Environmental Influences that Alter the Stress Circuitry

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(1)See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/228446328. Environmental Influences that Alter the Stress Circuitry Article in Hormone and Metabolic Research · July 2012 DOI: 10.1055/s-0032-1316326 · Source: PubMed. CITATION. READS. 1. 75. 6 authors, including: Ramón Sotomayor-Zárate. Jeffrey D Blaustein. Universidad de Valparaíso (Chile). University of Massachusetts Amherst. 24 PUBLICATIONS 166 CITATIONS. 182 PUBLICATIONS 7,557 CITATIONS. SEE PROFILE. SEE PROFILE. Katia Gysling. Kellie L Tamashiro. Pontifical Catholic University of Chile. Johns Hopkins Medicine. 75 PUBLICATIONS 1,509 CITATIONS. 107 PUBLICATIONS 2,932 CITATIONS. SEE PROFILE. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.. SEE PROFILE. Available from: Ramón Sotomayor-Zárate Retrieved on: 03 August 2016.

(2) 592 Review. Environmental Influences that Alter the Stress Circuitry. Authors. N. Ismail1*, R. Sotomayor-Zárate2, 3*, T. L. Bale4, J. D. Blaustein1, K. Gysling3, K. L. K. Tamashiro5. Affiliations. Affiliation addresses are listed at the end of the article. Key words ▶ prenatal period ● ▶ puberty ● ▶ stress ● ▶ sexual differentiation ● ▶ metabolism ● ▶ gene expression ●. In early development, there are critical periods, such as prenatal, perinatal, and pubertal periods, during which chemical, biological, and physical insults (i. e., nutritional restriction, maternal stress, etc.) exert permanent alterations on physiology, metabolism, and health of offspring [1]. Although most people are able to cope with stressful events and only display a brief stress response with heightened physiological activity before stress recovery, exposure to stressful events during these critical periods can lead to the development of long-term psychopathological conditions in a significant number of people [2]. A complex interplay between genetic and environmental factors is probably at the origin of this heterogeneity. These proceedings are based on a workshop session at the US-South America Workshop in Neuroendocrinology. The session was based on the diverse effects of exposure to stressors during critical periods of development. Therefore, in these proceedings, we discuss the effects of exposure to a stressor during critical periods of development on mental health, sexual differentiation, behavior, metabolism, and gene expression in the brain. These proceedings are not meant to be a comprehensive review of the literature. It is simply meant to bring together the diverse effects presented during the workshop.. received 22.12.2011 accepted 25.05.2012 Bibliography DOI http://dx.doi.org/ 10.1055/s-0032-1316326 Horm Metab Res 2012; 44: 592–597 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence N. Ismail, PhD Center for Neuroendocrine Studies University of Massachusetts Tobin Hall 135 Hicks Way Amherst MA 01003 USA Tel.: +1/978/549 3499 Fax: +1/413/545 0996 ismail@cns.umass.edu. Epigenetic Programming Effect of Prenatal Stress in Mice: Dysmasculinization in Second-Generation Offspring via the Paternal Lineage. ▼. Prenatal stress increases the incidence of neurodevelopmental disorders Numerous researchers have linked fetal antecedents with increased offspring disease risk. For instance, exposure to prenatal stress can * These 2 authors contributed equally to this work.. Ismail N et al. Stress, Gene, and Behavior … Horm Metab Res 2012; 44: 592–597. increase the incidence of neurodevelopmental and social behavior disorders, like schizophrenia and autism spectrum disorders [3–5]. The mechanisms through which factors such as stress or maternal diet contribute to increased offspring disease risk remain unclear, but are likely due to a complex intereaction between the maternal environment, placental changes, and epigenetic programming of the embryo. Moreover, it is unclear how offspring sex may influence the epigenetic response to a changing maternal environment [6]. The early gestational period appears to be the most vulnerable period to the programming effects of maternal stress in male mice [7]. More specifically, exposure to stress prenatally disrupts established sex differences by dysmasculinizing male offsprings on certain behavioral measures, such as stress responsivity in adulthood [8]. Human studies have shown that infants exposed prenatally to maternal depression or anxiety display higher levels of glucocorticoid methylation, which is associated with increased cortisol release in response to a mild stressor [9]. Since programming epigenetic changes can be transmitted to subsequent generations, it is possible that exposure to prenatal stress may predispose offspring of future generations to such neurodevelopmental disorders. Support for this possibility comes from animal research using models of early life stress. For instance, male mice exposed to chronic and unpredictable maternal separation display depression-like behavior and altered behavioral response to aversive environments in adulthood. Mice exposed to maternal separation also display altered DNA methylation profile in the promoter region of several candidate genes. Interestingly, the offspring of male mice subjected to maternal separation show comparable behavioral alterations and changes in DNA methylation [10]. These findings not only emphasize the negative impact of early life stress on behav-.

