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Differential Adaptive Responses to Chronic Stress of Maternally Stressed Male Mice Offspring
Abstract
It is well established that stress in early life can alter the activity of the hypothalamus-pituitary-adrenal (HPA) axis, but most studies to date have focused on HPA reactivity in response to a single acute stress. The present study addressed whether stress in pregnant mice could influence the adaptive responses of their offspring to chronic stress. Male offspring were exclusively used in this study. Elevated plus maze tests revealed that 14 d of repeated restraint stress (6 h per day; from postnatal d 50-63) significantly increased anxiety-like behavior in maternally stressed mice. NBI 27914, a CRH receptor antagonist, completely eliminated anxiety-related behaviors in a dose-dependent manner, indicating an involvement of a hyperactive CRH system. In accordance with increased anxiety, CRH contents in the hypothalamus and amygdala were significantly higher in these mice. Despite an increased basal activity of the CRH-ACTH system, the combination of chronic prenatal and postnatal stress resulted in a significant reduction of basal plasma corticosterone level, presumably because of a defect in adrenal function. Along with alterations in hypothalamic and hippocampal corticosteroid receptors, it was also demonstrated that a dysfunction in negative feedback inhibition of the HPA axis could be deteriorated by chronic stress in maternally stressed male mice. Taken together, these results indicate that exposure to maternal stress in the womb can affect an animal's coping capacity to chronic postnatal stress.
... The 8th edition of the Guide for the Care and Use of Laboratory Animals lists the recommended minimal floor area per animal for a female mouse and her litter as 51 in. 2 We sought to determine the effects of pair, trio, and harem breeding configurations on the maternal and weanling behavior of C57BL/6J (B6) and 129S6/SvEvTac (129) mice on the basis of nest scores and performance in pup retrieval tests, open-field test (OFT), elevated plus maze, and tail suspension test; we concurrently evaluated cage microenvironment, reproductive indices, and anatomic and clinical pathology. Harem breeding configurations enhanced B6 maternal behaviors as evidenced by significantly shorter pup retrieval times. ...
... The 8th edition of the NIH Guide for the Care and Use of Laboratory Animals (the Guide) 18 lists the minimal recommended floor space for a dam and her litter as 51 in. 2 By placing emphasis on minimal floor space, the Guide implies that a substantial decrease in space per animal in a standard shoebox cage may potentially lead to detrimental effects on both the mother and litter. The floor space recommendations proposed in the Guide for a breeding dam and her litter have led many institutions to discourage the use of trio or harem breeding configurations in standard shoebox cages due to the resulting increased cage population densities. ...
... For example, large cohorts of mice might not demonstrate increased aggression because of decreased space per mouse but because of increased social stress due to increased group size. 33 A large body of work addresses the effects of gestational and neonatal stress in mice, which range from decreased reproductive success 37 and developmental abnormalities 16 to changes in anxiety-like behavior 2,9,16 in pups and their offspring. In addition, anatomic pathologic changes associated with animal models of acute or chronic stress include changes in adrenal gland, thymic, and splenic weight and microscopically evident lymphoid depletion. ...
Although numerous studies have evaluated the effect of housing density on the wellbeing of laboratory mice, little is known about the effect of breeding configuration on mouse behavior. The 8th edition of the Guide for the Care and Use of Laboratory Animals lists the recommended minimal floor area per animal for a female mouse and her litter as 51 in.2 We sought to determine the effects of pair, trio, and harem breeding configurations on the maternal and weanling behavior of C57BL/6J (B6) and 129S6/SvEvTac (129) mice on the basis of nest scores and performance in pup retrieval tests, open-field test (OFT), elevated plus maze, and tail suspension test; we concurrently evaluated cage microenvironment, reproductive indices, and anatomic and clinical pathology. Harem breeding configurations enhanced B6 maternal behaviors as evidenced by significantly shorter pup retrieval times. Trio- and harem-raised B6 weanlings showed increased exploratory behaviors, as evidenced by greater time spent in the center of the OFT, when compared with pair-raised B6 mice. Conversely, breeding configuration did not alter pup retrieval times for 129 mice, and on the day of weaning trio- and harem-raised 129 mice demonstrated increased anxiety-like behavior, as evidenced by greater time spent in the periphery of the OFT, when compared with pair-raised counterparts. Behavioral differences were not noted on subsequent days for either strain. Trio- and harem-raised B6 and 129 weanling mice had significantly higher weaning weights than weanlings raised in a pair breeding configuration. Trio and harem breeding in a standard 67-in.2 shoebox cage did not detrimentally affect the evaluated welfare parameters in either C57BL/6J or 129S6/SvEvTac mice.
... PS has been found to decrease hippocampal MR mRNA levels, density, and binding capacity (Henry et al., 1994;Maccari et al., 1995;Koehl et al., 1999;Van Waes et al., 2006;Brunton and Russell, 2010), which could relate to the increased basal CRH levels in the PVN. Moreover, PS was shown to reduce hippocampal GR levels (Henry et al., 1994;Barbazanges et al., 1996;Koehl et al., 1999;Szuran et al., 2000;Chung et al., 2005;Van Waes et al., 2006;Mueller and Bale, 2008;Green et al., 2011;Bingham et al., 2013), attenuating its negative feedback on the HPA-axis, potentially explaining the stronger and prolonged corticosterone responses in PS animals (Chung et al., 2005;Koenig et al., 2005). These effects seemed to be mediated by increased prenatal corticosteroid exposure of the pups, as they were prevented by adrenalectomy in the mothers and reinstated by corticosterone injection in adrenalectomized dams (Barbazanges et al., 1996). ...
... PS has been found to decrease hippocampal MR mRNA levels, density, and binding capacity (Henry et al., 1994;Maccari et al., 1995;Koehl et al., 1999;Van Waes et al., 2006;Brunton and Russell, 2010), which could relate to the increased basal CRH levels in the PVN. Moreover, PS was shown to reduce hippocampal GR levels (Henry et al., 1994;Barbazanges et al., 1996;Koehl et al., 1999;Szuran et al., 2000;Chung et al., 2005;Van Waes et al., 2006;Mueller and Bale, 2008;Green et al., 2011;Bingham et al., 2013), attenuating its negative feedback on the HPA-axis, potentially explaining the stronger and prolonged corticosterone responses in PS animals (Chung et al., 2005;Koenig et al., 2005). These effects seemed to be mediated by increased prenatal corticosteroid exposure of the pups, as they were prevented by adrenalectomy in the mothers and reinstated by corticosterone injection in adrenalectomized dams (Barbazanges et al., 1996). ...
... For example, a combination of MS and later life corticosterone treatment or chronic stress exaggerated the impairing effects of either treatment alone on learning and memory, PPI, and hippocampal BDNF expression (Choy et al., 2008(Choy et al., , 2009Llorente et al., 2011). Moreover, PS appeared to increase vulnerability to chronic restraint stress in adulthood, elevating anxiety and basal hypothalamic CRH and ACTH levels, although basal corticosteroid levels were remarkably reduced (Chung et al., 2005). Behaviorally, MS animals were found more sensitive to social-defeat anhedonia (Der-Avakian and Markou, 2010), and to display elevated corticosterone stress responses and increased depression-like behavior as a consequence of repeated restraint stress in adulthood (Uchida et al., 2010). ...
Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.
... In small mammal population fluctuations, the individuals born in the peak are often under high-density environments as adults. Thus, in the process of population fluctuation, animals may experience two density stresses in the maternal period and adulthood, and the combined stresses can result in an increased risk of physiological or neurological abnormalities (Chung et al. 2005). ...
... The results discussed above reflected lower immunocompetence of offspring in the HH group, and further supported our hypothesis that combined density stresses during the maternal period and adulthood have a negative synergistic effect on individual immunocompetence. Chung et al. (2005) found that a dysfunction in the negative feedback inhibition of the HPA axis could be worsened by chronic stress in maternally stressed male mice. In this study, we found that the density-induced maternally stressed offspring in the HH group had the slowest acute immobilization stress response among the four treatment groups (Fig. 2), and this result was in accordance with that of Chung et al. (2005). ...
... Chung et al. (2005) found that a dysfunction in the negative feedback inhibition of the HPA axis could be worsened by chronic stress in maternally stressed male mice. In this study, we found that the density-induced maternally stressed offspring in the HH group had the slowest acute immobilization stress response among the four treatment groups (Fig. 2), and this result was in accordance with that of Chung et al. (2005). Numerous studies have shown that stress can change immune function through multiple pathways and levels (see review by Padgett and Glaser 2003;Bartolomucci 2007). ...
The literature reveals that stress in early life or adulthood can influence
immune function. As most studies on this are from the laboratory, there is a need for replicated studies in wild animals. This study aims to examine the effects of density stress during the maternal period and adulthood on immune traits of root vole (Microtus oeconomus) individuals. Four replicated high- and low-density parental populations were established, from which we obtained offspring and assigned each into four enclosures, two for each of the two density treatments used in establishing parental populations. The F1 offspring fecal corticosterone metabolite response to acute immobilization stress, anti-keyhole limpet hemocyanin immunoglobulin G (anti-KLH IgG) level, phytohemagglutinin (PHA)-delayed hypersensitivity and hematology at the end of the first breeding season, and prevalence and intensity of coccidial infection throughout the two breeding seasons, were tested. Density-induced maternally stressed offspring had delayed responses to acute immobilization stress. Density-stressed offspring as adults had reduced anti-KLH IgG levels and PHA responses, and the effects further deteriorated in maternally stressed offspring, leading to higher coccidial infection in the first breeding season than in the second. No correlations were found between immune traits or coccidial infection and survival over winter. These findings indicated that the combined density stresses during the maternal period and adulthood exhibited negative synergistic effects on immune traits. The synergistic effects lead to higher coccidial infection; however, this consequently reduced the risk of subsequent infection. The increased coccidial infection mediated by the synergistic effects may have an adaptive value in the context of the environment.
... In small mammal population fluctuations, the individuals born in the peak are often under high-density environments as adults. Thus, in the process of population fluctuation, animals may experience two density stresses in the maternal period and adulthood, and the combined stresses can result in an increased risk of physiological or neurological abnormalities (Chung et al. 2005). ...
... The results discussed above reflected lower immunocompetence of offspring in the HH group, and further supported our hypothesis that combined density stresses during the maternal period and adulthood have a negative synergistic effect on individual immunocompetence. Chung et al. (2005) found that a dysfunction in the negative feedback inhibition of the HPA axis could be worsened by chronic stress in maternally stressed male mice. In this study, we found that the density-induced maternally stressed offspring in the HH group had the slowest acute immobilization stress response among the four treatment groups (Fig. 2), and this result was in accordance with that of Chung et al. (2005). ...
... Chung et al. (2005) found that a dysfunction in the negative feedback inhibition of the HPA axis could be worsened by chronic stress in maternally stressed male mice. In this study, we found that the density-induced maternally stressed offspring in the HH group had the slowest acute immobilization stress response among the four treatment groups (Fig. 2), and this result was in accordance with that of Chung et al. (2005). Numerous studies have shown that stress can change immune function through multiple pathways and levels (see review by Padgett and Glaser 2003;Bartolomucci 2007). ...
The hypothesis that maternal effects act as an adaptive bridge in translating maternal environments into offspring phenotypes, and thereby affecting population dynamics has not been studied in the well‐controlled fields.
In this study, the effects of maternal population density on offspring stress axis, reproduction and population dynamics were studied in root voles ( Microtus oeconomus ). Parental enclosures for breeding offspring were established by introducing six adults per sex into each of 4 (low density) and 30 adults per sex into each of another 4 (high density) enclosures. Live‐trapping started 2 weeks after. Offspring captured at age of 20–30 days were removed to the laboratory, housed under laboratory conditions until puberty, and subsequently used to establish offspring populations in these same enclosures, after parental populations had been removed. [Correction added on 8 January 2015 after first online publication: ‘10–20 days’ has been changed to ‘20–30 days.’] Offspring from each of the two parental sources were assigned into four enclosures with two for each of the two density treatments used in establishing parental populations (referred to as LL and LH for maternally unstressed offspring, assigned in low and highdensity, and HL and HH for maternally stressed offspring, assigned in low and high density). Faecal corticosterone metabolites ( FCM ) levels, offspring reproduction traits and population dynamics were tested following repeated live‐trapping over two seasons.
Differential fluctuations in population size were observed between maternally density‐stressed and density‐unstressed offspring. Populations in LL and LH groups changed significantly in responding to initial density and reached the similar levels at beginning of the second trapping season. Populations in HL and HH groups, however, were remained relatively steady, and in HL group, the low population size was sustained until end of experiment. Maternal density stress was associated with FCM elevations, reproduction suppression and body mass decrease at sexual maturity in offspring. The FCM elevations and reproduction suppression were independent of offspring population density and correlated with decreased offspring quality.
These findings indicate that intrinsic state alterations induced by maternal stress impair offspring capacity in response to immediate environment, and these alterations are likely mediated by maternal stress system. The maladaptive reproduction suppression seen in HL group suggests intrinsic population density as one of ecological factors generating delayed density‐dependent effects.
... Many of these effects appear to be mediated by permanent changes in HPA axis functioning, mainly through perturbation of the negative feedback systems that regulate glucocorticoid secretion, such as the intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) (Banerjee et al., 2012; Cottrell and Seckl, 2009; Lupien et al., 2009; Welberg and Seckl, 2001). In mammals, pre-natal stress through immobilisation during six hours from day 8.5 of pregnancy to birth in mice (Mus musculus) resulted in a prolonged response to an acute stress (Chung et al., 2005). However, post-natal glucocorticoid treatment in rats led to a decreased stress response later in life (Vázquez et al., 2012). ...
... Conversely, post-hatching deprivation of maternal care in zebra finches (Taeniopygia guttata) resulted in a prolonged response to an acute stressor (Banerjee et al., 2012). In both mammals and birds, the prolonged response to acute stress is linked to a decreased expression of glucocorticoid receptors in areas of the brain linked with HPA negative feedback (Banerjee et al., 2012; Chung et al., 2005). When living in an environment with frequent exposure to stressful stimuli, an attenuated stress response could allow an individual to better cope with these conditions; repeated elevated levels of glucocorticoids have detrimental effects, and a quicker return to baseline levels may facilitate more adaptive behaviours (Love and Williams, 2008; Weinstock, 2008 ). ...
... Such behavioural responses in novel environments, where food availability is unknown, may allow individuals to better cope with periods of food shortage even in more familiar environments and as such could be considered adaptive (Carere et al., 2005). In mammals, it has been shown that exposure to pre-and post-natal stress can have cumulative effects, resulting in greater negative consequences than exposure to stress during a single developmental stage, or having opposite effects (Chung et al., 2005; Koo et al., 2003; Meaney et al., 2007; Vallée et al., 1999 ). In our case, the effects of preand post-hatching treatments on physiology and behaviour appeared to lead to cumulative effects in our birds that experienced both treatments: these birds were the fastest to feed in the novel environment , spent more time away from the introductory cage and in the zone of the enclosed feeder, were more likely to enter this feeder, and tended to eat more mealworms than control quail and those treated during a single developmental period. ...
