were wide. When combining NSW and WA results, high hCG MoM levels (>75th centile) were associated with increased risk of proximal hypospadias (odds ratio (OR) 4.34; 95% CI: 1.08-17.4) and bilateral UDT (OR 2.86; 95% CI: 1.02-8.03). LIMITATIONS, REASONS FOR CAUTION: There were only small numbers of proximal hypospadias and bilateral UDT in both cohorts and although we conducted pooled analyses, results reported on these should be interpreted with caution. Gestational age by ultrasound may have been inaccurately estimated in small and large for gestational age fetuses affecting hCG MoM calculation in those pregnancies. Despite the reliability of our datasets in identifying adverse pregnancy outcomes, we did not have pathology information to confirm tissue lesions in the placenta and therefore our composite outcome should be considered as a proxy for placental dysfunction. WIDER IMPLICATIONS OF THE FINDINGS: This is one of the largest population-based studies examining the association between maternal first trimester serum levels of free-beta hCG and genital anomalies-hypospadias and UDT; and the first to compare specific phenotypes by severity. Overall, our findings does not support the hypothesis that alteration in maternal hCG levels is associated with the development of male genital anomalies; however, high hCG free-beta levels found in severe types suggest different underlying etiology involving higher production and secretion of hCG. These findings require further exploration and replication. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Health and Medical Research Council (NHMRC) grant APP1047263. N.N. is supported by a NHMRC Career Development Fellowship APP1067066. C.B. was supported by a NHMRC Principal Research Fellowship #634341. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression.

CONTEXT: Elevated hypothalamic CRH has been implicated in melancholic major depression in nonpregnant individuals, but the role of placental CRH in maternal prenatal and postpartum depression is largely unexplored. OBJECTIVE: The objective of the study was to examine the association of maternal midpregnancy plasma CRH levels with prenatal and postpartum depression. PARTICIPANTS: The study included 800 participants in Project Viva, a pregnancy and childhood cohort. METHODS: CRH levels were analyzed from blood samples obtained at mean 27.9 wk gestation (+/- 1.3 sd; range 24.6-37.4 wk) and were normalized on the logarithmic scale. Depression was assessed with the Edinburgh Postpartum Depression Scale (range 0-30 points) in midpregnancy and at 6 months postpartum. We used logistic regression to estimate the odds of scoring 13 or more points on the Edinburgh Postpartum Depression Scale as indicative of major or minor depression. RESULTS: Seventy (8.8%) and 46 (7.5%) women had prenatal and postpartum depression symptoms, respectively. Mean log CRH was 4.93 (+/- 0.62 sd). After adjusting for confounders, an sd increase in log CRH was associated with nearly 50% higher odds of prenatal depression symptoms (odds ratio 1.48, 95% confidence interval 1.14-1.93). Higher CRH levels during pregnancy were unassociated with greater risk of postpartum depressive symptoms. In fact, there was a suggestion that prenatal CRH levels might be inversely associated with risk of postpartum depressive symptoms (odds ratio 0.82, 95% confidence interval 0.58-1.15). CONCLUSIONS: Elevated placental CRH levels in midpregnancy are positively associated with risk of prenatal depression symptoms but not postpartum depression symptoms.

Catecholamine synthesizing enzymes and their modulation by immobilization stress in knockout mice.

The c-fos knockout mice (c-fos KO) and corticotropin-releasing hormone knockout mice (CRH KO) can serve as interesting models for studying mechanisms involved in response of the organism to stress, focused mainly on the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system (SAS). The present study focused on the investigation of changes in gene expression of catecholamine biosynthesizing enzymes tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) in adrenal medulla of c-fos KO and CRH KO mice stressed by immobilization. Levels of TH, DBH, and PNMT mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR). Single immobilization for 2 h significantly increased adrenomedullary TH, DBH, and PNMT mRNA levels in both c-fos KO and wild-type (WT) mice compared to unstressed controls. In CRH KO mice, PNMT gene expression was not increased to the same extent after single, but especially after repeated immobilization as in WT mice, in contrast to TH and DBH mRNA levels. Thus, our data indicate that CRH deficiency can influence the PNMT mRNA level in adrenal medulla during stress, confirming the idea that the HPA axis plays the crucial role in PNMT gene regulation in mice. On the other hand, c-Fos protein probably does not play a crucial role in TH, DBH, and PNMT gene expression in adrenal medulla under stress conditions.

Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours.

Following its discovery 20 years ago, corticotropin-releasing hormone (CRH) has been postulated to mediate both hormonal and behavioural responses to stressors. Here, we characterize and describe a behavioural role for the murine gene, UcnIII, which encodes a recently discovered CRH-related neuropeptide, urocortin III. We found that mouse UcnIII is expressed predominantly in regions of the brain known to be involved in stress-related behaviours, and its expression in the hypothalamus increases following restraint. In addition, we found that intracerebroventricular administration of mUcnIII stimulates behaviours that are associated with reduced anxiety, including exploration of an open field and decreased latency to enter the lit compartment of a dark-light chamber, but has no effect on the elevated-plus maze. Finally, we found that mUcnIII does not exert any effects on the hormonal stress response. Based upon our findings, UcnIII may be an endogenous brain neuropeptide that is modulated by stress and stimulates behaviours associated with reduced anxiety. In this capacity, UcnIII may attenuate stress-related behaviours, which may be useful both to help cope with stressful situations as well as to avoid pathology associated with excessive reaction to stressors.

Lessons from CRH knockout mice.

Corticotropin-releasing hormone (CRH), the major regulator of hypothalamic-pituitary-adrenal (HPA) axis, has a wide spectrum of actions within the central nervous system and the periphery. The development and use of Crh knockout mice (Crh-/-) has been an important tool for addressing the physiologic and pathologic roles of CRH. This review describes the generation and characterization ofCrh -deficient mice as well as the use of these mice to study the role of CRH in maternal and fetal HPA axes development and in the regulation of the adult HPA axis and behavior. The review concludes with information about recently discovered CRH-related peptides and their possible roles in some of the functions thought initially to be mediated by CRH.

Maternal experiences of racism and violence as predictors of preterm birth: rationale and study design.

Chronic psychological stress may raise the risk of preterm delivery by raising levels of placental corticotropin-releasing hormone (CRH). Women who have been the targets of racism or personal violence may be at particularly high risk of preterm delivery. The aims of this study are to examine the extent to which: (1) maternal experiences of racism or violence in childhood, adulthood, or pregnancy are associated with the risk of preterm birth; (2) CRH levels are prospectively associated with risk of preterm birth; and (3) CRH levels are associated with past and current maternal experiences of racism or violence. We have begun to examine these questions among women enrolled in Project Viva, a Boston-based longitudinal study of 6000 pregnant women and their children.

Neural substrates of anorexia nervosa: a behavioral challenge study with positron emission tomography.

OBJECTIVE: To delineate functional brain abnormalities associated with anorexia nervosa (AN). STUDY DESIGN: Positron emission tomographic measurements of regional cerebral blood flow (rCBF) were performed on 8 female patients with AN and 8 healthy female control subjects during exposure to 3 types of stimuli: high-calorie foods, low-calorie foods, and non-food items. Heart rate and internal state analog scale scores were also obtained. Stereotactic transformation and statistical parametric mapping techniques were used to analyze imaging data. RESULTS: During the high-calorie condition, control subjects reported a significant desire to eat, whereas subjects with AN reported elevated anxiety and exhibited increases in heart rate. Patients with AN had elevated bilateral medial temporal lobe rCBF compared with control subjects. Planned comparisons for group-by-condition interactions demonstrated greater activation within left occipital cortex and right temporo-occipital cortex for the high-calorie versus low-calorie contrast in patients with AN compared with control subjects. CONCLUSIONS: Our finding of elevated rCBF within bilateral medial temporal lobes is similar to published results in patients with psychotic disorders and may be related to the body image distortion common to AN. The high-calorie food phobia exhibited by patients with AN appears to be associated with exaggerated responses in visual association cortex, as has been previously observed in studies of specific phobias.

The physiology of corticotropin-releasing hormone deficiency in mice.

A review of the generation and characterization of corticotropin-releasing hormone (CRH)-deficient mice is presented. The studies summarized demonstrate the central role of CRH in the pituitary-adrenal axis response to stress, circadian stimulation, and glucocorticoid withdrawal. Additionally, pro-inflammatory actions of CRH at sites of local inflammation are given further support. In contrast, behavioral effects during stress that had been ascribed to CRH action are not altered in CRH-deficient mice. The normal behavioral response to stress in CRH-deficient mice strongly suggests the importance of other, possibly as yet undiscovered, CRH-like molecules.