(3) Review 593. ior, but also highlight that these negative consequences impact across generations and alter DNA methylation in the paternal germline. These findings also raise the possibility that, similar to maternal separation, exposure to prenatal stress may also cause changes in epigenetic programming and transmit a dysmasculinized phenotype to male offspring of future generation via the paternal lineage.. Exposure to prenatal stress dysmasculinizes adult morphological measures and increases depression-like behavior in second generation offspring Male offspring of fathers exposed to chronic variable stress during gestation have reduced anogenital distances and reduced testis weights compared to male offspring of control nonstressed fathers [11]. Moreover, male offspring of prenatally stressed fathers spend significantly more time immobile than male offspring of control nonstressed fathers. In contrast, there is no difference in immobility time between female offspring of prenatally stressed fathers and female offspring of control nonstressed fathers [10]. These findings suggest that exposure to prenatal stress alters stress coping strategies in males towards a more passive coping strategy.. Exposure to prenatal stress dysmasculinizes the expression of certain genes Interestingly, examination of the whole-brain gene expression upon birth in male and female offspring of prenatally stressed fathers reveals that the expression of 13 out of 17 genes, which show basal sex differences at this age, in male offspring of prenatally stressed fathers is closer to the female offspring of control nonstressed fathers than of male offspring of control fathers. These findings suggest a mechanism through which the paternal dysmasculinized stress-sensitive phenotype may be programmed in males of the next generation [10]. Sex differences in gene expression result from combinations of chromosomal and hormonal effects. A surge of testosterone during the perinatal sensitive period organizes the male brain in a sex-specific manner. The neuronal-specific enzyme aromatase converts testosterone to estradiol where it alters gene expression to masculinize and defeminize neurocircuitry through estrogen receptors. An assessment of the expression of these potential mediators of the program of dysmasculinized gene expression revealed no difference in aromatase and estrogen receptor-α expression. However, estrogen receptor-β expression is elevated in male offspring of prenatally stressed fathers compared to those of control nonstressed fathers [10]. Since this difference could be due to reduced ligand availability, these results and the results of morphological measures of anogenital distances and testis weights suggest that perinatal testosterone levels are reduced in male offspring of prenatally stressed fathers. Physiological, behavioral, and neural sex differences emerge due to differential exposure to gonadal hormones during development [12, 13]. Gonadal hormones have effects that are organizational and activational. Organizational actions of gonadal hormones occur early in development and persist in the absence of circulating hormone. In contrast, activational actions of gonadal hormones take place during puberty and are dependent on the presence of hormones. Exposure to testosterone during both early postnatal and pubertal periods in males is necessary for the development of the sexually dimorphic male brain and reproductive physiology. Male mice treated with formestane, an. aromatase inhibitor, on postnatal day 1 display a female-like pattern of miRNA expression based on a hierarchical clustering analysis [10]. miRNAs are small nonprotein-coding RNAs involved in the posttranscriptional regulation of genes [14]. A single miRNA can interact with up to a hundred transcripts and regulate gene families involved in early neurodevelopment. Interestingly, male offspring of prenatally stressed fathers display dysmaculinized expression of 3 miRNAs (miR-322, miR574-3p, miR-873). All 3 dysmasculinized miRNA target the β-glycan gene [10]. β-Glycan is involved in regulating the release of gonadal hormones in pituitary gonadotrophs and gonadal Leydig cells [15–17]. Although the role of β-glycan in neurodevelopment has not been identified yet, the findings discussed above suggest that it may play an important role in the organization of the sexually dimorphic brain. Taken together, these findings support the early gestational period as vulnerable to prenatal stress and epigenetic programming of the male germline. These studies provide evidence for the transmission of prenatal stress effects on neurodevelopmental processes and stress responsivity to subsequent generations through the paternal lineage and changes in the epigenome.. Effect of Prenatal and Neonatal Insults in the Adult Rat: Implications of Prenatal Exposure to Stress and High Fat Diets, and Neonatal Exposure to Steroid Hormones. ▼. Programming by prenatal exposure to maternal diet and stress The concept of programming is referred to the physiological setting by an early stimulus or insult during a critical hormone-sensitive period, resulting in negative effects in adult life [18–20]. Hales and Barker [21] demonstrated through studies in humans and animals that low nutrition during the gestational period correlates with the development of obesity and diabetes in adulthood. On the other hand, prenatal stress programs neuroendocrine and behavioral responses [22] and produces metabolic changes in offspring [6]. Obesity and diabetes are not only programmed by prenatal exposure to stress or a dietary restriction during the gestational period, but they have also been associated with increased consumption of caloric and fatty food during pregnancy [23]. Tamashiro and colleagues [24, 25] have shown that animals subjected to high-fat diet and high-fat diet plus stress during the gestational period are born with overweight which is maintained during the lactation period and until 70 postnatal days. This effect is also observed in animals that have been exposed only to prenatal stress [24]. At the metabolic level, it was noted that high-fat diet during the gestational period produces an increase in plasma levels of leptin, insulin, and glucose at the end of weaning. These effects associated with overweight favor the appearance of glucose tolerance and insulin resistance [24, 26, 27]. These findings are very important and should be considered in public health policies, since psychosocial stressors and unhealthy diets are becoming increasingly common issues among pregnant women.. Programming by neonatal exposure to steroid sex hormones Animal research on programming has mainly focused on fetal exposure to stimulus or insult (prenatal programming), but recent research has extended the concept of programming to Ismail N et al. Stress, Gene, and Behavior … Horm Metab Res 2012; 44: 592–597.