Prolonged exposure to stress during development can have long-term detrimental effects on health and wellbeing. However, the environmental matching hypothesis proposes that developmental stress programs physiology and behaviour in an adaptive way that can enhance fitness if early environments match those experienced later in life. Most research has focused on the harmful effects that stress during a single period in early life may exert in adulthood. In this study, we tested the potential additive and beneficial effects that stress experienced during both pre- and post-hatching development may have on adult physiology and behaviour. Japanese quail experienced different stress-related treatments across two developmental life stages: pre-hatching corticosterone (CORT) injection, post-hatching unpredictable food availability, both pre- and post-hatching treatments, or control. In adulthood, we determined quails' acute stress response, neophobia and novel environment exploration. The pre-hatching CORT treatment resulted in attenuated physiological responses to an acute stressor, increased activity levels and exploration in a novel environment. Post-hatching unpredictable food availability decreased adults' latency to feed. Furthermore, there were cumulative effects of these treatments across the two developmental stages: quail subjected to both pre- and post-hatching treatments were the most explorative and risk-taking of all treatment groups. Such responses to novel environments could enhance survival in unpredictable environments in later life. Our data also suggest that these behavioural responses may have been mediated by long-term physiological programming of the adrenocortical stress response, creating phenotypes that could exhibit fitness-enhancing behaviours in a changing environment.
... Chronic exposure to stress may impair locomotor and physiological responses to novel environments and induce anxiety-like behavior (Jankord et al., 2011;Taylor et al., 2016;Holubová et al., 2018a,b). Studies by Chung et al. (2005) and Maccari et al. (1995) found that maternal stress induced longer periods of corticosterone (CORT) secretion in rodents after a single acute stress exposure compared to controls. Thus, it has been suggested that repeated postnatal stress may activate the stress system, and prolonged CORT secretion is a result of a failure to properly control the stress response. ...
... Thus, it has been suggested that repeated postnatal stress may activate the stress system, and prolonged CORT secretion is a result of a failure to properly control the stress response. This overexposure to stress hormones may then exacerbate a variety of chronic stress-induced diseases (McEwen, 2000;Chung et al., 2005). On the other hand, increased plasma levels of FIGURE 1 | Overview of groups used in the present study. ...
Methamphetamine (MA) is an illicit synthetic psychostimulant drug, and its abuse is growing worldwide. MA has been reported as the primary drug of choice, by drug-abusing women, during pregnancy. Since MA easily crosses the placental barrier, the fetus is exposed to MA in a similar fashion to the mother. This study aimed to evaluate the effect of long-term perinatal stressors and drug exposure on anxiety-like behavior in adult male rats using the open field test (OF) and elevated plus maze (EPM). Dams were divided into three groups according to drug treatment during pregnancy: controls (C), saline-SA [subcutaneous (s.c.), 1 ml/kg], and MA (s.c., 5 mg/kg). Litters were divided into four groups according to postnatal stressors: non-stressed controls (N), maternal separation (S), maternal cold water stress (W), and maternal separation plus maternal cold water stress (SW). Forty-five minutes before testing (in both OF and EPM), one-half of adult male rats received an (s.c.) injection of MA and the other half received an SA injection. Prenatal MA/stress exposure did not affect anxiety-like behavior in adult male rats in both tests. In the OF, an acute MA dose in adulthood increased the time spent in the central disk area, decreased time spent in the corners, and decreased time spent immobile and grooming. Also, postnatal stress increased time spent in the central disk area, decreased time spent in corners, and increased mobility compared to controls. All groups of rats exposed to postnatal stressors spent significantly less time in the closed arms of the EPM compared to controls. Overall, our results indicate that early postnatal stress and a single acute MA administration in adulthood decreases the parameters of anxiety-like behavior in adult male rats regardless of prenatal MA exposure. Moreover, postnatal stress via maternal separation impacts the effect of acute MA administration in adulthood. Long-term postnatal stress may thus result in improved adaptation to subsequent stressful experiences later in life.
... Maternally stressed adult offspring exhibit reduced sensitivity to the negative feedback mechanisms of the HPA axis, and epigenetic alterations have been proposed to underlie these adverse outcomes 3,4 . We have also demonstrated that prenatal stress, in addition to influencing cardiometabolic and endocrine phenotypes, can have longterm consequences on cognition and emotion through impacts on several brain regions, such as the hippocampus, amygdala, ventral midbrain, and paraventricular nucleus of the hypothalamus [5][6][7][8] . ...
... The maternal stress procedure was performed as described previously 5,6 . Briefly, pregnant ICR mice were obtained by mating 6-to 7-week-old females with inhouse adult males. ...
Maternal stress has long-lasting influences on the brain functions of offspring, and several brain regions have been proposed to mediate such programming. Although perinatal programming of crosstalk between the circadian and stress systems has been proposed, the functional consequences of prenatal stress on the circadian system and the underlying mechanisms remain largely unknown. Therefore, we investigated whether exposing pregnant mice to chronic restraint stress had prolonged effects on the suprachiasmatic nucleus (SCN), which bears the central pacemaker for mammalian circadian rhythms, of offspring. SCN explants from maternally stressed mice exhibited altered cyclic expression patterns of a luciferase reporter under control of the mouse Per1 promoter (mPer1::LUC), which manifested as a decreased amplitude and impaired stability of the rhythm. Bioluminescence imaging at the single-cell level subsequently revealed that impaired synchrony among individual cells was responsible for the impaired rhythmicity. These intrinsic defects appeared to persist during adulthood. Adult male offspring from stressed mothers showed advanced-phase behavioral rhythms with impaired stability as well as altered clock gene expression in the SCN. In addition to affecting the central rhythm, maternal stress also had prolonged influences on the circadian characteristics of the adrenal gland and liver, as determined by circulating corticosterone levels and hepatic glycogen content, and on canonical clock gene mRNA expression in those tissues. Taken together, our findings suggest that the SCN is a key target of the programming effects of maternal stress. The widespread effects of circadian disruptions caused by a misprogrammed clock may have further impacts on metabolic and mental health in later life.
... Elevation of GCs may have particular potent effects during development, when the phenotype remains sensitive to organizational programming effects (Metcalfe and Monaghan, 2001;Spencer et al., 2009). For instance, past research has demonstrated that elevated GC concentrations early in life can be correlated with heightened sensitivity to stressors later in life (Chung et al., 2005;Cottrell and Seckl, 2009;Spencer et al., 2009;Banerjee et al., 2012; although the reverse has also been reported; Love and Williams, 2008;Zimmer et al., 2013), declines in the expression of sexually selected traits (Spencer et al., 2003;Husak and Moore, 2008;Spencer and MacDougall-Shackleton, 2011;Schmidt et al., 2014;Dupont et al., 2019), and reduced life expectancy (Monaghan et al., 2012;Grace et al., 2017), with effects potentially being mediated by lifehistory tradeoffs (Hau et al., 2010;Vitousek et al., 2018). ...
... Indeed, nestlings in better body condition were also more likely to recruit in this study. Moreover, even if unrelated to fledging success and recruitment rates, elevated CORT concentrations during development may have deleterious effects on other phenotypic traits important to fitness, such as song learning and acquisition of sexual coloration (Spencer et al., 2003;Husak and Moore, 2008;Spencer and MacDougall-Shackleton, 2011;Schmidt et al., 2014), and may affect the function of the HPA axis during adulthood, with implications for stress-sensitivity (Chung et al., 2005;Cottrell and Seckl, 2009;Spencer et al., 2009;Banerjee et al., 2012). Exposure to ALAN could result in higher CORT concentrations via a number of mechanisms. ...
Artificial light at night (ALAN) can disrupt adaptive patterns of physiology and behavior that promote high fitness, resulting in physiological stress and elevation of steroid glucocorticoids (corticosterone, CORT in birds). Elevated CORT may have particularly profound effects early in life, with the potential for enduring effects that persist into adulthood. Research on the consequences of early-life exposure to ALAN remains limited, especially outside of the laboratory, and whether light exposure affects CORT concentrations in wild nestling birds particularly remains to be elucidated. We used an experimental setup to test the hypothesis that ALAN elevates CORT concentrations in developing free-living birds, by exposing nestling great tits (Parus major) to ALAN inside nest boxes. We measured CORT in feathers grown over the timeframe of the experiment (7 nights), such that CORT concentrations represent an integrative metric of hormone release over the period of nocturnal light exposure, and of development. We also assessed the relationships between feather CORT concentrations, body condition, nestling size rank and fledging success. In addition, we evaluated the relationship between feather CORT concentrations and telomere length. Nestlings exposed to ALAN had higher feather CORT concentrations than control nestlings, and nestlings in poorer body condition and smaller brood members also had higher CORT. On the other hand, telomere length, fledging success, and recruitment rate were not significantly associated with light exposure or feather CORT concentrations. Results indicate that exposure to ALAN elevates CORT concentrations in nestlings, which may reflect physiological stress. In addition, the organizational effects of CORT are known to be substantial. Thus, despite the lack of an effect on telomere length and survivorship, elevated CORT concentrations in nestlings exposed to ALAN may have subsequent impacts on later-life fitness and stress sensitivity.
... Moreover, PS can result in stable long-term changes in central and peripheral stress response systems as well as influence the response to stress in adulthood [7,8]. It has also been found that prenatal stress (PS) induces an enhanced fear-like behavioral profile and dysregulation of brain noradrenergic and HPA activity after a stress during adulthood [8,9]. ...
... It was proposed that PS may produce stable changes in central and peripheral stress response systems that represent a potential vulnerability to subsequent adult stress [7,8]. In particular, HPA hyperactivity has been described in the offspring of mother rats submitted to stress in the third week of gestation [28] and has been the most commonly proposed mechanism related to behavior alterations [29]. ...
Much evidence has suggested that early life adversity can have a lasting effect on behavior. The aim of this study was to explore the impact of prenatal exposure to stress on cognition in adult life and how it impacts chronic stress situations. In addition, we investigated the participation of glucocorticoids, neurotrophins and cytokines in prenatal stress effects. For this purpose, pregnant mice were placed in a cylindrical restraint tube for 2 h daily during the last week of pregnancy. Control pregnant females were left undisturbed during their entire pregnancy period. Object-in-place task results showed that adult female mice exposed to prenatal stress exhibited an impairment in spatial memory. However, in the alternation test this memory deficit was only found in prenatally stressed mice submitted to chronic stress. This alteration occurred in parallel with a decrease in BDNF, an increase in glucocorticoid receptors and an alteration of Th1/Th2 in the hippocampus. Interestingly, these changes were observed in peripheral lymph nodes as well. However, none of the mentioned changes were observed in adult male mice. These results indicate that lymphoid cells could be good candidates as peripheral markers of susceptibility to behavioral alterations associated with prenatal exposure to stress.
... Stress hormone levels are increased in pregnant females that encounter adverse environmental conditions. In order to experimentally model such adversity, pregnant females have been exposed to a variety of stressors such as daily handling, repeated saline injections, constant light, noise, forced swimming, olfactory cues of unknown males, or repeated restraint [39,[44][45][46][47][48][49][50][51]. ...
... Several authors, however, see it roughly as the range from weaning (PND [22][23][24][25] to adulthood (PND 55-65). The period of adolescence can be subdivided into three intervals, early-(prepubescent, PND 22-34), mid-(pubescent, PND [35][36][37][38][39][40][41][42][43][44][45][46][47] and late adolescence (sexually mature, PND 48-60) [78,79] which will be characterized in more detail in the following subsections. ...
With each trajectory taken during the ontogeny of an individual, the number of optional behavioural phenotypes that can be expressed across its life span is reduced. The initial range of phenotypic plasticity is largely determined by the genetic material/composition of the gametes whereas interacting with the given environment shapes individuals to adapt to/cope with specific demands. In mammalian species, the phenotype is shaped as the foetus grows, depending on the environment in the uterus, which in turn depends on the outer environment the mother experiences during pregnancy. After birth, a complex interaction between innate constitution and environmental conditions shapes individual lifetime trajectories, bringing about a wide range of diversity among individual subjects.
In laboratory mice inbreeding has been systematically induced in order to reduce the genetic variability between experimental subjects. In addition, within most laboratories conducting behavioural phenotyping with mice, breeding and housing conditions are highly standardised. Despite such standardisation efforts a considerable amount of variability persists in the behaviour of mice. There is good evidence that phenotypic variation is not merely random but might involve individual specific behavioural patterns consistent over time. In order to understand the mechanisms and the possible adaptive value of the maintenance of individuality we review the emergence of behavioural phenotypes over the course of the life of (laboratory) mice. We present a literature review summarizing developmental stages of behavioural development of mice along with three illustrative case studies. We conclude that the accumulation of environmental differences and experiences lead to a “mouse individuality” that becomes increasingly stable over the lifetime.
... However the data on sex differences is still in an ambiguous state because of the various results and the imbalanced research status quo that many more studies have focused on males. For example, some studies found more anxiety-and/or depression-like behavior induced by prenatal stress especially in male rats rather than female rats (Chung et al., 2005; Sun et al., 2013; Szymanska et al., 2009), but other studies have failed to find a similar enhancement in male rats (Bogoch et al., 2007; Estanislau and Morato, 2005; Zagron and Weinstock, 2006, 2011). Furthermore, the neural underpinnings that underlie these sex differences induced by prenatal stress are largely unknown, but glutamatergic system is likely involved. ...
... Similar findings had been noted that prenatal stress caused anxiogenic effects in the adult male and female offspring in the EPM test (Brunton and Russell, 2010; Marrocco et al., 2012; Salomon et al., 2011; Zohar and Weinstock, 2011 ). However, some studies found that prenatal stress caused more anxiogenic effects in the EPM test in adult male offspring than female offspring (Chung et al., 2005; Sun et al., 2013; Szymanska et al., 2009; Zuena et al., 2008 ). Moreover, others found more anxiogenic effects on female offspring than male offspring (Biala et al., 2011 ). ...
Severe adverse life events during pregnancy may increase the risk of anxiety disorders in the offspring. Glutamate receptors are neurobiological targets in anxiety disorders. In this study, we investigated the effects of prenatal chronic mild stress (PCMS) on anxiety-like behavior by using elevated plus maze (EPM), and evaluated the effects of PCMS and/or anxiogenic challenge on glutamate receptors in different brain regions. Our results showed that PCMS increased anxiety-like behavior in both male and female offspring. Moreover, compared with the male naïve rats, male EPM rats showed a significant reduction of mGluR2/3 in the prefrontal cortex, mGluR1 and mGluR2/3 in the hippocampus, and increments of mGluR5, NR1, NR2B and PSD95 in the amygdala. In contrast, compared with female naïve rats, female EPM rats showed decreased levels of mGluR5 in the hippocampus, and mGluR2/3 and mGluR5 in the prefrontal cortex, and increased levels of NR2B and PSD95 in the amygdala. Furthermore, PCMS seemed not to affect the baseline expression of glutamate receptors in adult offspring, but induced significant alterations of them triggered by anxiogenic challenge with a sex difference. These data strengthen the pathophysiological hypothesis that prenatal stress as a risk factor involves in the development of anxiety disorder in the offspring.
