Mechanisms of the primary response of the adrenal cortex to pain stress in dogs

A sharp decrease in the glucocorticoid content accompanied by an increase in the free cholesterol and a decrease in the content of esterified cholesterol were observed in the adrenal cortex of dogs 10–15 sec after nociceptive stimulation. The blood concentrations of the hormones were increased, mainly due to the proteinbound hydrocortisone fraction. The next phase of the response (30–60 sec after stimulation) was marked by activation of synthetic processes, leading to considerable accumulation of hormones in the gland. The blood glucocorticoid level was doubled, the original ratio of hydrocortisone to corticosterone was restored, and the transcortin depot was replenished. The role of the adrenal and transcortin deports of glucocorticoids in the feedback mechanism during stress is discussed.Department of Pathological Physiology, Rostov Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR V. K. Kulagin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 7, pp. 18–20, July, 1979.     

Influence of metyrapone treatment during pregnancy on the development and maturation of brain monoaminergic systems in the rat

Aim: This study examines the effect of reducing the corticosterone levels of gestating rat dams on the postnatal development and maturation of monoaminergic systems in their offspring’s brains. Methods: Metyrapone, an inhibitor of CORT synthesis, was administered to pregnant rats from E0 to E17 of gestation. Monoamine concentrations were determined in male and female offspring at postnatal days (PN) 23 and 90 in the hippocampus, hypothalamus and striatum. Results: Reducing maternal corticosterone (mCORT) during gestation led to alterations in dopamine and serotonin levels in all three brain areas studied at PN 23. Alterations persisted until at least PN 90 in the serotonergic systems; the dopamine content of the hippocampus also remained modified. Reduced mCORT during gestation also led to alterations in the development and maturation of the hypothalamic noradrenergic systems. Sexually dimorphic responses were observed in all these monoaminergic systems at different times. Conclusion: These results suggest that while they are still developing, brain monoaminergic systems are particularly sensitive to epigenetic influences. An adequate foetal level of CORT is required for the normal ontogeny of brain monoaminergic systems. The present data also provide that during the critical period of brain development, maternal CORT plays an important role in the sexual differentiation of monoaminergic systems, with particular influence on brain serotonergic neurones.     

Adrenocortical response to stress in fasted and unfasted artificially reared 12-day-old rat pups

Recent studies have compared artificially reared (AR) rats with dam-reared rats on behavioral outcomes but, despite the fact that they are deprived of their mothers during the stress hyporesponsive period (SHRP), little is known about the effects of AR on the development of the stress response. In this study, the corticosterone (CORT) response to a stressor (saline injection ip) on postnatal Day 12 was assessed in rat pups that had been either dam-reared (DR) or artificially reared since Day 5. In the preceding 24 hr, half the pups in the DR group were maternally deprived (DEP). To control for the food deprivation consequent to maternal deprivation in these groups, half the pups in the AR groups also underwent 24-hr food deprivation (DEP). In the nondeprived condition AR pups did not differ from DR pups on untreated CORT levels or on levels at 1-hr poststress (i.e., all rats demonstrated low levels of CORT characteristic of the SHRP). In contrast, both maternally deprived DR pups and food-deprived AR pups exhibited increased untreated CORT levels as well as a significant increase at 30-min poststress, but CORT elevations were lower in the AR groups than in the DR groups. Thus, long-term maternal deprivation through artificial rearing in rats does not affect the reduced CORT levels and reduced CORT responsiveness associated with the SHRP; however, if animals are food deprived, then all show increased basal CORT levels and a greater CORT response to stress, although this response is lower in AR groups than in DR groups. These results suggest that rat pups artificially reared with adequate nutrition will still exhibit the SHRP.     

Effects of brief stress exposure during early postnatal development in Balb/CByJ mice: II. Altered cortical morphology

Early life experience can significantly determine later mental health status and cognitive function. Neonatal stress, in particular, has been linked to the etiology of mental health disorders as divergent as mood disorder, schizophrenia, and autism. Our study uses a Balb/CByJ mouse model to test the hypothesis, that neonatal stress will alter development and subsequent environmental modulation of neocortex. Using a split litter design, we generated stressed mice (STR) and within litter controls (LMC) along with age‐matched, untreated animals (AMC), to serve as across litter controls. Short, daily exposure to a psychosocial/physical stressor, during the first week of life, resulted by adulthood in significant changes in neocortical thickness and architecture, which were further modulated by exposure to behavioral testing. Surprisingly, cortical size in LMC mice was also affected. These observations were compared to the effects of environmental enrichment in the same mouse strain. Our data indicate that LMC and STR males share with environmentally enriched males, an increase in thickness in infra‐granular cortical layers, while STR also display a stress selective decrease in supragranular layers, in response to behavioral training as adults. © 2012 Wiley Periodicals,Inc. Dev Psychobiol 54: 723–735, 2012.     

