Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus.

Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) initiate hypothalamic-pituitary-adrenal axis activity through the release of CRF into the portal system as part of a coordinated neuroendocrine, autonomic, and behavioral response to stress. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. Here, we characterize the electrophysiological and molecular properties of PVN-CRFR1 neurons and interrogate their monosynaptic connectivity using rabies virus-based tracing and optogenetic circuit mapping in male and female mice. We provide evidence that CRF neurons in the PVN form synapses on neighboring CRFR1 neurons and activate them by releasing CRF. CRFR1 neurons receive the majority of monosynaptic input from within the hypothalamus, mainly from the PVN itself. Locally, CRFR1 neurons make GABAergic synapses on parvocellular and magnocellular cells within the PVN. CRFR1 neurons resident in the PVN also make long-range glutamatergic synapses in autonomic nuclei such as the nucleus of the solitary tract. Selective ablation of PVN-CRFR1 neurons in male mice elevates corticosterone release during a stress response and slows the decrease in circulating corticosterone levels after the cessation of stress. Our experiments provide evidence for a novel intra-PVN neural circuit that is activated by local CRF release and coordinates autonomic and endocrine function during stress responses.SIGNIFICANCE STATEMENT The hypothalamic paraventricular nucleus (PVN) coordinates concomitant changes in autonomic and neuroendocrine function to organize the response to stress. This manuscript maps intra-PVN circuitry that signals via CRF, delineates CRF receptor type 1 neuron synaptic targets both within the PVN and at distal targets, and establishes the role of this microcircuit in regulating hypothalamic-pituitary-adrenal axis activity.

Salivary Biomarkers of Parenting Stress in Mothers Under Community Criminal Justice Supervision.

BACKGROUND: Community criminal justice supervised mothers are an underserved population who experience high rates of psychological distress and unique parenting challenges, but little is known about physiological stress system function in this population. OBJECTIVE: We tested the salivary biomarkers of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis function as predictors of subjective maternal stress. METHOD: We recruited 23 mothers (age: M = 35.6 years, SD = 9.3 years; 35% Hispanic, 22% Black, 22% White, 22% multiracial) who were court mandated to a residential treatment center. We measured salivary alpha-amylase (AA) and cortisol, which index SNS and HPA activity, respectively, before and after a naturalistic reminder of a stressful parenting experience. We assessed self-reported parenting stress using the Parenting Stress Index-Short Form (PSI-SF) subscales Parental Distress, Parent-Child Dysfunctional Interactions, and Difficult Child. We used regression to test AA and cortisol mean levels and reactivity as predictors of subscale scores. RESULTS: Mean, but not reactive, salivary stress biomarker levels were associated with parenting stress domains. Mean cortisol levels predicted scores on the Parent-Child Dysfunctional Interaction subscale (adj. R = .48), whereas mean AA predicted Difficult Child subscale scores (adj. R = .28). DISCUSSION: Our results demonstrate the potential predictive utility of AA and cortisol as salivary biomarkers of maternal stress in community-supervised mothers. Given that maternal stress is associated with criminal recidivism and child behavioral health in this population, these biomarkers could potentially inform interventions to improve dyadic health and social outcomes.

Hypothalamic-pituitary-adrenal axis hyperactivity and brain differences in healthy women.

BACKGROUND: Previous studies have suggested that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis leads to brain changes. However, few studies have examined the whole brain configuration for an association with HPA axis activity. We examined the relationship between HPA axis activity and the whole brain configuration. METHODS: The subjects in this study were 34 healthy female volunteers. HPA axis activity was assessed by the dexamethasone/corticotropin-releasing hormone test. Structural volumes of the brain and diffusion tensor images were obtained, and correlations were evaluated voxel-wise. RESULTS: There was a significantly negative correlation between fractional anisotropy value and cortisol levels at 16:00 h (CL-2) in the anterior cingulum, left parahippocampus and right occipital region. There were significantly positive correlations between mean diffusivity value and CL-2 in the left hippocampus and bilateral parahippocampal regions. CONCLUSIONS: Our data suggest that reduced feedback of the HPA axis is associated with reduced neural connectivity throughout the brain, and such an association may be strong in the anterior cingulate, the hippocampus and the parahippocampal regions.

Variable cortisol circadian rhythms in children with autism and anticipatory stress.