Copyright © 2015. Published by Elsevier Ltd.
... High glucocorticoid levels during early development can permanently alter HPA axis functioning via alteration of baseline or stress-induced glucocorticoid levels and/or negative-feedback during stress recovery. It has been generally shown that an increase in pre-or postnatal stress programmes a hyperactive HPA axis, indicative of a reduced negative-feedback (1)(2)(3)(4)8,(19)(20)(21)(22). However, a few studies have shown that early-life stress exposure can result in an attenuated physiological stress response later in life, suggesting enhanced negative-feedback efficiency (23)(24)(25)(26). ...
... In mammals, both prenatal and postnatal stress exposures have been shown to decrease hippocampal MR and GR expression, as well as GR expression in the hypothalamus and in the pituitary gland. The decrease in both GR and MR mRNA in these different brain regions results in an altered HPA axis function through alteration of baseline or stress-induced glucocorticoid levels and/or negative-feedback during stress recovery (2,8,20,34,52,53). By contrast, some studies have shown that early-life stress exposure can result in an attenuated physiological stress response associated with an increased GR and/or MR expression within the HPA axis suggesting enhanced negative-feedback efficiency (25,35,54). ...
Stress exposure during early life development can program individual brain and physiology. The hypothalamic-pituitary-adrenal (HPA) axis is one of the primary targets of this programming which is generally associated with a hyperactive HPA axis, indicative of a reduced negative feedback. This reduced feedback efficiency usually results from a reduced level of the glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR) within the HPA axis. However, a few studies have shown that early life stress exposure results in an attenuated physiological stress response, suggesting an enhance feedback efficiency. Here, we aimed to determine if early life stress had long-term consequences on GR and MR levels in quail and if the effects on the physiological response to acute stress observed in pre-natally stressed individuals were underpinned by changes in GR and/or MR levels in one or more HPA axis components. We determined GR and MR mRNA expression in the hippocampus, hypothalamus and pituitary gland in quail exposed to elevated CORT during pre-natal development, post-natal development or both and in control individuals exposed to none of the stressors. We showed that pre-natal stress increased the GR:MR ratio in the hippocampus, GR and MR expression in the hypothalamus and GR expression in the pituitary gland. Post-natal stress resulted in a reduced MR expression in the hippocampus. Both early life treatments permanently affected the expression of both receptor types in HPA axis regions. The effects of pre-natal stress are in accordance with a more efficient negative feedback within the HPA axis and thus can explain the attenuated stress response observed in these birds. Therefore, these changes in receptor density or number as a consequence of early life stress exposure might be the mechanism that allows an adaptive response to later life stressful conditions. This article is protected by copyright. All rights reserved.
... It has been suggested that exposure to prenatal stress (PS) causes stable long-term changes in central and peripheral stress response systems, and a vulnerability to subsequent adult stress exposure [1,2]. It has also been found that PS induces an enhanced fear-like behavioral profile and dysregulation of brain noradrenergic and hypothalamic-pituitary--adrenal axis (HPA) activity after adult stress exposure [3][4][5][6]. ...
... Corticosterone levels were determined using a standard radioimmunoassay [22]. [1,2,6, H(N)-corticosterone] (20 Ci/mmol) was from Perkin Elmer Inc. (Waltham, MA, USA). The antibody (Sigma-Aldrich, St. Louis, MO, USA) cross-reactivity with other relevant steroids was 4.5% (cortisol), 20% (deoxycorticosterone) and 7.9% (testosterone). ...
It has been demonstrated that a short-duration stress (acute stress) may result in immunopreparatory or immunoenhancing physiological conditions. The aim of the present study was to investigate whether exposure to prenatal restraint stress (PRS) influences the impact of acute stress on the T-cell response in the adult life. We found that female mice exposed to PRS (PS mice) did not exhibit changes in the T-cell-dependent IgG antibody production respect to prenatally non-stressed mice (no-PS mice). However, no-PS mice exposed to acute stress showed an increase of antibody production after antigen stimulation. In contrast, PS mice exhibited a decreased response after an acute situation. Spleen catecholamines and plasma corticosterone levels were increased in acute stress in both PS and no-PS mice. Nevertheless, lymphocyte response to hormones was altered in PS mice. Particularly, inhibitory effect of corticosterone was higher on lymphocytes from PS mice. In addition, an increase in protein levels and mRNA expression of glucocorticoid receptor was found in lymphoid cells from PS mice. These results show that prenatal stress alters the immune intrinsic regulatory mechanism that in turn induces an increased vulnerability to any stressful situation able to modify immune homeostasis.
... Auch die Exposition gegenüber PS führt in den Nachkommen zu einer Beeinträchtigung der HHN-Achsen-Funktion (Sosnowski et al., 2018). PS führte in zahlreichen Studien zu einer gesteigerten Corticosteronstressantwort mit sowohl gesteigerten Corticosteronspitzenspiegeln als auch einer verlängerten Corticosteronantwort, wohingegen die basalen Corticosteronspiegel unverändert blieben (z.B. Henry et al., 1994;Maccari et al., 1995;Chung et al., 2005). Infolge von Stressexposition in utero während der fetalen Periode konnten Veränderungen der GR-und CRH-Expression, die mit einer gesteigerte HHN-Achsen-Reaktivität im Erwachsenenalter einhergingen, gefunden werden (Mueller & Bale, 2008). ...
Angsterkrankungen gehören zu den am weitesten verbreiteten psychischen Erkrankungen und stellen eine beträchtliche soziale und wirtschaftliche Herausforderung für unsere Gesellschaft dar. Aversive frühe Erfahrungen sind ein bekannter Risikofaktor für die Entwicklung verschiedener psychischer Erkrankungen, insbesondere Angststörungen. Während der frühen Entwicklung findet die Programmierung der Hypothalamus-Hypophysen-Nebennierenrinden- (HHN)-Achse, die die Ausschüttung des Stresshormons Cortisol in Menschen bzw. Corticosteron in Mäusen steuert, statt. Wenn Individuen in dieser kritischen Phase Stress ausgesetzt sind, wird die regelrechte Ausbildung der HHN-Achse gestört, was zu dysregulierten Verhaltensantworten auf Stressreize im späteren Leben führen kann. Das Serotonin (5-HT)-System als eines der ausgedehntesten Neurotransmittersysteme ist an der Vermittlung der Effekte von früher Stressexposition auf angstähnliche Verhaltensweisen beteiligt. Das Ziel dieser Studie ist es, die Interaktion zwischen genetischer Prädisposition und negativen Einflüssen in frühen Entwicklungsstadien auf die Ausbildung von Angstverhalten im Erwachsenenalter näher zu beleuchten. In dieser Studie wurden Tryptophanhydroxylase 2 (Tph2)-defiziente weibliche Mäuse als Modell für ein lebenslanges konstitutives 5-HT Synthesedefizit im zentralen Nervensystem verwendet. Nachkommen dieser Mauslinie wurden im frühen Lebensalter Maternaler Separation (MS), d.h. einem mütterlichen Trennungsparadigma, unterzogen und im Erwachsenenalter im „Open field“ (OF) oder in der „Dark-light box“ (DLB) getestet. Im Anschluss an die Verhaltensexperimente wurde die neuronale Aktivierung immunhistochemisch durch Darstellung des frühzeitig auftretenden Genprodukts c-Fos bestimmt. In der DLB zeigten homozygot Tph2-defiziente Mäuse eine verringerte motorische Aktivität im hellen Kompartiment, und dieser Effekt konnte durch MS normalisiert werden. Zusätzlich verstärkte MS bei diesem Genotyp das Auftreten von fluchtartigen Sprüngen. Im OF hat MS fluchtartige Verhaltensweisen in homo- und heterozygoten Tph2-defizienten Mäusen befördert. Beide Verhaltenstests führten zu spezifischen neuronalen Aktivierungsmustern, die mithilfe von c-Fos- Immunhistochemie ausgewertet wurden. Die Durchführung des DLB-Tests führte in Abhängigkeit vom Vorhandensein von Tph2 zur Aktivierung des paraventrikulären Kerns des Hypothalamus (PVN) und der basolateralen Amygdala (BL), wohingegen die Exposition gegenüber dem OF-Test zu einer Aktivierung der lateralen Amygdala (La) in Tieren, die einem mütterlichen Trennungsparadigma unterzogen wurden, sowie einer Aktivierung des ventrolateralen (VLPAG) und dorsolateralen (DLPAG) periaquäduktalen Höhlengraus in Abhängigkeit von Tph2 und MS führte. Zusammenfassend weisen die Ergebnisse dieser Studie darauf hin, dass MS aktive Verhaltensantworten auf aversive Reize in Abhängigkeit vom Vorhandensein von 5-HT im Gehirn fördert. Diese Effekte könnten durch die spezifische Aktivierung von mit Angstverhalten in Zusammenhang stehenden Gehirnregionen während der Verhaltensexperimente vermittelt werden.
... CRHR1 antagonists were previously shown to reverse the sequelae of early developmental or adult stress 76,77 , CRF administration 78 , and mir-34 knockout 37 . Here, maternal post-PRS subchronic treatment with the CRHR1 antagonist NBI reverses PRS-induced changes in Crhr1 expression in neonate offspring, as well as abnormalities in serum CORT and behavior in adult progeny (Figs. 3, 4c-f, and Table S9). ...
Pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in first (F1)- and second-generation (F2) offspring and increases mRNA expression of corticotropin-releasing factor receptor type 1 (Crhr1) in oocytes and in neonate offspring brain. Here, we ask whether the expression of Crhr1 and Crhr1-targeting microRNA is altered in brain, blood, and oocytes of exposed females and in the brain of their neonate and adult F1 and F2 offspring. In addition, we inquire whether maternal post-stress drug treatment reverses PRS-induced abnormalities in offspring. We find that PRS induces a selective increase in Crhr1-targeting mir-34a and mir-34c in blood and oocytes, while non-Crhr1 microRNA molecules remain unaltered. PRS induces similar microRNA changes in prefrontal cortex of F1 and F2 neonates. In adult animals, cortical Crhr1, but not mir-34, expression is affected by both maternal and direct stress exposure. Post-PRS fluoxetine (FLX) treatment increases pup mortality, and both FLX and the Crhr1 antagonist NBI 27914 reverse some of the effects of PRS and also have independent effects on F1 behavior and gene expression. PRS also alters behavior as well as gene and miRNA expression patterns in paternally derived F2 offspring, producing effects that are different from those previously found in maternally derived F2 offspring. These findings extend current knowledge on inter- and trans-generational transfer of stress effects, point to microRNA changes in stress-exposed oocytes as a potential mechanism, and highlight the consequences of post-stress pharmacological interventions in adolescence.
... Similar findings have been observed in European starlings, whereby maternal stress increased male embryonic mortality, whilst female chick quality was significantly enhanced (Love et al., 2005). In other species, CORT administration to sows tended to decrease male piglet survivability (Mack et al., 2014), whilst disruption of HPA axis regulation was seen in male rats whose dams were exposed to chronic variable stress, accompanied by down-regulation of the glucocorticoid receptor (GR) (Chung et al., 2005;Weinstock 2008). Sex-specific, phenotypic variation, particularly as a result of chronic maternal stress is strongly linked to the development of the HPA axis and its neighbouring endocrine pathways, which are responsible for a range of physiological functions (De Groef, Grommen, and Darras 2008;Lu et al., 2008). ...
Environmental factors, both positive and negative, experienced by breeder hens during their reproductive life, can have significant influence on the productive efficiency and health of their progeny. This is particularly important considering that commercial chicken meat birds spend a significant proportion of their life in ovo, and alteration to the in ovo environment can permanently ‘program’ progeny endocrine pathways. The maternal environment is greatly influenced by factors such as nutrition and stress, both of which play a significant role in the chicken meat breeder industry due to feed restriction practices, ranging from 25% to 80% ad libitum intake. The effects of nutrition and stress and their influence on the maternal environment have been extensively investigated in mammalian literature, primarily focusing on the development and function of the hypothalamic-pituitary-adrenal axis (HPA) in offspring including the exposure of the stress hormone cortisol. Disruption of the HPA axis can inadvertently disrupt other important endocrine pathways, involved in growth and metabolism, including the growth hormone-insulin-like growth factor I axis (GH/IGF-I) and the hypothalamic-pituitary-thyroid axis (HPT). The disruption or ‘reprogramming’ of metabolic endocrine axes through maternal influences has been linked to variations in progeny performance, including growth rate and body composition; however, the underlying physiological mechanisms responsible for these phenotypic differences still remain unclear, especially in poultry. The aim of this review is to assess current industry practices that may influence the maternal (breeder hen) environment, whilst reviewing the concept of developmental programming, and its application to chicken meat production.
... En outre, des études réalisées chez le rat montrent qu'un stress prénatal entraîne une plus forte libération de CRF (Corticotropin-releasing factor) dans l'amygdale suite à une dépolarisation (Cratty et al., 1995) associée à une augmentation du nombre de récepteurs CRF (Ward et al., 2000). Une étude chez la souris montre que des animaux stressés in utero sont plus vulnérables au développement de troubles de type anxieux après un stress chronique et montrent une augmentation du CRF dans l'amygdale (Chung et al., 2005). Il a également été mis en évidence une diminution du nombre de GR dans l'amygdale (Lee et al., 2011 (Kessler et al., 1995(Kessler et al., , 2005Olaya et al., 2015;Santiago et al., 2013). ...
Les altérations mnésiques associées au trouble de stress post-traumatique (TSPT) constituent un aspect fondamental de la symptomatologie de cette pathologie. Cette altération qualitative de la mémoire inclut à la fois une hypermnésie, c’est-à-dire une intensification de la mémoire vis-à-vis du coeur de l’événement traumatique, et une amnésie de type déclaratif pour les éléments contextuels péri-traumatiques. Les données chez l’Homme suggèrent que ces altérations mnésiques pourraient être sous-tendues par une hyper-activation amygdalienne et un dysfonctionnement hippocampique, respectivement. Cependant, les bases neurobiologiques, et en particulier moléculaires, du TSPT restent largement méconnues. Un modèle comportemental développé chez la souris au laboratoire et basé sur un conditionnement aversif permet précisément de comparer une mémoire de peur normale, c’est-à-dire « contextualisée » et adaptée, à une mémoire pathologique de type TSPT, c’est-à-dire « décontextualisée » et focalisée sur un élément saillant du trauma. Dans la mesure où il a été montré que le développement d’une mémoire de peur contextuelle implique certaines modifications épigénétiques spécifiques, nos travaux ont eu pour objectif de déterminer les altérations des modifications post-traductionnelles d’histones qui sous-tendent le développement d’une mémoire traumatique au lieu d’une mémoire de peur normale. Nos résultats révèlent (1) que des profils spécifiques différents des états d’acétylation/méthylation de l’histone H3 dans le réseau hippocampo-amygdalien sont associés à une mémoire de peur normale et à une mémoire traumatique de type TSPT. Spécifiquement, une mémoire de peur normale est associée à une forte acétylation de H3K9 hippocampique, tandis qu’une mémoire traumatique de type TSPT s’accompagne d’une hyperméthylation de H3K9 dans l’hippocampe, traduisant une répression transcriptionnelle, ainsi que d’une diminution de la tri-méthylation de H3K27 dans l’amygdale latérale, caractéristique d’une activation transcriptionnelle. De plus, nos travaux montrent (2) qu’une modulation pharmacologique de la balance des états d’acétylation/méthylation de H3K9 dans l’hippocampe permet de promouvoir ou de prévenir le développement d’une mémoire traumatique. Enfin, (3) une dernière série d’expériences révèle (i) qu’un stress prénatal est un facteur de risque au développement d’une mémoire traumatique, (ii) que cette dernière est associée à des profils épigénétiques spécifiques, et (iii) qu’une telle vulnérabilité peut se transmettre de manière intergénérationnelle.