(4) 594 Review. early postnatal exposures (neonatal programming), also known to be a critical phase of development in early life [28–31]. Handling and unpredictable sequences of aversive stimuli during the first 10 postnatal days produce an increase in maternal aggressive behavior and reduce sexual behavior [32] in adult rats, possibly through alterations in noradrenergic neurotransmission in the locus coeruleus [30]. Another way to induce neonatal programming is to administer steroid sex hormones such as estradiol and testosterone at birth. For example, neonatal administration of testosterone and estradiol produces changes in dopaminergic and serotonergic neurotransmission in frontal cortex [33, 34], dorsal raphe [34], and ventromedial hypothalamus [35] of adult rats. On the other hand, neonatal estradiol administration in female rats reprograms their reproductive function in adulthood changing estrous cyclicity, reducing normal follicles and corpus luteum, and increasing atretic follicles and ovarian cysts [29]. Neonatal programming with steroid sex hormones mimics the exposure to pollutants with steroidogenic activity and allows evaluation of long-term effects of steroid sex hormones in the early stages of development on reproductive tissues and central nervous system of adult rats.. Exposure to Pubertal Immune Challenge Alters the Behavioral Responsiveness to Estradiol in Adult Mice. ▼. Exposure to pubertal immune challenge decreases sexual receptivity in adult ovariectomized hormoneprimed mice Like the prenatal and neonatal periods, the pubertal period is also a critical period of development that is vulnerable to exposure to stressors. Puberty is defined as the period during which sexual maturity is attained [36]. This period is accompanied by numerous physiological, emotional, behavioral, and social changes that have an impact on behavior later in life [37, 38]. Puberty is also a period of significant brain organization [39]. Previous research has shown that C57Bl/6 mice exposed to a shipping stressor from a supplier at 6 weeks of age display decreased sexual receptivity in ovariectomized adult mice primed with estradiol and progesterone compared to mice shipped younger or older [40]. Shipping stress has been found to activate the HPA axis increasing corticosterone release [41]. During shipping, mice can be exposed to a wide variety of stressors including disruptions in circadian rhythms, temperature fluctuations, social instability, noise, predator odors, decreases in food and water intake, and vibrations. Surprisingly, exposure to other controlled typical stressors known to activate the HPA axis and increase corticosterone release, like restraint stress, 36-h food deprivation and a multiple stressor regimen comprising three 45-min sessions of heat, light and restraint per day for 3 days, fails to decrease female sexual receptivity in adulthood [42]. These findings suggest that pubertal activation of the HPA axis and increase in corticosterone release is not sufficient to decrease sexual receptivity in adult mice. Interestingly, pubertal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), which is believed to activate the HPA axis and induce sickness for 1 or 2 days and an immune response, decreases sexual receptivity in adult ovariectomized mice primed with estradiol and progesterone [42]. These findings suggest that exposure to an immune challenge during the pubertal period decreases the behavioral responsiveness to estradiol and progesterone in adulthood. This effect is not peculiar and limited to the inbred Ismail N et al. Stress, Gene, and Behavior … Horm Metab Res 2012; 44: 592–597. C57Bl/6 strain of mice; it also extends to outbred CD1 mice [43]. To summarize, exposure to shipping stressor or to LPS at 6 weeks of age decreases sexual receptivity and behavioral responsiveness to estradiol and progesterone in female mice.. Exposure to pubertal immune challenge alters the responsiveness of depression-like behavior to estradiol treatment in adult mice Besides playing an important role in reproductive behaviors, estradiol also alters mood and cognitive function [44, 45]. More specifically, estradiol modulates the expression of depressionlike behaviors in rats and mice [46–48]. The study of depressionlike behavior in animal models is challenging, since many of the core symptoms of depression cannot be readily examined. Current animal models of depression rely on 2 principles: actions of known antidepressants and response to stress [49]. Two common tests of depression-like behavior in rodents are the forced swim and tail suspension tests. In both tests, the duration of immobility is recorded and is linked to the behavioral despair symptom of depression. Moreover, estradiol modulates the duration of immobility in these tests. Ovariectomy increases and estradiol replacement decreases immobility duration [46, 50]. Interestingly, in mice treated with LPS during puberty, estradiol treatment not only fails to decrease the duration of immobility, but it actually