OBJECTIVE: Autism is characterized by impairment in communication and social interaction, by repetitive behaviours and by difficulty in adapting to novel experiences. The objective of the current investigation was to replicate and extend our previous findings showing variable circadian rhythm and significant elevations in cortisol following exposure to a novel stimulus (mock magnetic resonance imaging [MRI]). METHODS: Circadian rhythms of cortisol were estimated in 22 children with and 22 children without autism via analysis of salivary samples collected in the morning, afternoon and evening over 6 separate days. We assessed hypothalamic-pituitary-adrenal (HPA) responsiveness by examining changes in salivary cortisol in response to a mock MRI. One-half of the children were re-exposed to the MRI environment. RESULTS: Children with autism showed a decrease in cortisol in the morning over 6 days while maintaining higher evening values. Children with autism also showed more within-and between-subject variability in circadian rhythms. Although the cortisol values tended to be higher in some of the children with autism, a statistically significant elevation in cortisol in response to the initial mock MRI was not observed. Rather, both groups showed heightened cortisol at the arrival to the second visit to the imaging centre, suggesting an anticipatory response to the re-exposure to the mock MRI. CONCLUSION: Children with autism showed dysregulation of the circadian rhythm evidenced by variability between groups, between children and within individual child comparisons. Both groups demonstrated increased salivary cortisol in anticipation of re-exposure to the perceived stressor.

From Malthus to motive: how the HPA axis engineers the phenotype, yoking needs to wants.

The hypothalamo-pituitary-adrenal (HPA) axis is the critical mediator of the vertebrate stress response system, responding to environmental stressors by maintaining internal homeostasis and coupling the needs of the body to the wants of the mind. The HPA axis has numerous complex drivers and highly flexible operating characterisitics. Major drivers include two circadian drivers, two extra-hypothalamic networks controlling top-down (psychogenic) and bottom-up (systemic) threats, and two intra-hypothalamic networks coordinating behavioral, autonomic, and neuroendocrine outflows. These various networks jointly and flexibly control HPA axis output of periodic (oscillatory) functions and a range of adventitious systemic or psychological threats, including predictable daily cycles of energy flow, actual metabolic deficits over many time scales, predicted metabolic deficits, and the state-dependent management of post-prandial responses to feeding. Evidence is provided that reparation of metabolic derangement by either food or glucocorticoids results in a metabolic signal that inhibits HPA activity. In short, the HPA axis is intimately involved in managing and remodeling peripheral energy fluxes, which appear to provide an unidentified metabolic inhibitory feedback signal to the HPA axis via glucocorticoids. In a complementary and perhaps a less appreciated role, adrenocortical hormones also act on brain to provide not only feedback, but feedforward control over the HPA axis itself and its various drivers, as well as coordinating behavioral and autonomic outflows, and mounting central incentive and memorial networks that are adaptive in both appetitive and aversive motivational modes. By centrally remodeling the phenotype, the HPA axis provides ballistic and predictive control over motor outflows relevant to the type of stressor. Evidence is examined concerning the global hypothesis that the HPA axis comprehensively induces integrative phenotypic plasticity, thus remodeling the body and its governor, the brain, to yoke the needs of the body to the wants of the mind. Adverse side effects of this yoking under conditions of glucocorticoid excess are discussed.

Adrenal steroid metabolism in birds: anatomy, physiology, and clinical considerations.

The hypothalamo-pituitary-adrenal system in birds is anatomically and functionally different from that in mammals. The adrenal gland structure and corticosteroid hormone physiology of birds will be reviewed. The anatomy and physiology sections of this article will be important for better understanding the pathogenesis, diagnosis, and possible treatment of primary or secondary adrenal gland disease. Causes of hyper- and hypoadrenocorticism in birds also will be reviewed. The article will conclude with current indications and complications to the clinical use of glucocorticoids in birds.

[Neuro-physiological and morphological manifestations of posttraumatic stress disorder (review of literature)].

The article presents the review of neurophysiological and neuro-morphological researches of combat posttraumatic stress disorder. Also in the article presented data about the existence by the veterans, suffered by combat posttraumatic stress disorder, a regular dysfunction of hypothalamus-pituitary-paranephric system, approving by excessive allowance ruffling ofcortisol, tending the activation neuro-trasmitteric systems. These changes conjoin with predominance of sympaticotony and of increased psycho and physiological inflammability in response to cues, associated with real or imaginable danger. Methods of neurovisulisation show the existence of changes in visceral brain, prefrontal and sense-motorical zone of cerebrum, corresponded to stress signals. The article presents the discuss of cause-and-effects conditions between the morphological changes in central nervous system, influence of stress-factors and advance of disease.

Neuroanatomical pathways underlying the effects of hypothalamo-hypophysial-adrenal hormones on exploratory activity.