... Hormone measurement. Corticosterone levels in adrenal lysates and plasma samples were assayed using a commercial corticosterone radioimmunoassay kit (DPC, Los Angeles, CA) as previously described 37 . ...
The mammalian circadian timing system consists of the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and subsidiary peripheral clocks in other tissues. Glucocorticoids (GCs) are adrenal steroid hormones with widespread physiological effects that undergo daily oscillations. We previously demonstrated that the adrenal peripheral clock plays a pivotal role in circadian GC rhythm by driving cyclic GC biosynthesis. Here, we show that the daily rhythm in circulating GC levels is controlled by bimodal actions of central and adrenal clockwork. When mice were subjected to daytime restricted feeding to uncouple central and peripheral rhythms, adrenal GC contents and steroidogenic acute regulatory protein expression peaked around zeitgeber time 00 (ZT00), consistent with shifted adrenal clock gene expression. However, restricted feeding produced two distinct peaks in plasma GC levels: one related to adrenal GC content and the other around ZT12, which required an intact SCN. Light pulse-evoked activation of the SCN increased circulating GC levels in both wild-type and adrenal clock-disrupted mutant mice without marked induction of GC biosynthesis. In conclusion, we demonstrate that adrenal clock-dependent steroidogenesis and a SCN-driven central mechanism regulating GC release cooperate to produce daily circulatory GC rhythm.
... In the literature, large interindividual differences in the outcome of early stress are found not only in human, but also in animal, studies. Whereas the findings of some studies suggest conditional adaptations, showing, for example, that rats who experienced more early life stress showed adaptations such as less depression-like behavior and increased learning under stressful conditions (Champagne et al., 2008; Kiank, Mundt, & Schuett, 2009 ), other studies exclusively suggest detrimental effects of stress (Chung et al., 2005; Llorente et al., 2011). Results of our study confirm these interindividual differences. ...
The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
... receptors (Berger et al., 2002), which in turn activates Nurr1 (Chung et al., 2005). High levels of Nurr1 might up-regulate TH expression (Smidt and Burbach, 2007), and eventually DAT and VMAT2, which will increase DA levels in an attempt to compensate for the misbalance produced by PS. ...
There is a large consensus that the prenatal environment determines the susceptibility to pathological conditions later in life. The hypothesis most widely accepted is that exposure to insults inducing adverse conditions in-utero may have negative effects on the development of target organs, disrupting homeostasis and increasing the risk of diseases at adulthood. Several models have been proposed to investigate the fetal origins of adult diseases, but although these approaches hold true for almost all diseases, particular attention has been focused on disorders related to the central nervous system, since the brain is particularly sensitive to alterations of the microenvironment during early development. Neurobiological disorders can be broadly divided into developmental, neurodegenerative and neuropsychiatric disorders. Even though most of these diseases share genetic risk factors, the onset of the disorders cannot be explained solely by inheritance. Therefore, current understanding presumes that the interactions of environmental input, may lead to different disorders. Among the insults that can play a direct or indirect role in the development of neurobiological disorders are stress, infections, drug abuse, and environmental contaminants. Our laboratories have been involved in the study of the neurobiological impact of gestational stress on the offspring (Dr. Antonelli’s lab) and on the effect of gestational exposure to toxicants, mainly methyl mercury (MeHg) and perfluorinated compounds (PFCs) (Dr. Ceccatelli’s lab). In this focused review, we will review the specialized literature but we will concentrate mostly on our own work on the long term neurodevelopmental consequences of gestational exposure to stress and neurotoxicants.
... Behavioral studies. Behavioral assessments were performed as described previously with modifications 33,35 . ...
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) is a molecule enriched in the brain and neurons that regulates intracellular calcium levels via signaling through the inositol trisphosphate receptor. In the present study, we found that IP3K-A expression is highly enriched in the central nucleus of the amygdala (CeA), which plays a pivotal role in the processing and expression of emotional phenotypes in mammals. Genetic abrogation of IP3K-A altered amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors. In agreement with the changes in amygdala gene expression profiles, IP3K-A knockout (KO) mice displayed more robust responses to aversive stimuli and spent less time in the open arms of the elevated plus maze, indicating high levels of innate fear and anxiety. In addition to behavioral phenotypes, decreased excitatory and inhibitory postsynaptic current and reduced c-Fos immunoreactivity in the CeA of IP3K-A KO mice suggest that IP3K-A has a profound influence on the basal activities of fear- and anxiety-mediating amygdala circuitry. In conclusion, our findings collectively demonstrate that IP3K-A plays an important role in regulating affective states by modulating metabotropic receptor signaling pathways and neural activity in the amygdala.
... The alterations in the reactivity of HPA axis in PS rats are correlated with the functional changes of different types of corticosteroid receptors. Thus, PS results in the downregulation of both high-affinity mineralocorticoid receptors (MRs) and low-affinity glucocorticoid receptors (GRs) in rats' offspring [34,53,[69][70][71], affecting the binding capacity of MR only [53]. ...
Early life adversaries have a profound impact on the developing brain structure and functions that persist long after the original traumatic experience has vanished. One of the extensively studied brain structures in relation to early life stress has been the hippocampus because of its unique association with cognitive processes of the brain. While the entire hippocampus shares the same intrinsic organization, it assumes different functions in its dorsal and ventral sectors (DH and VH, resp.), based on different connectivity with other brain structures. In the present review, we summarize the differences between DH and VH and discuss functional and structural effects of prenatal stress in the two sectors, with the realization that much is yet to be explored in understanding the opposite reactivity of the DH and VH to stressful stimulation.
... In addition, it was found that the expression of corticotropin-releasing hormone (CRH) in the amygdala is increased in response to prenatal psychosocial stress hereby inducing anxiety-like behavior [52,53]. Indeed, increased anxiety-like behavior in male offspring of prenatally stressed rat and mouse mothers has been repeatedly confirmed [50,[53][54][55][56]. In female offspring contradictory results were observed in tests for anxiety, possibly relating to the well-documented behavioral variance in the course of the female estrous cycle (for review see [49]). ...
Background:
Depression and schizophrenia are debilitating mental illnesses with significant socio-economic impact. The high degree of comorbidity between the two disorders, shared symptoms and risk factors, suggest partly common pathogenic mechanisms. Supported by human and animal studies, maternal immune activation (MIA) has been intimately associated with the development of schizophrenia. However, the link between MIA and depression has remained less clear, in part due to the lack of appropriate animal models.
Objective:
Here we aim to summarize findings obtained from studies using MIA animal models and discuss their relevance for preclinical depression research.
Methods:
Results on molecular, cellular and behavioral phenotypes in MIA animal models were collected by literature search (PubMed) and evaluated for their significance for depression.
Results:
Several reports on offspring depression-related behavioral alterations indicate an involvement of MIA in the development of depression later in life. Depression-related behavioral phenotypes were frequently paralleled by neurogenic and neurotrophic deficits and modulated by several genetic and environmental factors.
Conclusion:
Literature evidence analyzed in this review supports a relevance of MIA as animal model for a specific early life adversity, which may prime an individual for the development of distinct psychopathologies later life. MIA animal models may present a unique tool for the identification of additional exogenous and endogenous factors, which are required for the determination of a specific neuropsychiatric disorder, such as depression, later in life. Hereby, novel insights into the molecular mechanism involved in the pathophysiology of depression may be obtained, supporting the identification of alternative therapeutic strategies.
... It is assumed that the decrease in body weight is a good physiological marker of stress, and hence the intensity and duration of the stressor would be determining factors in the results. With more intense stressors, such as IMO for 14 days [53] or 8 hours restriction/day plus the use of a variable stress paradigm [3], more spectacular results have been achieved. However, in the present work we failed to detect significant differences in weight gain in the restrained animals subjected later to the i.p. procedure or in those treated with SERT. ...
... It is assumed that the decrease in body weight is a good physiological marker of stress, and hence the intensity and duration of the stressor would be determining factors in the results. With more intense stressors, such as IMO for 14 days [53] or 8 hours restriction/day plus the use of a variable stress paradigm [3], more spectacular results have been achieved. However, in the present work we failed to detect significant differences in weight gain in the restrained animals subjected later to the i.p. procedure or in those treated with SERT. ...
The serotonergic system in the brain plays a major role in mood and anxiety regulation when exposed to stress. The aim of the present study was to evaluate the effects of Sertraline administration in coping with stress using the behavioural paradigms of the acoustic startle reflex (ASR) and its prepulse inhibition (PPI) in both sexes. Wistar rats were divided into two groups: intact animals and exposed to restraint stress (RS) 3 times per day during 7 days, which were then subdivided into three other groups: injected with Sertraline (5 mg/kg/day) or the drug vehicle saline for 8 consecutive days, and non-injected. ASR and PPI values were analyzed along 4 sessions to determine behavioral changes. Upon it, we also determine the effects of acute immobilization stress analyzing physiological stress indicators in blood. Our data show sex differences in response to stress paradigms. RS affected more intensely males than females, disturbing the males' growth and the long-term startle habituation that were not affected in females. PPI increased in the vehicle injected animals when compared to baseline in both sexes, and Sertraline reversed more efficiently it in females. Moreover, despite both sexes exposed to stressful paradigms exhibited a significant increase in serum glutamic-oxaloacetic transaminase and lactate dehydrogenase enzymes when compared with intact controls, as well as leucopenia, some differences according to sex were found in the haemostatic response to stress. Notably, the repeated injections procedure disturbed the early response to stress, which Sertraline only attenuated in both sexes. Our data suggest that 8-day Sertraline administration is effective in reversing stress-induced changes in some physiological parameters, but insufficient to return immunological values to normality.
... It is known that the timing and duration of stressors, in addition to the type of environmental stressor, can generate a wide variety of postnatal behavioral outcomes [33][34][35]. The effect of PHX on behavior, brain regional volume, and neurochemical patterns in WT and HRM at 6 months of age was different than our previous study in mice at 3 months of age [30]. ...
Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizo-phrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies , we examined the long-term effects of PHX in heterozy-gous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6 months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor-1α (HIF-1α) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorti-coid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene–environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specific-ity of the gene of interest.
... Early life experiences are known to impact the short and long-term functioning of the HPA axis, but previous work on the organizational effects of exposure to glucocorticoids during development has yielded mixed findings. Some work indicates that exposure to elevated levels of glucocorticoids during development results in heightened response to stressors in adulthood (e.g., Hayward and Wingfield, 2004;Chung et al., 2005;Banerjee et al., 2012), whereas other work has found that exposure to elevated glucocorticoids during development results in an attenuated stress response later in adulthood (e.g., Lingas and Matthews, 2001;Love and Williams, 2008a;Vázquez et al., 2012). In this study, exposure to KLH during both pre-natal and post-natal development resulted in relatively low stress-induced CORT levels, and a more rapid cessation of CORT production in the 40 min following the stressor, both of which may be beneficial traits for an individual exposed to many such stressors (sensu Love and Williams, 2008a;Weinstock, 2008;Love et al., 2013). ...
Both maternal exposure to stressors and exposure of offspring to stressors during early life can have lifelong effects on the physiology and behavior of offspring. Stress exposure can permanently shape an individual's phenotype by influencing the development of the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the production and regulation of glucocorticoids such as corticosterone (CORT). In this study we used captive zebra finches (Taeniopygia guttata) to examine the effects of matching and mismatching maternal and early post-natal exposure to one of two types of antigens or a control on HPA axis reactivity in adult offspring. Prior to breeding, adult females were injected with lipopolysaccharide (LPS), keyhole limpet hemocyanin (KLH) or a control. Offspring of females in each of the three treatments were themselves exposed to LPS, KLH or a control injection at 5 and 28days post-hatch. When offspring were at least 18months of age, standardized capture and restraint stress tests were conducted to determine the impact of the treatments on adult stress responsiveness. We found significant interaction effects between maternal and offspring treatments on stress-induced CORT levels, and evidence in support of the environment matching hypothesis for KLH-treated birds not LPS-treated birds. KLH-treated offspring of KLH-treated mothers exhibited reduced stress-induced CORT levels, whereas LPS-treated or control offspring of KLH-treated mothers exhibited elevated stress-induced CORT levels. Although the treatment effects on baseline CORT were non-significant, the overall pattern was similar to the effects observed on stress-induced CORT levels. Our results highlight the complex nature of HPA axis programming, and to our knowledge, provide the first evidence that a match or mismatch between pre and post-natal antigen exposure can have life-long consequences for HPA axis function.
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... The influence of PS experience on brain and behavior in rats has been studied by employing a number of stress paradigms with variable frequency and duration. For example, previous studies employed restraint stress that lasted for as short as 20 minutes (Gomez-Gonzalez & Escobar, 2010) to as long as six hours (Chung et al., 2005) with a variable frequency of one day (Cannizzaro et al., 2006) to throughout gestation (Weinstock, Matlina, Maor, Rosen, & McEwen, 1992). In addition to procedural differences, the effect of PS on behavioral modulation, and neuronal anatomy and physiology depends on a variety of other factors, such as stage of brain development, sex, age of animal tested, test protocol, etc. (reviewed by . ...
... This difference rapidly disappeared, and was later counteracted, a trend that persisted into adulthood. Even though, this is in disagreement with earlier studies addressing prenatal stress in which PS delayed development (Pollard, 1984;Lordi et al., 1997;Berger et al., 2002), recently it has been reported in males (Chung et al., 2005;Mueller and Bale, 2006;Abe et al., 2007) and in both sexes (García-Cáceres et al., 2010). Many factors may be involved in these differences, including maternal sensitivity (Mueller and Bale, 2006), the timing of exposure to stress, or the physical properties of the stressors employed (Abe et al., 2007). ...