Interaction of genotype and environment as determinants of corticosteroid response to stress

The temporal pattern of plasma corticosterone concentrations following electric shock was studied in 10-week old mice from two inbred strains (C57BL/10J and DBA/2) and their reciprocal crosses, half of which had been subjected to infantile stimulation. The roles of genotype, maternal factors, and handling were assessed as determinants of corticosteroid response to stress. Highly significant and opposing genetic and maternal effects interacted to limit extreme plasma corticosterone concentrations following stress. Infantile stimulation also acted to produce intermediate steroid responses.     

Effects of litter‐overlapping on emotionality,stress response,and reproductive functions in male and female rats

In rats, mating at postpartum estrus and delayed dispersal of the young would result in the overlapping of two different‐age litters. As a consequence, newborn pups' early experience will include not only that acquired during the interaction with the mother and age‐matched littermates, but also with older siblings. As early‐life experience modulates rodents' brain function, behavior and reproduction, we aimed to assess how changes in the early environment provoked by the overlapping of litters would affect emotionality, stress response and reproductive functions of male and female pups during adulthood. Results showed that both male and female overlapped reared pups exhibited a reduced behavioral inhibition in the open field test during adulthood. In addition, overlapped reared adult females, but not males, showed a blunted corticosterone response to an acute stressor during diestrus and a reduction in sexual behavior. In summary, natural changes in early experience provoked by the overlapping of litters, long‐term modulate affective and reproductive behaviors, and the endocrine stress response in a sex dimorphic manner. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 259–267, 2009     

Effects of preweaning exposure to novel maternal odors on maternal responsiveness and selectivity in adulthood

We examined the effects of odor exposure in the nest on the offspring's subsequent adult responsivity to pups scented with the same odor or a different odor. It was hypothesized that animals receiving exposure to the odor in the nest would be more maternally responsive to pups scented with the (same) exposed odor than to unscented (water-scented) pups. In the first part of the study (Part A), Sprague-Dawley female rat pups (days 1-18 of age) either received exposure to an artificial lemon odor or to the natural (water) odor in the nest. In the second part of the study (Part B), rat pups were exposed daily to lemon or neutral odorants in an incubator at a distance from the mother and the nest. On day 21, animals received odor preference tests for lemon versus neutral pine bedding. On day 60, animals were mated and their pups were removed at 15-min intervals at the time of parturition. Animals were then tested for maternal behavior to foster pups on day 1 or 7 after parturition. Foster pups were scented either with the lemon odor or with water (unscented). Early exposure to lemon in the nest context enhanced animals' attraction to the lemon odor in juvenile tests. In adult maternal tests, exposure to odor on the mother and in the nest had two effects. It increased the latency for animals to express maternal behavior; however, once mothers expressed maternal behavior, they spent more time licking and crouching over pups scented with the same odorant to which they had been exposed earlier on their own mothers. Simple exposure to the lemon odorant out of context of the nest had no effect on adult maternal latencies or behavior.     

Medial prefrontal cortex activity can disrupt the expression of stress response habituation

Recent findings suggest that the expression of hypothalamic–pituitary–adrenal (HPA) axis stress response adaptation in rats depends on top–down neural control. We therefore examined whether the medial prefrontal cortex (mPFC) modulates expression of stress response habituation. We transiently suppressed (muscimol microinfusion) or stimulated (picrotoxin microinfusion) mPFC neural activity in rats and studied the consequence on the first time response to psychological stress (restraint) or separately on the development and expression of habituation to repeated restraint. We monitored both the hormonal (corticosterone) and neural (forebrain c-fos mRNA) response to stress. Inactivation of the mPFC had no effect on the HPA-axis response to first time restraint, however increased mPFC activity attenuated stress-induced HPA-axis activity. In a three day repeated restraint stress regimen, inactivation of the mPFC on days 1 and 2, but not day 3, prevented the expression of HPA-axis hormone response habituation. In these same rats, the mPFC activity on day 3 interfered with the expression of c-fos mRNA habituation selectively within the mPFC, lateral septum and hypothalamic paraventricular nucleus. In contrast, inactivation of the mPFC only on day 3, or on all 3 days did not interfere with the expression of habituation. We conclude that the mPFC can permit or disrupt expression of HPA-axis stress response habituation, and this control depends on alteration of neural activity within select brain regions. A possible implication of these findings is that the dysregulation of PFC activity associated with depression and post-traumatic stress disorder may contribute to impaired expression of stress-response adaptation and consequently exacerbation of those disorders.     

Dysregulation of the stress response in asthmatic children

The stress system co-ordinates the adaptive responses of the organism to stressors of any kind. Inappropriate responsiveness may account for increased susceptibility to a variety of disorders, including asthma. Accumulated evidence from animal models suggests that exogenously applied stress enhances airway reactivity and increases allergen-induced airway inflammation. This is in agreement with the clinical observation that stressful life events increase the risk of a new asthma attack. Activation of the hypothalamic–pituitary–adrenal (HPA) axis by specific cytokines increases the release of cortisol, which in turn feeds back and suppresses the immune reaction. Data from animal models suggest that inability to increase glucocorticoid production in response to stress is associated with increased airway inflammation with mechanical dysfunction of the lungs. Recently, a growing body of evidence shows that asthmatic subjects who are not treated with inhaled corticosteroids (ICS) are likely to have an attenuated activity and/or responsiveness of their HPA axis. In line with this concept, most asthmatic children demonstrate improved HPA axis responsiveness on conventional doses of ICS, as their airway inflammation subsides. Few patients may experience further deterioration of adrenal function, a phenomenon which may be genetically determined.     