When injected via the intracerebroventricular route, corticosterone-releasing hormone (CRH) reduced exploration in the elevated plus-maze, the center region of the open-field, and the large chamber in the defensive withdrawal test. The anxiogenic action of CRH in the elevated plus-maze also occurred when infused in the basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex. The anxiogenic action of CRH in the defensive withdrawal test was reproduced when injected in the locus coeruleus, while the amygdala, hippocampus, lateral septum, nucleus accumbens, and lateral globus pallidus contribute to center zone exploration in the open-field. In addition to elevated plus-maze and open-field tests, the amygdala appears as a target region for CRH-mediated anxiety in the elevated T-maze. Thus, the amygdala is the principal brain region identified with these three tests, and further research must identify the neural circuits underlying this form of anxiety.

Income inequality, gene expression, and brain maturation during adolescence.

Income inequality is associated with poor health and social outcomes. Negative social comparisons and competition may involve the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in underlying some of these complex inter-relationships. Here we investigate brain maturation, indexed by age-related decreases in cortical thickness, in adolescents living in neighborhoods with differing levels of income inequality and household income. We examine whether inter-regional variations relate to those in glucocorticoid receptor (HPA) and androgen receptor (HPG) gene expression. For each sex, we used a median split of income inequality and household income (income-to-needs ratio) to create four subgroups. In female adolescents, the high-inequality low-income group displayed the greatest age-related decreases in cortical thickness. In this group, expression of glucocorticoid and androgen receptor genes explained the most variance in these age-related decreases in thickness across the cortex. We speculate that female adolescents living in high-inequality neighborhoods and low-income households may experience greater HPA and HPG activity, leading to steeper decreases in cortical thickness with age.

Evidence that the bed nucleus of the stria terminalis contributes to the modulation of hypophysiotropic corticotropin-releasing factor cell responses to systemic interleukin-1beta.

Systemic infection activates the hypothalamic-pituitary-adrenal (HPA) axis, and brainstem catecholamine cells have been shown to contribute to this response. However, recent work also suggests an important role for the central amygdala (CeA). Because direct connections between the CeA and the hypothalamic apex of the HPA axis are minimal, the present study investigated whether the bed nucleus of the stria terminalis (BNST) might act as a relay between them. This was done by using an animal model of acute systemic infection involving intravascular delivery of the proinflammatory cytokine interleukin-1beta (IL-1beta, 1 microg/kg). Unilateral ibotenic acid lesions encompassing the ventral BNST significantly reduced both IL-1beta-induced increases in Fos immunoreactivity in corticotropin-releasing factor (CRF) cells of the hypothalamic paraventricular nucleus (PVN) and corresponding increases in adrenocorticotropic hormone (ACTH) secretion. Similar lesions had no effect on CRF cell responses to physical restraint, suggesting that the effects of BNST lesions were not due to a nonspecific effect on stress responses. In further studies, we examined the functional connections between PVN, BNST, and CeA by combining retrograde tracing with mapping of IL-1beta-induced increases in Fos in BNST and CeA cells. In the case of the BNST, these studies showed that systemic IL-1beta administration recruits ventral BNST cells that project directly to the PVN. In the case of the CeA, the results obtained were consistent with an arrangement whereby lateral CeA cells recruited by systemic IL-1beta could regulate the activity of medial CeA cells projecting directly to the BNST. In conclusion, the present findings are consistent with the hypothesis that the BNST acts as a relay between the CeA and PVN, thereby contributing to CeA modulation of hypophysiotropic CRF cell responses to systemic administration of IL-1beta.

Immunohistochemical localization of delta sleep-inducing peptide-like immunoreactivity in the central nervous system and pituitary of the frog Rana ridibunda.