Sertraline is a clinically effective Selective Serotonin Reuptake Inhibitor known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behaviour and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to sertraline throughout adolescence on behavioural and physiological developmental parameters in prenatally stressed Wistar rats. Sertraline was administered (5mg/kg/day p.o.) from the age of 1-3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term sertraline treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed ‘catch-up’ growth found in PS females. Neither prenatal stress nor Sertraline treatment induced remarkable alterations in behaviour and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behaviour in the open field, while in females, it impaired startle habituation. In both cases, sertraline treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by sertraline. The present findings are evidence that continuous sertraline administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats.
... Prenatal environment can influence an individual's development profoundly, inducing changes lasting into adulthood. Numerous extrinsic and intrinsic adverse stressors constantly challenge the dynamic equilibrium that maintains the development of an offspring 1 . ...
Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral and mood disorders manifesting into adulthood. This study examined the effects of prenatal stress on the postnatal expression of sexually differentiated spatial memory in male and female wistar rats. Pregnant dams were subjected to restraint stress 6 hours per day during 11-21 days of pregnancy. The offspring of control and prenatally stressed dams were tested for spatial memory performance. Prenatally stressed male rats exhibited spatial memory deficits evidenced by longer target quadrant entry latencies and less time spent in the target quadrant. Prenatal stress had no effect on the spatial memory performance in female rats. Thus prenatal stress altered subsequent spatial memory performance in a sex-specific manner. These data reinforce the view that prenatal stress affects behavioral development interfering with sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic learning disabilities in a spatial memory task.
... Immobility, defined as the absence of volitional body or limb movement, was scored as the percentage of time spent immobile during the last 4 min. EPM EPM testing was performed as previously described (Chung et al., 2005). The maze consisted of two open (5 3 30 cm) and two enclosed (5 3 30 cm) arms with 20 cm high walls. ...
The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.
... But the observed interplay between maternal and early environmental effects appeared to be weaker than expected, also when compared to mammals. In case of the latter, the interplay (e.g., of chronic stress and maternal effects) affected anxiety, even though both treatments in themselves did not alter anxiety (Chung et al., 2005). This inconsistency of the observed effects in this study and among previous studies may be taken as indication that maternal and early environmental effects are not the main source of variation of neophobia in (altricial) birds (Table 1). ...
Neophobia, the fear of new objects or stimuli, has been shown to be affected by both maternal effects and the environmental conditions experienced during development. However, both pathways have so far only been studied in isolation, even though maternal effects are known to have significant effects on early development. Thus, maternal yolk hormones — an important mediator of maternal effects — may affect neophobia both through direct effects on neophobic behaviour and/or by affecting the early development. Both pathways may even act in concert. We measured the neophobic response and habituation to novel food, as well as the response to a novel object in 8-months-old canaries (Serinus canaria). All birds hatched from eggs with elevated yolk testosterone levels or control-treated eggs, and grew up in distinct experimentally-manipulated positions within the sibling hierarchy, which allowed us to test whether and how the effects of prenatally elevated yolk testosterone levels on neophobic behaviour vary with the environmental conditions experienced post-hatch. Neither the experimentally-manipulated yolk testosterone levels nor the position within the sibling hierarchy had a direct effect on neophobic behaviour. The elevation of the yolk testosterone levels modulated the neophobic behaviour and the habituation to novel situations of juvenile canaries only in interplay with the experimentally manipulated position in the sibling hierarchy and offspring sex. The strongest increase of neophobic behaviour was observed in individuals that hatched from eggs with elevated yolk testosterone content while growing up in a superior position in the sibling hierarchy — and in males. However, these effects varied with the focal explanatory variable. Based on our results and a review of the literature, we conclude that neither prenatal maternal nor early environmental effects post-hatching form the main source of variation of neophobia in itself, but that the effects observed as well as the inconsistency thereof can best be explained by the interaction of different partly unknown pathways.
... In the literature, large interindividual differences in the outcome of early stress are found not only in human, but also in animal, studies. Whereas the findings of some studies suggest conditional adaptations, showing, for example, that rats who experienced more early life stress showed adaptations such as less depression-like behavior and increased learning under stressful conditions (Champagne et al., 2008;Kiank, Mundt, & Schuett, 2009), other studies exclusively suggest detrimental effects of stress (Chung et al., 2005;Llorente et al., 2011). Results of our study confirm these interindividual differences. ...
In the study reported here, the main question we investigated was whether attention style could be a conditional adaptation. We organized participants of the TRacking Adolescents' Individual Lives Survey (TRAILS; N = 2,230) into shifters, sustainers, and two comparison groups, depending on their performance on a shifting- and a sustained-attention task at age 11 years. Compared with sustainers, shifters reported more pre- and perinatal risk factors and more childhood stress, and they adopted a faster life-history strategy. These differences were not found between the comparison groups, who performed well or poorly on both tasks, which suggests that specialization for either sustained or shifting attention is the key to conditional adaptation. In a subsample (n = 860), we found that stress did not increase depression risk in shifters, whereas a mismatch between early and recent stress predicted depression in sustainers. Cumulative stress predicted depression in the comparison group. These results suggest that shifters retain high levels of plasticity throughout life, whereas sustainers' adapted their phenotype early in life to the expected mature environment.
... Prenatal stress had no significant influence on locomotor activity in rats [21,24], but decreased investigative activity [12]. Stress also had no effect on anxiety in rats [18,24] or mice [33], but produced significant increases in the risk of developing anxiety-like behavior on exposure of mice to chronic stress [13]. ...
The aim of the present work was to study the effects of prenatal alcohol and stress on behavior in adult mice. Pregnant females received drinking solution containing 11% ethanol from days 1–21 of pregnancy and were subjected to stress (restriction for 2 h) on days 15–21. Their offspring (the Alcohol + Stress group) were tested at age three months using standard behavioral tests. Animals of the Alcohol + Stress group buried more marbles in the marble test, which models obsessive-compulsive disorder (OCD). In the “social behavior” test, males of the Alcohol + Stress group licked and sniffed a juvenile male longer than did controls. Prenatal alcohol and stress had no significant influence on motor activity, anxiety, or investigative behavior in adult male mice. These results led to the conclusion that the combined actions of ethanol and stress during the prenatal period induced a predisposition to the development of OCD.
... The monoaminergic system plays an important role in mental health, and its dysregulation leads to psychiatric dysfunction, such as behavioral depression, anxiety disorder, and Parkinsonism (Weiss et al., 1981;Elsworth and Roth, 1997;Morilak and Frazer, 2004). It is noteworthy that prenatal stress can cause profound and long-lasting deficits in brain functions (Chung et al., 2005;Son et al., 2006). Maternally-stressed male mice have been shown to indicate altered dopaminergic responses (Son , 2007). ...
Zinc oxide (ZnO) nano-sized particles (NPs) are beneficial materials used for sunscreens and cosmetics. Although ZnO NPs are widely used for cosmetics, the health effects of exposure during pregnancy on offspring are largely unknown. Here we investigated the effects of prenatal exposure to ZnO NPs on the monoaminergic system of the mouse brain. Subcutaneous administration of ZnO NPs to the pregnant ICR mice (total 500 μg/mouse) were carried out and then measured the levels of dopamine (DA), serotonin (5-HT), and noradrenalin, and their metabolites in 9 regions of the brain of offspring (6-week-old) using high performance liquid chromatography (HPLC). HPLC analysis demonstrated that DA levels were increased in hippocampus in the ZnO NP exposure group. In the levels of DA metabolites, homovanillic acid was increased in the prefrontal cortex and hippocampus, and 3, 4-dihydroxyphenylacetic acid was increased in the prefrontal cortex by prenatal ZnO NP exposure. Furthermore, DA turnover levels were increased in the prefrontal cortex, neostriatum, nucleus accumbens, and amygdala in the ZnO NP exposure group. We also found changes of the levels of serotonin in the hypothalamus, and of the levels of 5-HIAA (5-HT metabolite) in the prefrontal cortex and hippocampus in the ZnO NP-exposed group. The levels of 5-HT turnover were increased in each of the regions except for the cerebellum by prenatal ZnO NP exposure. The present study indicated that prenatal exposure to ZnO NPs might disrupt the monoaminergic system, and suggested the possibility of detrimental effects on the mental health of offspring.
... The con centration of glucocorticoids in samples was evaluated by a calibration curve obtained with standard corticos terone solutions (INC Biochemical, United States) (Men'shikov, 1987). Corticosterone is a major gluco corticoid in rodents, so it can be used for calculating the calibration curve (Chung, 2005). ...
We investigated the glucocorticoid level in plasma and adrenal glands of pregnant rats in the period of early organogenesis.
Tests were performed 24 hours after stress of different etiology (acute hypobaric hypoxia, intermittent normobaric hypoxia,
and immobilization) and then repeated in the adult offspring. There was a significant decrease in the glucocorticoid level
in pregnant rats 24 hours after hypoxic stress. Various changes of the basal glucocorticoid level were found in the offspring
after antenatal stress. Changes were mostly found in female offspring.
Livestock grazing increases the abundance of small burrowing mammals by reducing vegetation height and cover. However, habitats with low food quality may not be able to maintain high-density populations. The combination of an open habitat and high-quality food may be a critical component in understanding the dynamics of small burrowing mammal populations. Plateau pikas are small burrowing lagomorphs endemic to the Qinghai–Tibet Plateau (QTP). Overgrazing by livestock has induced a dramatic increase in the population density of plateau pikas for decades, but the mechanism is poorly understood. On the QTP, degraded meadows caused by livestock overgrazing provide abundant high-protein food resources for plateau pikas, a key factor driving population fluctuations in many small mammals. We examined the effect of protein on the individual fitness of plateau pikas by feeding them three pelleted chows containing 10%, 15% and 20% protein. We hypothesized that high-protein foods would elevate pika fitness by promoting the ability to cope with immediate environmental perturbations and increasing individual growth, immunity, and reproductive performance. We found that individuals from the 10% protein group had a delayed response to acute immobilization stress, while those from the 20% protein group had larger body mass, an increased PHA response, increased anti-KLH IgG levels, and a reduced intensity of coccidian infection. Pikas in the 20% protein group had higher concentrations of gonadotropin-releasing hormone, luteinizing hormone, estradiol, progesterone and testosterone than those in the 10% protein group. These results suggest that the high-protein foods found in heavily grazed meadows may be a key factor in generating and maintaining high-density populations of plateau pikas.
Prenatal overexposure to glucocorticoids (GC) can lead to behavioral changes in adulthood. We aimed to explore the effects of gestational administration of vitamin D on the behavioral responses of dams and their offspring prenatally exposed to dexamethasone (DEX). Vitamin D (500UI) was given daily during the whole pregnancy (VD group). Half of the groups that received vitamin D were treated with DEX (0.1 mg/kg, VD + DEX group) daily between the 14th and 19th days of pregnancy. The corresponding control groups of progenitors were assigned (CTL and DEX groups, respectively). Maternal care and the dam's behaviors were evaluated during lactation. The offspring had developmental and behavioral parameters evaluated during lactation and at 3, 6, and 12 months of age. Gestational administration of vitamin D increased maternal care and had an anxiolytic-like effect on the dams, but the latter was blocked in DEX-treated dams. Prenatal DEX partially impaired neural development and caused an anxiety-like phenotype in the male and female offspring at 6 months, which was prevented by gestational administration of vitamin D. As well, gestational vitamin D improved memory just in the male offspring, but this response was suppressed by prenatal DEX. We concluded that gestational vitamin D could prevent anxiety-like behavior in adult male and female rats prenatally exposed to DEX, which might be, in part, a result of the maternal care improvement.
Le stress est une réponse spontanée d’adaptation de l’organisme, visant à mobiliser les ressources nécessaires pour faire face à une situation perçue comme menaçante. Son influence a majoritairement été décrite au sein de structures limbiques. Or, en tant que processus adaptatif, il module les comportements et impacterait les structures impliquées dans la motricité, dont le cortex moteur primaire (M1). Cette aire cérébrale, à l’origine de la commande motrice volontaire, partage en effet des connexions avec des structures clés de l’axe corticotrope. Peu de données existent cependant, quant à la relation entre le stress et le M1. Une meilleure compréhension de l’impact du stress sur le fonctionnement du réseau neuronal au sein du M1 en conditions physiologiques, permettrait de mieux apprécier ses effets en cas de réseau cortical moteur altéré, comme observé dans le cas de la sclérose latérale amyotrophique (SLA). Ce travail de recherche visait ainsi à définir chez la souris adulte, l’influence du stress sur l’excitabilité et la plasticité du M1 de souris en conditions physiologiques, et d’en évaluer les conséquences dans le cadre de la SLA, en utilisant un modèle murin de la pathologie, la souris SOD1G93A (SOD). Dans un premier temps, les enregistrements électrophysiologiques in vitro et in vivo respectivement de l’excitabilité des interneurones du M1, et de la plasticité du réseau formé par les M1 des deux hémisphères cérébraux (M1-M1) ont révélé qu’un stress aigu tend à promouvoir une augmentation de l’activité globale du M1 chez les WT, mais au contraire à favoriser une diminution de cette activité chez les SOD. Une approche immunohistochimique a également montré suite au stress, des modifications dans le M1 de l’expression de KCC2 et NKCC1, deux cotransporteurs au chlorure régulant l’efficacité de la transmission GABAergique inhibitrice, avec une augmentation de l’expression de KCC2 chez les WT et de NKCC1 chez les SOD. La modification du ratio KCC2/NKCC1 pourrait suggérer une modulation différentielle de la transmission inhibitrice entre ces deux groupes. Dans un second temps, en utilisant les mêmes techniques d’électrophysiologie in vivo et d’immunohistochimie nous avons mis en évidence qu’un stress prénatal favorisait également l’augmentation de l’activité neuronale au sein du M1 des WT, et sa réduction chez les SOD, associé à une augmentation de l’expression de KCC2 et NKCC1 quel que soit le génotype, qui pourraient être en lien avec leurs rôles respectifs dans la formation d’épines dendritiques de novo et la régulation de l’inflammation. Dans un troisième temps, l’utilisation d’une batterie de tests comportementaux a démontré que les souris stressées (stress aigu ou prénatal) WT et SOD, présentaient des déficits cognitifs. En revanche seules les souris soumises à un stress prénatal ont démontré une diminution des performances motrices, suggérant une possible relation entre les changements de la plasticité observés suite à un stress prénatal et les apprentissages moteurs. Enfin, bien que le stress prénatal n’ait pas influencé la survie des animaux SOD, il semble légèrement précipiter l’apparition des symptômes de la SLA. Dans l’ensemble, ces données démontrent l’influence du stress sur l’activité et la plasticité du M1 et pointe vers la nécessité d’une meilleure compréhension de l’implication de ces changements dans la réponse au stress mais également dans l’évolution de la SLA.