Repressor element silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) can act as an enhancer as well as a repressor of corticotropin-releasing hormone gene transcription.

The repressor element-1/neuron-restrictive silencing element (RE-1/NRSE) mediates transcriptional repression by the repressor element silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) in many neuron-specific genes. REST/NRSF is expressed most highly in non-neural tissues, where it is thought to repress gene transcription, but is also found in developing neurons and at low levels in the brain. Its null mutation in vivo results in embryonic lethality in mice. While the RE-1/NRSE-mediated repressive influence of REST/NRSF is well established, results in transgenic studies have suggested that the action of the system is more complex. Here, we report that transcription of the corticotropin releasing hormone (CRH) gene is regulated by REST/NRSF, in part through the RE-1/NRSE. Expression of transfected Crh-luciferase constructs was down-regulated by REST/NRSF in a RE-1/NRSE-dependent fashion in both muscle-derived L6 and REST/NRSF co-transfected neuronal PC12 cells. Treatment of L6 cells with trichostatin A revealed that REST/NRSF repression depends, in part, on histone deacetylase activity in these cells. In another neuronal cell line, NG108, REST/NRSF also repressed expression from constructs containing an intact RE-1/NRSE. However, unexpectedly, REST/NRSF up-regulated expression levels of constructs lacking an intact RE-1/NRSE. These results suggest that REST/NRSF can act as both a repressor of Crh transcription, via the Crh RE-1/NRSE, and an enhancer of Crh transcription, via a mechanism independent of the Crh RE-1/NRSE.

Endocrinologic and psychological effects of short-term dexamethasone in anorexia nervosa.

Patients with anorexia nervosa (AN) have hyperactivity of their hypothalamic-pituitary-adrenal (HPA) axis, sometimes accompanied by elevations of cortisol. We examined whether the normal effects of short-term dexamethasone treatment upon HPA axis suppression and appetite stimulation are observed in these patients. Five young women with AN and ten healthy female controls received one week of high-dose oral dexamethasone (2 mg/m2/d) preceded and followed by hormonal evaluation of sensitivity to glucocorticoids and psychological assessments. No differences in hormone levels of the HPA axis were observed between the two groups and control groups at baseline, after dexamethasone suppression, or following ACTH stimulation testing. However, fasting insulin levels were significantly lower in the AN group, both before and after dexamethasone therapy and their serum leptin levels were also significantly lower. The AN group had significantly lower scores on the Anorexia Nervosa Subtest and the Beck Depression Inventory after dexamethasone compared to controls. On daily analog scales, AN patients had higher anxiety scores while on dexamethasone. Normal sensitivity to glucocorticoids was observed in all parameters examined except for mild abnormalities in pancreatic beta-cell function. These data suggest that AN may represent a state of partial glucocorticoid resistance, as in other states of restricted food intake. Furthermore, these pilot data, including the effects of dexamethasone upon psychological outlook in AN, suggest that glucocorticoids are not an effective therapy for these patients.

Effects of various mutations in the neurophysin/glycopeptide portion of the vasopressin gene on vasopressin expression in vitro.

The vasopressin gene encodes three polypeptides besides the signal peptide: vasopressin, neurophysin II (neurophysin), and the carboxy-terminal glycopeptide (glycopeptide). Although the function of vasopressin is well characterized, those of the latter two are not completely understood. In the present study, we investigated the effects of various mutations within the neurophysin/glycopeptide portion of the vasopressin gene on vasopressin secretion in vitro, to clarify the role of each peptide in vasopressin biosynthesis. Expression vectors containing the vasopressin gene, either wild-type or various mutants, were transiently transfected into AtT20 cells, which are known to have the enzymes necessary for the proper processing of the vasopressin precursor protein. The amount of vasopressin secreted into the culture medium was estimated by specific radioimmunoassay. Variable degrees of decreased vasopressin secretion were observed with mutant vasopressin genes harboring deletions or amino acid substitutions in neurophysin. The naturally-occurring frame-shift mutation in the hereditary diabetes insipidus (Brattleboro) rat completely eliminated vasopressin expression. In contrast, a missense mutation found in patients with familial neurogenic diabetes insipidus only partially decreased vasopressin secretion. Finally, the mutant vasopressin gene lacking the N-linked glycosylation site in glycopeptide had no effect on vasopressin expression. Our data suggest that 1) intact neurophysin is not indispensable for vasopressin expression, although an altered structure of neurophysin significantly affects the secretion of the hormone; 2) the pathogenesis of diabetes insipidus with the two naturally-occurring mutations found in the rat (Brattleboro rat) and human (familial central diabetes insipidus) seem to be different; and 3) glycosylation of the carboxy-terminal glycopeptide is not essential for the expression of vasopressin.

Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency.

The hypothalamic-pituitary-adrenal (HPA) axis, including hypothalamic corticotropin-releasing hormone (CRH) and pituitary corticotropin, is one of the first endocrine systems to develop during fetal life, probably because glucocorticoid secretion is necessary for the maturation of many essential fetal organs. Consistent with this, pregnant mice with an inactivating mutation in the Crh gene deliver CRH-deficient offspring that die at birth with dysplastic lungs, which can be prevented by prenatal maternal glucocorticoid treatment. But children lacking the ability to synthesize cortisol (because of various genetic defects in adrenal gland development or steroidogenesis) are not born with respiratory insufficiency or abnormal lung development, suggesting that the transfer of maternal glucocorticoid across the placenta might promote fetal organ maturation in the absence of fetal glucocorticoid production. We used pregnant mice with a normal HPA axis carrying fetuses with CRH deficiency to characterize the relative contributions of the fetal and maternal adrenal to the activity of the fetal HPA axis, and related these findings to fetal lung development. We found that in the presence of fetal adrenal insufficiency, normal fetal lung development is maintained by the transfer of maternal glucocorticoid to the fetus, specifically during the circadian peak in maternal glucocorticoid secretion.

Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.

Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.

Impaired basal and restraint-induced epinephrine secretion in corticotropin-releasing hormone-deficient mice.

CRH is thought to play a role in responses of the adrenocortical and adrenomedullary systems during stress. To investigate the role of CRH in stress-induced secretions of corticosterone and epinephrine, we subjected wild-type (WT) and CRH-deficient (knockout, KO) mice to restraint, and analyzed plasma corticosterone, plasma catecholamines, and adrenal phenylethanolamine N-methyltransferase (PNMT) gene expression and activity before and during 3 h of restraint. Plasma corticosterone increased over 40-fold in WT mice, but minimally in CRH KO mice. Adrenal corticosterone content tended to increase in CRH KO mice, although to levels 5-fold lower than that in WT mice. CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint. Adrenal PNMT messenger RNA content in CRH KO mice tended to be lower than that in WT mice, though the degree of induction was similar in both genotypes. PNMT enzyme activity was significantly lower in CRH KO mice. Pharmacological adrenalectomy abolished restraint-induced corticosterone secretion and PNMT gene expression in WT mice, consistent with an absolute requirement of glucocorticoids for PNMT gene expression. We conclude that glucocorticoid insufficiency in CRH KO mice leads to decreased basal and restraint-induced plasma epinephrine and adrenal PNMT gene expression and enzyme activity.

CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors.

We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress.

Neuroanatomy of human appetitive function: A positron emission tomography investigation.

OBJECTIVE: The mediating neuroanatomy of human appetitive function is poorly understood. A state induction paradigm was employed, in conjunction with positron emission tomography, to test the hypothesis that limbic/paralimbic regions respond to the desirability of food stimuli. METHODS: Eight normal subjects were studied during each of three conditions, involving visual exposure to high-caloric food, low-caloric food, and nonfood stimuli. Subjective indices of hunger were measured via analog scales. RESULTS: Planned contrasts demonstrated significant increases in desire to eat and decreases in left temporoinsular cortical blood flow during the high-caloric versus control conditions. DISCUSSION: Results implicate the temporo-insular cortex in normal appetitive function, suggesting that activity within this region is associated with the desirability or valence of food stimuli, prior to ingestion. These data will provide a broad foundation for future studies of patients with eating disorders.

Pituitary-adrenal axis regulation in CRH-deficient mice.

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.