The purpose of the present study was to investigate the distribution of delta sleep-inducing peptide in the brain and pituitary of the frog Rana ridibunda and to determine the possible effect of this nonapeptide on adrenocorticotropic hormone and corticosteroid secretion. Delta sleep-inducing peptide-like immunoreactive fibres were observed throughout the brain of the frog. These fibres generally exhibited the characteristics of glial cell processes. Scarce delta sleep-inducing peptide-positive fibres were seen in the olfactory bulb and in the periventricular areas of the telencephalon. In the diencephalon, numerous delta sleep-inducing peptide-containing processes were noted in the preoptic nucleus, the infundibular nuclei and the median eminence. A few cerebrospinal fluid-contacting cells were visualized in the ventral nucleus of the infundibulum. Delta sleep-inducing peptide-positive fibres were also observed in the mesencephalon, radiating through the different layers of the tectum. In the cerebellum, all Purkinje cells exhibited delta sleep-inducing peptide-like immunoreactivity. More caudally, numerous delta sleep-inducing peptide-positive fibres were noted in the vestibular nucleus of the rhombencephalon. A dense network of delta sleep-inducing peptide-containing fibres was seen in the pars nervosa of the pituitary. In the distal lobe, a population of endocrine cells located in the anteroventral region contained delta sleep-inducing peptide-immunoreactive material. Labelling of consecutive sections of the pituitary by delta sleep-inducing peptide and adrenocorticotropic hormone antiserum revealed that a delta sleep-inducing peptide-related peptide is expressed in corticotroph cells. The possible role of delta sleep-inducing peptide in the control of adrenocorticotropic hormone and corticosteroid release was studied in vitro, using the perifusion system technique. Administration of graded doses of delta sleep-inducing peptide (from 10(-8) to 10(-6) M) to perifused frog anterior pituitary cells did not affect the spontaneous release of adrenocorticotropic hormone. In addition, prolonged infusion of delta sleep-inducing peptide (10(-6) M) did not alter the stimulatory effect of corticotropin-releasing factor (10(-7) M) on adrenocorticotropic hormone secretion. Similarly, exposure of frog interrenal slices to delta sleep-inducing peptide did not induce any modification of spontaneous or adrenocorticotropic hormone-evoked secretion of corticosterone and aldosterone. Our results provide the first evidence for the presence of a delta sleep-inducing peptide-related peptide in lower vertebrates. The occurrence of delta sleep-inducing peptide-like immunoreactivity in specific areas of the brain suggests that the peptide may act as a neuromodulator.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis.

The hypothalamo-pituitary-adrenocortical (HPA) axis is the primary modulator of the adrenal glucocorticoid stress response. Activation of this axis occurs by way of a discrete set of neurons in the hypothalamic paraventricular nucleus (PVN). The PVN neuron appears to be affected by multiple sources, including (1) brainstem aminergic/peptidergic afferents; (2) blood-borne information; (3) indirect input from limbic system-associated regions, including the prefrontal cortex, hippocampus, and amygdala; and (4) local-circuit interactions with the preoptic-hypothalamic continuum. Analysis of the literature suggests that different classes of stressor employ different stress circuits. Severe physiologic ("systemic") stress appears to trigger brainstem/circumventricular organ systems that project directly to the paraventricular nucleus. In contrast, stressors requiring interpretation with respect to previous experience ("processive" stressors) reach the PVN by way of multisynaptic limbic pathways. Limbic regions mediating processive stress responses appear to have bisynaptic connections with the PVN, forming intervening connections with preoptic/hypothalamic GABAergic neurons. Stressors of the latter category may thus require interaction with homeostatic information prior to promoting an HPA response. The HPA stress response thus appears to be a product of both the physiologic importance of the stimulus and the specific pathways a given stimulus excites.

Psychoneuroendocrinology and brain imaging in depression.

In the past three decades, psychoneuroendocrinologic investigations have generated a great volume of information, particularly in the field of affective disorders, which has formed the basis for designing studies with newer tools such as anatomic and functional imaging. In this article, the authors focus on endocrine imaging in psychiatry and attempt to relate morphometric findings to physiologic neuroendocrine dysfunction in depression.

The hippocampus and depression.

The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT(2A) receptors in the hippocampus using positron emission tomography (PET) to detect regional changes in [18F]altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.

[Effect of prenatal stress on the pituitary-adrenal axis in blue foxes]. / Vliianie prenatal'nogo stressa na gipofizarno-nadpochechnikovuiu sistemu u pestsov.

Handling is a source of stress for farm bred blue foxes. The influence of handling during the late gestation period on the pituitary--adrenal axis was studied in 10-day old male and female blue foxes. Cortisol and progesterone were measured by radioimmunoassay in the plasma, adrenal homogenates, and in vitro incubates from animals of both sexes. Adrenals were incubated in vitro in the absence or presence of ACTH. In addition, the adrenal weight and plasma concentration of ACTH were assessed. In cubs of both sexes, the adrenal weight was decreased after prenatal stress. The plasma concentration of progesterone and the adrenal cortisol in vitro production were elevated in the prenatally stressed female cubs, as compared to the control, along with the adrenal progesterone in vitro production in prenatally stressed male cubs. The adrenal cortisol and progesterone content and plasma ACTH and cortisol concentrations were not affected by prenatal stress. In conclusion, the results of this study suggest that the prenatal stress induced by handling pregnant vixens can affect the pituitary--adrenal axis in neonatal offspring, this effect being more pronounced in female cubs.

Neuroanatomy and physiology of the avian hypothalamic/pituitary axis: clinical aspects.

This article describes the anatomy of the avian hypothalamic/pituitary axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the somatotrophic axis, and neurohypophysis.