Differential corticosterone responses to stress in the lung in two strains of Flinders rats

Background Acute stress affects a variety of organs and cellular systems. These include the hypothalamic–pituitary–adrenal (HPA) axis, corticotropin‐releasing factor (CRF), mast cells and nerves. Flinders‐sensitive (FSL) rat strains have hypercholinergic responses and are more sensitive than Flinders‐resistant rats (FRL) to anaphylaxis. Objective To investigate the effects of acute water avoidance stress (1 h) on FSL and FRL tracheal epithelial tissue. Methods We measured short circuit current (I_sc) as a measure of tracheal response, and the effect of substance P (SP) on tracheal epithelium in Ussing chambers. Electron microscopy was performed to assess mast cell activation. Results Both strains showed increased I_sc responses to stress, inhibited by prior injection of the CRF receptor 1 and 2 antagonist, α‐helical CRF‐(9–41). No increases in conductance were seen. Stress responses were accompanied by electron microscopic morphologic evidence for mast cell degranulation, which was not completely inhibited by α‐helical CRF‐(9–41) pre‐treatment. Stress primed the epithelium for an enhanced response to SP in FSL, but this again was not inhibited by α‐helical CRF‐(9–41). FRL had 2.5 times the corticosterone response of FSL. Conclusion Acute stress affects the tracheal epithelium, not accompanied by changes in ion permeability, but associated with mast cell degranulation. Because blunted HPA axis responses are associated with vulnerability to inflammation, this may partially explain the findings. These stress effects on the lung have a genetic basis associated with relative corticosterone responses, are complex and only in part mediated by CRF.     

Impacts of early social experience on cognitive development in infant rhesus macaques

Although much is known about the influences of early life experiences on the neurobiology and behavior of macaque models of child development, there is scant literature on cognitive development with respect to early rearing. Here, we examined the effects of rearing condition on affective reactivity and cognitive development in infant rhesus macaques. Infants were pseudo-randomly assigned to one of the two rearing conditions: nursery reared (NR, N = 32; 16 peer-reared, 16 surrogate-peer-reared) or mother-peer-reared (MPR, N = 7). During the first month of life, infants were administered the Primate Neonatal Neurobehavioral Assessment (PNNA). Beginning at 4 months old, infants were tested on cognitive tasks that assessed reward association, cognitive flexibility, and impulsivity. We found no gross cognitive differences between MPR and NR infants. However, MPR infants were more reactive than NR infants on the PNNA. Additionally, reactivity on the PNNA correlated with impulsivity, such that infants who were more reactive at 1 month of age completed fewer trials correctly on this task at 8–10 months. These findings are the first to directly compare cognitive development in MPR and NR infants, and add to the existing literature elucidating the influences of early social experience on temperament and development.     

Characteristics of the pituitary-adrenal system in the syracuse high-and low-avoidance strains of rats (Rattus norvegicus)

After many generations of selective breeding, rats of the high-avoidance strain (SHA) average 67% avoidance responses in a two-way shuttle box, whereas those of the low-avoidance strain (SLA) average 0%. Adrenal gland weights, both absolutely and relative to body weight, are 40–50% greater in adult SLA than SHA rats of both sexes. Females of both strains have larger adrenal glands than males. Morphometry revealed that the difference in adrenal size in adults is entirely in the three cortical zones. The strain difference occurs as early as 21 days of age, whereas the sex difference appears only after puberty. A 2-min exposure to ether vapor induced an elevation in adrenal concentration of corticosterone which was significantly greater in SHA than SLA animals of both sexes at some time periods following the ether stress. Despite having smaller glands, older previously stressed SHA rats have higher basal adrenal concentrations of corticosterone than do SLA animals. The reduced steroidogenesis in the large adrenals of SLA rats suggests that there may be an enzymatic defect of genetic origin in those animals.This research was supported in part by David Ross Fellowships from the Purdue University Research Foundation to M. D. Isaacson and I. M. Rykaszewski and by Research Grant MH39230 to F. R. Brush from the National Institute of Mental Health.     

Influence of maternal stress on the development of the fetal genital system

During the last trimester of pregnancy, rat mothers were exposed to various forms of stress including immobilization-illumination, crowding and cold. At birth, male offspring from all experimental groups showed a shortened anogenital distance. In addition, offspring of mothers exposed to immobilization-illumination or cold showed reduced weight of body, testis and adrenals. It was suggested that corticosteroids secreted by the stressed mother suppressed gonadal secretions of the male fetus, thereby interfering with the sexual differentiation.