Chronic social defeat stress (CSDS) has been found to produce different impacts on anxiety-like behaviors, spatial cognitive function and memory in rodents with different susceptibilities. However, the impacts of chronic social defeat on social behaviors in adult male mice with different susceptibilities to social defeat and the underlying mechanisms in the brain remain unclear. In the present study, we found that CSDS reduced the tendency of susceptible adult male C57 mice to approach an unfamiliar individual and increased their avoidance of an unfamiliar CD-1 mouse but had no effects on resilient individuals. In addition, ten days of chronic social defeat enhanced anxiety-like behavior in susceptible animals but produced no effects in the resilient group. Meanwhile, CSDS increased the number of corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus of the hypothalamus and CRF-R2-positive neurons in the accumbens nucleus shell in both resilient and susceptible animals. Chronic social defeat increased the number of CRF-R1-positive neurons and CRF-R1 mRNA expression in the prelimbic cortex (PrL) and the number of CRF-R2-positive neurons in the basolateral amygdala but reduced the number of CRF-R2-positive neurons and mRNA expression in the PrL in susceptible animals. Therefore, the different effects of CSDS on sociability and anxiety-like behavior in mice with different susceptibilities may be associated with region- and type-specific alterations in CRF receptor levels. These findings help us understand the underlying mechanism by which social stress affects emotion and social behavior and provides an important basis for the treatment of disorders of social and emotional behavior caused by social stress.
Stress während der pränatalen Periode hat verschiedene Auswirkungen auf das soziale und sexuelle Verhalten bei den Nachkommen von Mensch und Tier. Die vorliegende Studie untersucht die Auswirkungen von chronischem „restraint“ Stress im zweiten versus dritten Trimenon der Schwangerschaft auf die Produktion von Ultraschallvokalisationen männlicher C57BL/6N Mäuse im Erwachsenenalter. Hierfür wurde eine neuartige Cluster Analyse entwickelt und genutzt. Außerdem wurde der Einfluss einer heterozygoten Mutation des Glukokortikoid-Rezeptors (GR) auf die Vokalisation analysiert. Schließlich wurden auch Kortikosteron- und Testosteronspiegel gemessen. Pränataler Stress im dritten, nicht aber im zweiten Trimenon führt zu einer signifikanten qualitativen Veränderung der Ultraschallvokalisationen der Mäuse, unabhängig von ihrem GR-Genotyp. Der Kortikosteron-Serumspiegel bei pränatal im 3. Trimenon gestressten Tieren ist signifikant erhöht. Der Testosteron-Serumspiegel bei GR +/- Männchen ist im Vergleich zu Wildtypen tendenziell erhöht, während pränataler Stress hierauf keinen Einfluss zeigt. Pränatale Stress-Exposition im dritten Trimenon ändert die "mating songs“ erwachsener Männchen qualitativ und signifikant. Zuletzt zeigen wir erstmals erhöhte basale Kortikosteronspiegel in GR +/- Männchen nach pränatalem Stress, was darauf hindeutet, dass das GR +/- Mausmodell der Depression auch als Modell für pränatalen Stress bei männlichen Nachkommen dienen könnte.
Individuals in poor physiological condition are known to be more susceptible to infection that, once it occurs, further deteriorates the individuals' conditions, making them even more susceptible to infection and leading to death. This vicious synergy between the host condition and infection has recently been proposed to be among the key factors determining the oscillation characteristics in natural populations. Field studies that directly test such a hypothesis, however, are currently scarce, and the physiological traits involved remain largely unclear.
In this field study, we systematically examined the synergistic effects of maternal stress and coccidian parasitic interaction on the physiological conditions and overwinter survival of offspring in the root vole ( Microtus oeconomus ) via repeated live trapping and measurements of faecal corticosterone metabolite (FCM) levels and immunocompetence in captured animals.
We found that maternal density stress significantly increased FCM levels and both the prevalence and intensity of coccidian infection in offspring, significantly suppressed offspring immunocompetence and reduced offspring overwinter survival. Coccidian infection significantly potentiated increases in FCM levels and exacerbated the immune suppression induced by maternal density stress. Coccidian infection also significantly accelerated a decrease in overwinter survival and a population decline in maternal‐density‐stressed populations.
Our findings indicate that both stress and immune systems are involved in the synergistic process through which stressors and parasites interact with the host to influence the fitness of individuals and cause a population decline in the natural environment.
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Stress during the prenatal period has various effects on social and sexual behavior in both human and animal offspring. The present study examines the effects of chronic restraint stress in the second vs third trimester in pregnancy and glucocorticoid receptor (GR) heterozygous mutation on C57BL/6N male offspring’s vocal courtship behavior in adulthood by applying a novel analyzing method. Finally, corticosterone and testosterone levels as well as bone mineral density were measured.
Prenatal stress in the third, but not in the second trimester caused a significant qualitative change in males’ courtship vocalizations, independent of their GR genotype. Bone mineral density was decreased also by prenatal stress exclusively in the third trimester in GR mutant and wildtype mice and – in contrast to corticosterone and testosterone – highly correlated with courtship vocalizations. In Gr+/− males corticosterone serum levels were significantly increased in animals that had experienced prenatal stress in the third trimester. Testosterone serum levels were overall increased in Gr+/− males in comparison to wildtypes as a tendency – whereas prenatal stress had no influence.
Prenatal stress alters adult males’ courtship vocalizations exclusively when applied in the third trimester, with closely related changes in bone mineral density. Bone mineral density seems to reflect best the complex neuroendocrine mechanisms underlying the production of courtship vocalizations.
Besides, we demonstrated for the first time elevated basal corticosterone levels in Gr+/− males after prenatal stress which suggests that the Gr+/− mouse model of depression might also serve as a model of prenatal stress in male offspring.
Prenatal stress (PNS) is associated with increased biological risk for mental disorders such as anxiety and depression later in life, and stress appear to be additive to the PNS influences. Among the most widely cited and accepted alternative hypotheses of anxiety and depression is dysfunction of the HPA axis, a system that is central in orchestrating the stress response. Therefore, understanding how PNS exerts profound effects on the HPA axis and stress-sensitive brain functions including anxiety and depression has significant clinical importance. In this mini-review, we will focus on novel and evolving concepts regarding the potential mechanisms underlying the short and long-term effects of PNS involving CRH peptide family. We present evidence demonstrating prenatal hypoxia exposure induced anxiety-like behavior in adult male rat offspring and CRHR1 in PVN of the hypothalamus is involved.
The aim of the present work was to evaluate the delayed effects of acute prenatal stress in white rats. Stress was imposed by forced swimming in cold water on days 7 or 14 of pregnancy. The results showed that this procedure leads to significant decreases in the birth weight of rat pups and slowing of their growth during the second month of life. Animals subjected to prenatal stress showed changes in investigative activity and anxiety, with increases in emotional tension, along with learning impairment at age 1–2 months. Thus, acute stress on days 7 or 14 of pregnancy induces long-term adverse changes in the behavior of the offspring of the stressed animals.
We previously reported that gestational intermittent hypoxia (GIH) causes anxiety-like behavior in neonatal rats. Here, we showed that the anxiogenic effect was correlated with upregulation of corticotropin-releasing hormone receptor 1 (CRHR1) in the hypothalamic paraventricular nuclei (PVN) by GIH, and was selective to male offspring. The anxiety-like behavior was assessed by both the open field (OF) and elevated plus maze (EPM) tests. We demonstrated that GIH triggered anxiety-like behavior in male offspring, but not in female offspring or in the postpartum dams. Microinjection of antalarmin, a CRHR1-selective antagonist, into the PVN of the male offspring significantly increased the distance travelled and time spent in the central portion of the OF, and the time spent in the open arms in the EPM compared with controls. However, microinjection of the CRHR2 agonist, urocortin III, into the PVN did not affect anxiogenic behavior in the male offspring. These findings clearly demonstrate a gender-selective effect of GIH to increase anxiety-like behavior and this anxiogenic effect might be linked to embryogenically-driven upregulation of PVN CRHR1.
There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral adaptation to stress in the adult offspring. Mechanisms by which stress in the pregnant rat can influence development of the offspring are still unknown. In the present study, we investigated the involvement of maternal corticosterone secretion during pregnancy on the hypothalamo-pituitary-adrenal axis activity of adult offspring. We investigated stress-induced corticosterone secretion and hippocampal type I and type II corticosteroid receptors in male adult rats submitted to prenatal stress born to either mothers with intact corticosterone secretion or mothers in which stress-induced corticosterone secretion was blocked by adrenalectomy with substitutive corticosterone therapy. Repeated restraint during the last week of pregnancy was used as prenatal stressor. Furthermore, the specific role of an injection of corticosterone before the restraint stress on adrenalectomized mothers with substitutive corticosterone treatment was also studied. We report here that blockade of the mother's stress-induced glucocorticoid secretion suppresses the prolonged stress-induced corticosteroid response and the decrease in type I hippocampal corticosteroid receptors usually observed in prenatally stressed adults. Conversely, corticosterone administered during stress, to mothers in which corticosterone secretion is blocked, reinstates the effects of prenatal stress. These results suggest for the first time that stress-induced increases in maternal glucocorticoids may be a mechanism by which prenatal stress impairs the development of the adult offspring's glucocorticoid response.
It is well known that the hypothalamo-pituitary-adrenal (HPA) axis is altered by early environmental experiences, particularly in the perinatal period. This may be one mechanism by which the environment changes the physiology of the animal such that individual differences in adult adaptative capabilities, such as behavioral reactivity and memory performance, are observable. To determine the origin of these behavioral individual differences, we have investigated whether the long-term influence of prenatal and postnatal experiences on emotional and cognitive behaviors in adult rats are correlated with changes in HPA activity. To this end, prenatal stress of rat dams during the last week of gestation and postnatal daily handling of rat pups during the first 3 weeks of life were used as two environmental manipulations. The behavioral reactivity of the adult offspring in response to novelty was evaluated using four different parameters: the number of visits to different arms in a Y-maze, the distance covered in an open field, the time spent in the corners of the open field, and the time spent in the open arms of an elevated plus-maze. Cognitive performance was assessed using a water maze and a two-trial memory test. Adult prenatally stressed rats showed high anxiety-like behavior, expressed as an escape behavior to novelty correlated with high secretion of corticosterone in response to stress, whereas adult handled rats exhibited low anxiety-like behavior, expressed as high exploratory behavior correlated with low secretion of corticosterone in response to stress. On the other hand, neither prenatal stress nor handling changed spatial learning or memory performance. Taken together, these results suggest that individual differences in adult emotional status may be governed by early environmental factors; however, perinatal experiences are not effective in influencing adult memory capacity.
Behavioral stress has detrimental effects on subsequent cognitive performance in many species, including humans. For example, humans exposed to stressful situations typically exhibit marked deficits in various learning and memory tasks. However, the underlying neural mechanisms by which stress exerts its effects on learning and memory are unknown. We now report that in adult male rats, stress (i.e., restraint plus tailshock) impairs long-term potentiation (LTP) but enhances long-term depression (LTD) in the CA1 area of the hippocampus, a structure implicated in learning and memory processes. These effects on LTP and LTD are prevented when the animals were given CGP39551 (the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, before experiencing stress. In contrast, the anxiolytic drug diazepam did not block the stress effects on hippocampal plasticity. Thus, the effects of stress on subsequent LTP and LTD appear to be mediated through the activation of the NMDA subtype of glutamate receptors. Such modifications in hippocampal plasticity may contribute to learning and memory impairments associated with stress.
Corticotropin releasing factor (CRF) is the key coordinator of the neuroendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-dependent limbic seizures. These seizures, like other CRF effects, result from activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF1 and CRF2), are found in the amygdala, site of origin of CRF-induced seizures, and may therefore mediate these seizures. To determine which receptor is responsible for the excitatory effects of CRF on limbic neurons, a selective, non-peptide CRF1 antagonist was tested for its ability to abolish the seizures, in comparison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF1 blocker (NBI 27914) increased the latency and decreased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and prevented epileptic discharges in concurrent electroencephalograms recorded from the amygdala. The selective CRF1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier penetration. Urocortin, a novel peptide activating both types of CRF receptors in vitro, but with preferential affinity for CRF2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic seizures, indistinguishable from those induced by CRF, were abolished by pretreatment with NBI 27914, consistent with their dependence on CRF1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF1 receptor. CRF1-messenger RNA levels are maximal in sites of seizure origin and propagation during the age when CRF is most potent as a convulsant. Taken together, these facts strongly support the role of the developmentally regulated CRF1 receptor in mediating the convulsant effects of CRF in the developing brain.
This study investigated whether 21 days of restraint stress (6 hr/day) and the subsequent hippocampal dendritic atrophy would affect fear conditioning, a memory task with hippocampal-dependent and hippocampal-independent components. Restraint-stressed rats were injected daily (21 days) with tianeptine (10 mg/kg; to prevent hippocampal atrophy) or vehicle then tested on fear conditioning (Days 23-25, with 2 tone-shock pairings) and open field (Day 25). Restraint stress enhanced freezing to context (hippocampal-dependent behavior) and tone (hippocampal-independent) and decreased open-field exploration, irrespective of whether tianeptine was given. Results confirmed that stress produced CA3 dendritic atrophy and tianeptine prevented it. Moreover, CA3 dendritic atrophy was not permanent but reversed to control levels by 10 days after the cessation of restraint stress. These data argue that different neural substrates underlie spatial recognition memory and fear conditioning.
Although corticotropin-releasing hormone (CRH), a regulator of stress responses, acts through two receptors (CRH1 and CRH2), the role of CRH2 in stress responses remains unclear. Knock-out mice without the CRH2 gene exhibit increased stress-like behaviors. This profile could result either directly from the absence of CRH2 receptors or indirectly from developmental adaptations. In the present study, CRH2 receptors were acutely blocked by alpha-helical CRH (alpha(h)CRH, CRH1/CRH2 antagonist; 0, 30, 100, and 300 ng) infusion into the lateral septum (LS), which abundantly expresses CRH2 but not CRH1 receptors. Freezing, locomotor activity, and analgesia were tested after infusion. Intra-LS alpha(h)CRH blocked shock-induced freezing without affecting activity or pain responses; infusions into lateral ventricle or nucleus of the diagonal band had no effects. The same behavioral profile was obtained with d-Phe-CRH((12-41)) (100 ng), another CRH1/CRH2 antagonist. A selective CRH1 antagonist (NBI27914), in doses that reduced freezing on intra-amygdala (central nucleus) infusion (0, 0.2, and 1.0 microg), did not affect freezing when infused into the LS. Ex vivo autoradiography revealed that binding of [125I]sauvagine, a mixed CRH1/CRH2 agonist, was prevented in the LS by previous intra-LS infusion of alpha(h)CRH but not NBI27914. In vitro studies demonstrated that [125I]sauvagine binding in the LS could be inhibited by a CRH1/CRH2 antagonist but not by the selective CRH1 receptor antagonist, confirming that in the LS, alpha(h)CRH antagonized exclusively CRH2 receptors. Acute antagonism of CRH2 receptors in the LS thus produces a behaviorally, anatomically, and pharmacologically specific reduction in stress-induced behavior, in contrast to results of recent knock-out studies, which induced congenital and permanent CRH2 removal. CRH2 receptors may thus represent a potential target for the development of novel CRH system anxiolytics.