Activation of HPA axis and remodeling of body chemical composition in response to an intense and exhaustive exercise in C57BL/6 mice.

Several deleterious effects may occur when intense and exhaustive exercise (IE) is not well-planned. This study aimed to investigate the effects of a short duration IE on body chemical composition and hypothalamic-pituitary-adrenal (HPA) axis. C57Bl/6 mice were distributed into four groups (10 mice per group): control (C-4D and C-10D), 4 days (E-4D), and 10 days of IE (E-10D). IE program consisted of a daily running session at 85 % of maximum speed until the animal reached exhaustion. Body weight as well as total body water, fat and protein content were determined from animal carcasses. HPA activation was assessed by plasma corticosterone levels measured by radioimmunoassay and the weight of both the adrenal glands and thymus were measured. Plasma corticosterone levels increased by 64 % in both the E-4D and E-10D groups. The weight of the adrenal glands augmented by 74 % and 45 %, at 4 and 10 days of IE, respectively, whereas thymus weight diminished by 15 % only in the E-10D group. The total carcass fat content decreased by 20 % only at 4 days IE, whereas protein content decreased by 20 % in both E-4D and E-10D groups. A relationship between corticosterone plasma levels and loss of body protein content in both E-4D and E-10D groups was observed (R(2)=0.999). We concluded that IE may be related to HPA axis activation associated with remodeling of body chemical composition in C57BL/6 mice.

Stress abnormalities in individuals at risk for psychosis: a review of studies in subjects with familial risk or with "at risk" mental state.

Increased sensitivity to stress is known to play an important role in the transition to first episode psychosis (FEP). Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and, in general, an increased sensitivity to stress, have been hypothesised to be components of the vulnerability to psychosis, but whether these abnormalities are already present before the onset of psychosis has not yet been systematically reviewed. Here we have reviewed all studies examining psychological and biological markers of the stress response in the relatives of psychotic patients and in individuals at Ultra High Risk (UHR) for psychosis. In relatives, there is evidence of increased sensitivity to stress, as shown by increased emotional reactivity to daily life stress, increased adrenocorticotropic hormone (ACTH) in response to stress, increased pituitary volume and reduced hippocampal volume. However, evidence of increased cortisol levels is less consistent. On the other hand, subjects who experience attenuated psychotic symptoms show increased cortisol levels as well as increased pituitary and reduced hippocampal volumes. Moreover, this HPA axis hyperactivity seems to be even greater among those individuals who subsequently develop frank psychosis. In summary, an enhanced HPA axis response to stress appears to be part of the biological vulnerability to psychosis which is present prior to the onset of psychosis. A further increase in cortisol levels during the transition to FEP suggests the presence of an additive factor, possibly environmental, at this stage of the illness. Possible causes and consequences of HPA axis impairment in risk for psychosis are discussed.

Genistein stimulates the hypothalamo-pituitary-adrenal axis in adult rats: morphological and hormonal study.

Genistein, the soy isoflavone structurally similar to estradiol, is widely consumed for putative beneficial health effects. However, there is a lack of data about the genisteins' effects in adult males, especially its effects on the hipothalamo-pituitary-adrenal (HPA) axis. Therefore, the present study was carried out to investigate the effects of genistein on the HPA axis in orchidectomized adult rats, and to create a parallel with those of estradiol. Changes in the hypothalamic corticotrophin-releasing hormone (CRH) neurons and pituitary corticotrophs (ACTH cells) were evaluated stereologically, while corticosterone and ACTH levels were determined biochemically. Orchidectomy (Orx) provoked the enlargement (p<0.05) of: hypothalamic paraventricular nucleus volume (60%), percentage of CRH neurons (23%), percentage of activated CRH neurons (45%); pituitary weight (15%) and ACTH level (57%). In comparison with Orx, estradiol treatment provoked the enlargement (p<0.05) of: percentage of CRH neurons (28%), percentage of activated CRH neurons (2.7-fold), pituitary weight (131%) and volume (82%), ACTH level (69%), the serum (103%) and adrenal tissue (4.8 fold) level of corticosterone. Clearly, Orx has induced the increase in HPA axis activity, which even augments after estradiol treatment. Also, compared to Orx, genistein treatment provoked the enhancement (p<0.05) of: percentage of activated CRH neurons (2.3-fold), pituitary weight (28%) and volume (21%), total number of ACTH cells (22%) ACTH level (45%), the serum (2.6-fold) and adrenal tissue (2.8 fold) level of corticosterone. It can be concluded that an identical tendency, concerning the HPA axis parameters, follows estradiol and genistein administration to the orchidectomized adult rats.