The mammalian gonadotropin-releasing hormone (GnRH) gene consists of four short exons (denoted as 1, 2, 3, and 4) and three intervening introns (A, B, and C). Recently, we demonstrated that excision of the first intron (intron A) from the GnRH transcript is regulated in a tissue- and developmental stage-specific fashion and is severely attenuated in hypogonadal (hpg) mouse because of its lack of exonic splicing enhancers (ESE) 3 and 4. In the present study, we examined the influence of intron A on translational efficiency, thereby establishing a post-transcriptional control over GnRH biosynthesis. First, we verified that an intron A-retained GnRH transcript is a splicing variant but not a splicing intermediate. Intron A-retained transcripts can be transported to the cytoplasm in contrast to intron B-containing transcripts, which are restricted to the nucleus. This result implicates the intron A-retained GnRH transcript as a splicing variant; it has a long 5'-untranslated region, as the GnRH prohormone open reading frame (ORF) begins on exon 2. We investigated whether an intron A-retained GnRH transcript can properly initiate translation at the appropriate start codon and found that intron A completely blocks the translation initiation of its downstream reporter ORF both in vivo and in vitro. The inhibition of translation initiation appears to be due to the presence of a tandem repeat of ATG sequences within intron A. Constructs bearing mutations of ATGs to AAGs restored translation initiation at the downstream start codon; the extent of this restoration correlated with the number of mutated ATGs. Besides the failure in the translation initiation of GnRH-coding region in the intron A-containing variant, the present study also suggests that the interference between mature GnRH mRNA and intron A-retained splicing variant could occur to lower the efficiency of GnRH biosynthesis in the GT1-1-immortalized GnRH-producing cell line. Therefore, our results indicate that the precise and efficient excision of intron A and the joining of adjacent exons may be a critical regulatory step for the post-transcriptional regulation of GnRH biosynthesis.
Repeated restraint stress induces an atrophy of apical dendrites of CA3c pyramidal neurons in the hippocampus, but the relationship between stress and adrenocortical activation has not been thoroughly investigated. In order to better understand the relationship between neural and non-neural indices of the severity of stress, we investigated the temporal relationship between CA3c dendritic atrophy and indices of adrenal steroid stress responsiveness. For this purpose, we used two different stress regimens: repeated restraint stress (6 h/day) and a chronic multiple stress paradigm (shaking, restraint and swimming, each day), differing in the degree of adrenal activation produced over 14 and 21 days. Atrophy of dendrites of CA3c neurons was found after 21 days of stress, but not after 14 days, and was of a similar magnitude for both stressors. However, non-neural measures differed between the two stress paradigms: (i) chronic restraint stress caused a significant habituation by day 21 in the corticosterone response to acute restraint, whereas chronic multiple stress exposure was not accompanied by habituation of the corticosterone response to restraint; (ii) chronic restraint stress caused neither adrenal hypertrophy nor thymus atrophy, but did reduce the rate of body weight gain throughout the 21 days, whereas chronic multiple stress caused a transient adrenal hypertrophy (on day 14), delayed suppression of thymus weight (on day 21) and transient reduction of body weight gain (on days 7 and 14, but not on day 21). Thus the non-neural indices of response to stress—although complex in their time course—suggest that the multiple stress regimen is a somewhat more potent chronic stressor for corticosterone and adrenal responses. Yet both stress regimens produced the same degree of apical dendritic atrophy in CA3c pyramidal neurons.
Giving rats opportunity to explore an enclosed or an elevated alleyway permitted study of exploratory drive in situations arousing different intensities of fear. It was concluded that such novel situations may induce approach avoidance conflict behavior. It was further found that strength of fear drive to novel situations declines as a function of time of direct exposure; after a period of non-exposure, spontaneous recovery of the fear reaction may be observed, "the magnitude of which depends upon the amount of fear extinguished to that stimulation on previous occasions."
Prenatal stress impairs activity of the hypothalamo–pituitary–adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 302–315, 1999
Sexual dimorphism of the mammalian central nervous system (CNS) has been widely documented. Morphological sex differences in brain areas underlie sex differences in function. To distinguish sex differences in physiological function from underlying sexual dimorphisms, we use the term, sexual diergism, to encompass differences in function between males and females. Whereas the influence of sex hormones on CNS morphological characteristics and function of the hypothalamic–pituitary–gonadal axis has been well-documented, little is known about sexual diergism of CNS control of the hypothalamic–pituitary–adrenal (HPA) axis. Many studies have been conducted on both men and women but have not reported comparisons between them, and many animal studies have used males or females, but not both. From a diergic standpoint, the CNS cholinergic system appears to be more responsive to stress and other stimuli in female than in male mammals; but from a dimorphic standpoint, it is anatomically larger, higher in cell density, and more stable with age in males than in females. Dimorphism often produces diergism, but age, hormones, environment and genetics contribute differentially. This review focuses on the sexual diergism of CNS cholinergic and vasopressinergic systems and their relationship to the HPA axis, with resulting implications for the study of behavior, disease, and therapeutics.
The present study examined the effects of stereotaxic delivery of corticosterone to the amygdala on anxiety-like behavior and corticotropin-releasing factor (CRF) mRNA level in the central nucleus of the amygdala (CeA). Micropellets (30 μg) of crystalline corticosterone or cholesterol (control) were implanted bilaterally at the dorsal margin of the CeA in Wistar rats. Seven days post-implantation, anxiety-like behavior was accessed using an elevated plus-maze. CRF mRNA level in the CeA was determined by in situ hybridization 4 h after being tested on the elevated plus-maze. Corticosterone implants increased indices of anxiety on the elevated plus-maze and produced a concomitant increase in both basal level of CRF mRNA per neuron and the number of neurons with CRF hybridization signal in the CeA. The plus-maze increased CRF mRNA levels in the CeA of cholesterol implanted rats to the elevated basal levels observed in corticosterone treated animals. Exposure to the plus-maze did not increase CRF mRNA level in the CeA of corticosterone implanted rats beyond elevated basal levels. Taken together, these findings support the involvement of the amygdala in anxiety-like behaviors in response to chronically elevated corticosterone and suggests that elevated glucocorticoids may increase anxiety by inducing CRF expression in the CeA.
Integration of the hypothalamo–pituitary–adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat (`systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures (`processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.
Restraint stress, 6 h/day for 21 days, caused an impairment, during acquisition, of the performance of a spatial memory task, the eight-arm radial maze. The impairment was reversible, temporally limited and blocked by phenytoin, a blocker of excitatory amino acid action, or tianeptine, an antidepressant, which lowers extracellular serotonin. These effects on behavior parallel the reversible stress-induced atrophy of dendrites of hippocampal CA3 neurons that are also blocked by the drugs.
The hippocampus is vulnerable to the damaging actions of insults such as transient ischemia and repetitive stimulation, as well as repeated exposure to exogenous glucocorticoids. This study investigated effects of a repeated psychological stressor, restraint, on the CA3 pyramidal neurons which are vulnerable to damage by repetitive stimulation. Repeated daily restraint stress for 21 days caused apical dendrites of CA3 pyramidal neurons to atrophy, while basal CA3 dendrites did not change. Rats undergoing this treatment were healthy and showed some adaptation of the glucocorticoid stress response over 21 days; however, stress reduced body weight gain by 14% and increased adrenal weight relative to body weight by 20%. Results are discussed in relation to the possible role of adrenal steroids and excitatory amino acids.
This study investigated the hypotheses that unpredictable prenatal stress (1) has effects on the offspring, similar to those induced by perinatal administration of glucocorticoids and (2) increases the vulnerability to stressful situations at adulthood. Rats were exposed to random noise and light stress throughout pregnancy. Offspring were tested for the development of spontaneous alternation behavior (SA) and at adulthood, their response to novel or aversive situations, open field, extinction and punishment following acquisition of an appetitive response and two-way active avoidance, were assessed. In prenatally stressed rats, the development of SA was significantly delayed. On repeated exposure to an open field they were less active; control rats had elevated plasma corticosterone (CCS) on days 2 and 4 of open field exposure, while prenatally stressed rats had significantly raised plasma CCS after each exposure (days 1–8). Furthermore, punishment-induced suppression of an appetitive response was enhanced. Acquisition of active avoidance was faciliated in female but reduced in male prenatally stressed offspring. It is suggested that random prenatal noise and light stress may cause impairment of development of hippocampal function which lasts into adulthood. This impairment is manifested as an increase in vulnerability and a decrease in habituation to stressful stimuli.
The rat adrenal hormone corticosterone can cross the blood-brain barrier and bind to two intracellular receptor populations in the brain--the mineralocorticoid and glucocorticoid receptors. Recent studies have revealed that the corticosteroid hormones are able to restore changes in neuronal membrane properties induced by current or neurotransmitters, probably through a genomic action. In general, mineralocorticoid receptors mediate steroid actions that enhance cellular excitability, whereas activated glucocorticoid receptors can suppress temporarily raised neuronal activity. The steroid-mediated control of excitability and the implications for information processing in the brain are reviewed in this article.
A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.
To clarify the regulatory mechanisms for the secretion of somatostatin (SRIF) from the hypothalamus, the effects of intracerebroventricular (i.c.v.) administration of growth hormone-releasing factor (GRF) and corticotropin-releasing factor (CRF) on SRIF secretion into hypophysial portal blood were examined in pentobarbital-anesthetized male rats. Neither the concentration of SRIF in portal plasma nor the secretion rate of SRIF was changed after i.c.v. administration of 0.9% saline. Administration of 10 ng or 5 micrograms human GRF i.c.v. produced a significant increase in the portal plasma concentration and secretion rate of SRIF. Likewise, 5 micrograms CRF significantly increased the portal plasma concentration and secretion rate of SRIF. These results suggest that the neuropeptides GRF and CRF centrally influence SRIF secretion into hypophysial portal blood.
This chapter reviews the present knowledge concerning the cell biology of how glucocorticoids (GCs) damage hippocampal neurons. It presents studies that suggest that GCs leave hippocampal neurons in a state of metabolic vulnerability. In the absence of a coincident metabolic challenge, this vulnerability is survived readily. However, when co-incident insults occur, neuronal viability is compromised, at least in part via exacerbation of the EAA cascade of damage. These observations are of some potential relevance, in that they suggest that exogenous GCs, in the aftermath of some insults, can potentially exacerbate hippocampal damage, and should be avoided if possible. It has been shown that inhibiting the GC stress response in the aftermath of status epilepticus seizures, by administering the adrenal steroidogenesis inhibitor metyrapone, diminish hippocampal damage. In an approach meant to decrease the total lifetime exposure to GCs, the chapter demonstrates that a neonatal behavioral intervention that reduces adult basal GC concentrations in the rat prevents some neuron loss and spatial learning deficits that characterize aging in the rat.
In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing's syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing's syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 microgram/kg i.v.) induced a GH peak of 14.5 +/- 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 +/- 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 +/- 1.1 ng/ml after Dex 8 mg and 1.8 +/- 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 micrograms p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 +/- 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 +/- 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex (595 +/- 47).(ABSTRACT TRUNCATED AT 250 WORDS)
Repeated escapable shock, yoked-inescapable shock, or no-shock treatments were administered to female rats before parturition to investigate the effects of stressor controllability on offspring pituitary-adrenal hormone concentrations and stress-induced analgesic reactions. Female rats exposed to escapable shock treatments received tail-shock in boxes containing a wheel that allowed shocks to be terminated after rotation. Rats in the yoked-inescapable shock group received an identical amount and pattern of tail-shock. However, shock was terminated only after wheel rotation by the rat undergoing escapable shock treatments. Female rats in the no-shock group were simply placed in wheel-turn boxes. Fourteen-day-old offspring were exposed for 10-min to either a separation-stress or shock-induced stress test. The former test consisted of separating and isolating the pup from the mother and siblings, whereas the latter involved the administration of five brief, 1.0 sec, low intensity, 0.5 mA, foot-shocks. Immediately after exposure to foot-shocks, pups were given a tail-flick test to assess their analgesic response. Plasma was obtained from pups immediately after separation and tail-flick tests and ACTH and corticosterone concentrations were assayed by radioimmunoassay. Results indicated that prenatal inescapable shock treatments resulted in offspring with significantly higher plasma ACTH and corticosterone concentrations than offspring exposed to prenatal escapable shock or no-shock treatments. Offspring of females exposed to inescapable shock also exhibited greater increases from basal concentrations in ACTH and corticosterone after stress. Furthermore, prenatal escapable and inescapable shock treatments significantly altered shock-induced analgesic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of central corticotropin-releasing factor (CRF) in the regulation growth hormone (GH) secretion was studied in freely moving conscious male rats with indwelling intra-atrial and intracerebroventricular (i.c.v.) cannulae. GH measurements in blood samples obtained every 20 min from 10.00 to 14.00 h in control animals injected with saline either intravenously (i.v.) or into the lateral cerebral ventricle revealed that spontaneous GH secretion was pulsatile, and occurred regularly at around 12.00 h. When ovine CRF (10 micrograms) was injected i.c.v., spontaneous GH secretion was inhibited (mean plasma GH [11.20-13.00 h]: 20 +/- 7 ng/ml vs. control: 126 +/- 22 ng/ml, p less than 0.01). In contrast, the intravenous injection of CRF (10 micrograms) did not affect spontaneous GH secretion (mean plasma GH [11.20-13.00 h]: 162 +/- 25 ng/ml vs. control: 193 +/- 31 ng/ml). This GH suppressive action of central CRF was blocked by the i.v. injection (0.5 ml) of antisomatostatin serum (AS), but not of normal sheep serum (NS), (mean plasma GH [11.20-13.00 h]: NS + CRF: 15 +/- 2 ng/ml vs. AS + CRF: 202 +/- 30 ng/ml, p less than 0.01). The mean plasma GH value [11.20-13.00 h] in animals receiving AS and CRF was not significantly different from those in animals receiving saline (i.v.) together with AS. These results suggest a potential inhibitory role of central CRF in the regulation of spontaneous GH secretion in the rat which is mediated by the stimulation of hypothalamic somatostatin.
Local intracerebral implants of the synthetic glucocorticoid, dexamethasone, prevented the expected adrenalectomy-induced enhancement of both corticotropin-releasing factor (CRF) and vasopressin immunoreactivity in parvocellular neurosecretory neurons of the paraventricular nucleus of the hypothalamus (PVH). Control experiments employing either cholesterol-filled cannulae aimed at the PVH, or dexamethasone-filled cannulae aimed at parts of the septum, amygdala or basomedial hypothalamus were ineffective in this paradigm. Coupled with recent evidence for existence of glucocorticoid receptors on CRF-containing neurons in the PVH, the results suggest that the inhibitory effect of glucocorticoids on the expression of both CRF and vasopressin in the parvocellular neurosecretory system can be mediated by receptors on the peptide-synthesizing neurons, themselves.
The effect of glucocorticoids on corticotropin-releasing factor (CRF) gene expression was studied by combination of in situ hybridization histochemistry and steroid implantation. Dexamethasone micropellets, implanted around the hypothalamic paraventricular nucleus (PVN), caused total inhibition of the hybridizable CRF mRNA signal above the parvocellular neurons of the PVN. Unilateral implantation of dexamethasone around the PVN resulted in a decrease of hybridizable CRF mRNA at the dexamethasone-implanted side. Dexamethasone implants into the cerebral cortex, dorsal hippocampus, ventral subiculum, lateral septum or amygdala were without any effect on the CRF expression in the PVN. Corticosterone did not result in any significant change in CRF mRNA, when implanted into the paraventricular region, dorsal hippocampus or ventral subiculum. When it was placed into the amygdala however, in a few cases it slightly inhibited the CRF mRNA levels in the ipsilateral PVN.
The effect of synthetic SRIF on GH release induced by hypothalamic ventromedial (VMN) and basolateral amygdaloid (BLA) electrical stimulation has been investigated in rats anesthetized by pentobarbital. SRIF administered as an intravenous infusion during stimulation (500 μg/rat) or subcutaneously 5 min before stimulation (20 μg/100 g body wt) completely blocked the 4-5 fold rise in plasma GH levels which occurred after VMN stimulation. A smaller single intravenous dose of SRIF (10 μg/100 g body wt) was effective in preventing VMN induced release when administered at the end of stimulation but not when given immediately before stimulation. SRIF (20 μg/100 g body wt SC) was also effective in blocking BLA induced GH release. These results indicate that SRIF is active in preventing acute GH release induced by stimulation of either brain region and suggest that the site of blockade is at the pituitary level.
Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.
Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.
Using in situ hybridization histochemistry, we report differential expression of corticotropin-releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA) and the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following systemic treatment with corticosterone (CORT) in adrenally-intact rats. Both injection of low (1 mg/kg/day) and high (5 mg/day) CORT reduced CRH mRNA expression in the PVN in a dose-dependent manner, although it returned to normal at the low dose by 14 days. By contrast, the high dose of CORT increased CRH mRNA transiently in the CEA at 4 days, although the low dose of CORT decreased it at 14 days. In a second experiment, we implanted a slowly-releasing CORT pellet for 2 weeks (200 mg, 60 day release) subcutaneously. This treatment produced an elevation of CRH mRNA in the CEA both at 1 and 2 weeks, whereas CRH mRNA in the PVN was decreased to a large extent as seen in the high CORT group of the first experiment. These results suggest that glucocorticoids can facilitate CRH mRNA expression in the CEA, a site implicated in anxiety and fear, while restraining the hypothalamic-pituitary-adrenal axis as indicated by the reduction in CRH mRNA in the PVN.
Research suggests that endogenous corticotropin-releasing factor (CRF) in the amygdala plays a role in the expression of stress-induced behavior. This study examined in rats whether antagonism of CRF receptors in the central amygdala (CA) region using alpha-helical CRF9-41, a CRF antagonist, was effective in attenuating the occurrence of stress-induced freezing. Bilateral infusions of 50, 100, or 200 ng of the CRF antagonist were made in the CA region using 33-gauge cannula immediately prior to testing. Freezing was measured in two test conditions. In one condition, the effects of the CRF antagonist on freezing was assessed immediately after exposure to electric foot shock. In the other condition, freezing was examined in shock-experienced rats that were re-exposed to the shock environment. Results suggested that 50 and 100 ng of the CRF antagonist were effective in reducing the duration of freezing in the immediate post-shock period. In addition, the 100 ng dose produced a significant reduction in freezing duration after rats were re-exposed to the shock environment. Collectively, data suggest that antagonizing the action of endogenous CRF in the CA region contributes to a general alleviation of stress-induced freezing.
The human organism is in a state of dynamic equilibrium, homeostasis. The stress system is activated when homeostasis is challenged by extrinsic or intrinsic forces, the stressors. This system, whose central component is the central nervous system (CNS) and includes corticotropin-releasing hormone (CRH) and noradrenergic neurons, respectively, in the hypothalamus and the brain stem, has as its peripheral limbs the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic (sympathetic) nervous system. Normal development and preservation of life and species are dependent on a normally functioning stress system. Maladaptive neuroendocrine responses, i.e., dysregulation of the stress system, may lead to disturbances in growth and development, and cause psychiatric, endocrine/metabolic, and/or autoimmune diseases or vulnerability to such diseases.
We investigated the effects of acute adrenal steroid treatment on spatial memory using the Y-maze and employing adrenal steroid receptor antagonists and agonists. For receptor activation, adrenalectomized rats were injected 2 h prior to their first Y-maze trial with sesame oil (adrenalectomy or SHAM), stress levels of corticosterone, a Type I receptor agonist (aldosterone), or a Type II receptor agonist (RU362). For receptor inactivation, unoperated rats were injected with a Type I receptor antagonist (RU318), a Type II receptor antagonist (RU555), sesame oil, or not injected at all. The findings indicated that spatial memory was impaired when the Type II receptors were blocked (RU555) or highly occupied (corticosterone or RU362) and normal for the other treatment conditions. These data suggest that the Type II receptors may be responsible for the inverted U-shaped relationship between spatial memory and corticosterone levels reported by others.
Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals.
The primary hormonal mediators of the stress response, glucocorticoids and catecholamines, have both protective and damaging effects on the body. In the short run, they are essential for adaptation, maintenance of homeostasis, and survival (allostasis). Yet, over longer time intervals, they exact a cost (allostatic load) that can accelerate disease processes. The concepts of allostasis and allostatic load center around the brain as interpreter and responder to environmental challenges and as a target of those challenges. In anxiety disorders, depressive illness, hostile and aggressive states, substance abuse, and post-traumatic stress disorder (PTSD), allostatic load takes the form of chemical imbalances as well as perturbations in the diurnal rhythm, and, in some cases, atrophy of brain structures. In addition, growing evidence indicates that depressive illness and hostility are both associated with cardiovascular disease (CVD) and other systemic disorders. A major risk factor for these conditions is early childhood experiences of abuse and neglect that increase allostatic load later in life and lead individuals into social isolation, hostility, depression, and conditions like extreme obesity and CVD. Animal models support the notion of lifelong influences of early experience on stress hormone reactivity. Whereas, depression and childhood abuse and neglect tend to be more prevalent in individuals at the lower end of the socioeconomic ladder, cardiovascular and other diseases follow a gradient across the full range of socioeconomic status (SES). An SES gradient is also evident for measures of allostatic load. Wide-ranging SES gradients have also been described for substance abuse and affective and anxiety disorders as a function of education. These aspects are discussed as important, emerging public health issues where the brain plays a key role.
Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
Glucocorticoids may underlie the association between low birth weight and adult disorders such as hypertension, type 2 diabetes and affective dysfunction. We investigated the behavioural and molecular consequences of two paradigms of prenatal dexamethasone administration in rats. Rats received dexamethasone (100 microg/kg per day) throughout pregnancy (DEX1-3), in the last third of pregnancy only (DEX3) or vehicle. Both dexamethasone treatments reduced birth weight, only DEX1-3 offspring had reduced body weight in adulthood. In adult offspring, both prenatal dexamethasone paradigms reduced exploratory behaviour in an open field. In contrast, only DEX3 reduced exploration in an elevated plus-maze and impaired behavioural responses and learning in a forced-swim test. This behavioural inhibition may reflect increased baseline corticotrophin-releasing hormone mRNA levels (30% higher) in the central nucleus of the amygdala in both dexamethasone-exposed groups. Adult DEX3 offspring also showed increased corticotrophin-releasing hormone mRNA with unaltered glucocorticoid receptor mRNA in the hypothalamic paraventricular nucleus and reduced hippocampal glucocorticoid- and mineralocorticoid receptor mRNA expression, suggesting reduced hippocampal sensitivity to glucocorticoid suppression of the stress axis. In contrast, DEX1-3 rats had no changes in hippocampal corticosteroid receptors, but showed increased mRNA levels for both receptors in the basolateral nucleus of the amygdala. From this data we suggest that prenatal glucocorticoid exposure programs behavioural inhibition perhaps via increased amygdalar corticotrophin-releasing hormone levels, while DEX3 also impairs coping and learning in aversive situations, possibly via altered hippocampal corticosteroid receptor levels. Overexposure to glucocorticoids, especially late in gestation, may explain the link between reduced early growth and adult affective dysfunction.
In previous studies, we have shown that male Wistar rats exposed to a single inescapable stressor session (15 min restraint) exhibited 24 h later an anxiogenic-like behavior in the elevated plus-maze (EPM), which was reversed by inhibition of corticosterone (CS) synthesis with metyrapone (75 mg/kg i.p.) 3 h before stress. Since CS binds to two central corticosteroid receptors, the mineralocorticoid (MR) and the glucocorticoid (GR) receptors, involvement of MR and GR in the modulation of anxiogenic responses was assessed in the EPM. Administration of the GR agonist dexamethasone (Dex, 1.25 microg/kg s.c.) to metyrapone-pretreated rats 1 h before restraint restored the anxiogenic-like response induced by the stressor. Removal of the adrenals also inhibited the anxiogenic-like effect, which was restored by either Dex (1.25 microg/kg s.c.), the MR agonist deoxycorticosterone (0.8 mg/kg s.c.) or CS, the common endogenous agonist of MR and GR (5 mg/kg s.c.) administered 1 h before stress. Intracerebroventricular infusion to intact animals 15 min before restraint of either a selective GR antagonist (A-GR, RU 38486, 100 ng/2 microl), a selective MR antagonist (A-MR, RU 28318, 100 ng/2 microl) or a combination of A-GR and A-MR (100 ng of each one/2 microl), abolished the stress-induced anxiogenic-like effect. The present findings indicate that both MR and GR are involved in the long-term CS modulation of the anxiety response induced by restraint. Both receptors mediate CS effects in an independent manner.
Throughout life organisms are challenged with various physiological and psychological stressors, and the ability to handle these stressors can have profound effects on the overall health of the organism. In mammals, the effects of stressors on the aging process and age-related diseases are complex, involving the nervous, endocrine and immune systems. Certain types of mild stress, such as caloric restriction, may extend lifespan and reduce the risk of diseases, whereas some types of psychosocial stress are clearly detrimental. We now have a basic understanding of the brain regions involved in stress responses, their neuroanatomical connections with neuroendocrine pathways, and the neuropeptides and hor mones involved in controlling responses of different organ systems to stress. Not surprisingly, brain regions involved in learning and memory and emotion play prominent roles in stress responses, and monoaminergic and glutamatergic synapses play particularly important roles in transducing stressful sensory inputs into neuroendocrine responses. Among the neuropeptides involved in stress responses. corticotropin-releasing hormone appears to be a pivotal regulator of fear and anxiety responses. This neuropeptide is responsible for activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is critical for mobilizing energy reserves and immune responses, and improper regulation of the HPA axis mediates many of the adverse effects of chronic physical and psychosocial stress.
Recent experiments investigating the effects of adrenal stress hormones on memory provide extensive evidence that epinephrine and glucocorticoids modulate long-term memory consolidation in animals and human subjects. Release of norepinephrine and activation of beta-adrenoceptors within the basolateral amygdala is critical in mediating adrenal stress hormone regulation of memory consolidation.
The present study analyzed the effects of maternal stress on behavior and macrophage activity of mice. Pregnant mice received a daily footshock (0.2 mA) from gestational days 15 (GD15) to 19. Experiments were performed on male offspring, challenged or not with another footshock (0.2 mA) on postnatal day 30 (PND30) or 60. The following results were obtained for maternal stress: (1) increment in locomotor activity of juvenile but not of adult mice observed in both open-field and plus-maze; (2) increment in rearing frequency of juvenile but not of adult mice observed in the open-field; (3) decrement in macrophage spreading of adult but not of juvenile mice; (4) abolishment of postnatal footshock effects in both macrophage spreading on PND30 and macrophage nitric oxide (NO) production on PND60; (5) reversion of postnatal footshock effects on H(2)O(2) spontaneous and PMA-induced release by macrophage on PND30; (6) modification of postnatal stress effects on macrophage phagocytosis on PND60. These changes were unrelated to differences in gestational parameters and did not reflect altered maternal-pup interactions or nutritional factors. The observed data provide experimental evidence that maternal stress alters behavior, and macrophage activity at the same time and in the same litter. These data were discussed in the light of possible neuroimmune interactions that involve catecholaminergic pathways.
Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.
Chronic restraint stress has been shown to induce structural remodelling throughout the interconnected dentate gyrus-CA3 fields. To find out how this stressor affects the rate of adult hippocampal neurogenesis, we subjected rats to acute or chronic restraint stress and assessed the proliferation, survival and differentiation of newly born cells in the dentate gyrus. We also examined polysialylated neural cell adhesion molecule expression, a molecule normally expressed in immature neurons and important for morphological plasticity. The results show that acute restraint stress did not change either the proliferation of dentate gyrus precursor cells or the expression of polysialylated neural cell adhesion molecule, whereas 3 weeks of chronic restraint stress suppressed proliferation by 24% and increased polysialylated neural cell adhesion molecule expression by 40%. The study was extended for an additional 3 weeks to trace the survival and development of the cells born after the initial 3 weeks of restraint. Rats subjected to 6 weeks of daily restraint stress exhibited suppressed cell proliferation and attenuated survival of the recently born cells after the extended time course, resulting in a 47% reduction of granule cell neurogenesis. Furthermore, 6 weeks of chronic stress significantly reduced the total number of granule cells by 13% and the granule cell layer volume by 5%. Expression of polysialylated neural cell adhesion molecule followed a biphasic time course, displaying a significant up-regulation after 3 weeks of daily restraint stress that was lost after 6 weeks of stress. These studies may help us understand the basis for hippocampal shrinkage and raise questions about the ultimate reversibility of the effects of chronic stress.
Neuroendocrinology and pathophysiology of the stress system Stress: basic mechanisms and clinical impli-cations
- Stratakis Ca
- Chrousos Gp Chrousos Gp
- R Mccarty
- K Pacak
- G Cizza
- E Sternberg
- Gold Pw
- Kvetnansky
Stratakis CA, Chrousos GP 1995 Neuroendocrinology and pathophysiology of the stress system. In: Chrousos GP, McCarty R, Pacak K, Cizza G, Sternberg E, Gold PW, Kvetnansky R, eds. Stress: basic mechanisms and clinical impli-cations. New York: The New York Academy Science; 1–18
Manipulating the mouse embryo The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist
- Hogan B F Costantini
- Lacy
- Chalmers Tz Dt Baram
- De Souza
Hogan B, Costantini F, Lacy E 1986 Manipulating the mouse embryo. New York: Cold Spring Harbor Laboratory Press 26. Baram TZ, Chalmers DT, Chen C, Koutsoukos Y, De Souza EB 1997 The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. Brain Res 770:89 –95