increases immobility duration in ovariectomized mice. This effect was not due to a difference in locomotion between the groups [51]. The difference in responsiveness to estradiol between mice treated with LPS during puberty and those treated during adulthood is not due to a differential immune response following LPS treatment. These findings suggest that pubertal LPS treatment not only decreases the behavioral responsiveness to estradiol; rather it alters it.. Pubertal LPS treatment blocks estradiol’s ability to improve cognitive function As mentioned above, estradiol also modulates cognitive function [45]. However, the effects of estradiol on cognition depend on the cognitive task and the brain regions recruited during these tasks [52–54]. While some tasks predominantly recruit the hippocampus, others recruit the striatum. Both of these regions in turn activate numerous other brain regions. Estradiol enhances the performance on hippocampus-dependent tasks [52–54]. Consistent with the effects of pubertal immune challenge on the effects of ovarian hormones on sexual behavior and depressionlike behaviors, estradiol fails to improve cognitive function on hippocampus-dependent tasks in mice treated with LPS during puberty [55]. The hippocampus-dependent tasks that were administered in this study were the object recognition, spatial recognition, social discrimination, and social recognition tasks. Regardless of the task administered, a similar pattern of results was obtained. Estradiol enhances cognitive performance in saline-treated mice and in mice treated with LPS in adulthood. However, in mice treated with LPS during puberty, estradiol fails to enhance cognitive performance. The difference in responsiveness to estradiol treatment between mice treated with LPS during puberty and those treated in adulthood does not seem referable to a differential immune response following LPS treatment [52]. These findings suggest that exposure to an immune challenge during puberty reduces the effects of estradiol on hippocampus-dependent cognitive tests. These findings, in addition to those on sexual behavior and depression-like behaviors suggest that a wide variety of the brain’s response to ovarian.

(5) Review 595. hormones is altered in mice exposed to an immune challenge during puberty.. Effects of Chronic Stress in Adult Rats: Implications on Metabolism and Behavior Related to Drugs of Abuse. ▼. Repeated or chronic exposure to stressful stimuli is associated with pathological effects at the neuroendocrine, metabolic, and behavioral levels. In humans, certain occupations can lead to chronic stress exposure. For example, firefighters have significantly higher plasma levels of catecholamines compared to individuals with other occupations and have a higher prevalence of neuropsychiatric disorders such as depression [56]. Basic research has used laboratory animals to model the effects of physiological stressors such as diet, hunger, insomnia and changes in environmental temperature [57], and psychosocial stressors such as subordination [58–61]. One of the most important physiological responses produced by exposure to stress is the activation of the hypothalamic-pituitary-adrenal gland axis [62, 63]. Acute exposure to physiological stressors such as fasting, cold, and heat produces endocrine changes like increases in serum ACTH and corticosterone levels [57, 62]. A similar effect is observed following exposure to a psychosocial stressor like aggression [57]. Another psychosocial stressor widely validated in the literature is the Visible Burrow System (VBS), based primarily on the establishment of a hierarchy between dominants and subordinates [25, 58–60, 64, 65].. Metabolic Effects of Chronic Exposure to Psychosocial Stress. ▼. VBS is a psychosocial stress model that mimics the natural habitat of rats and the hierarchical order that is established in this environment. This test lasts 14 days and usually consists in housing a group of 6 rats (4 males and 2 females) together. A few days after initiation of the test, 1 male takes the role of the dominant male and the others 3 males become subordinates. One of the most important effects observed in the VBS is that subordinate males have an obvious loss of body weight compared to the dominant male and control males (males individually caged with a female) [25, 65]. The dominant males also show a significant decrease in body weight when compared to control males. The drastic loss of body weight of subordinate rats is produced by a significant reduction in food intake compared to dominant rats during the development of VBS [25]. The reduction in food intake causes weight loss in dominant and subordinate males and is associated with a loss of fat mass in both experimental groups. However, subordinate rats also show a loss of lean mass [64, 65]. The VBS also produces a significant reduction in serum levels of testosterone, leptin, and insulin in subordinate rats [65] with a significant increase in corticosterone serum levels [23, 64, 66]. Thus, the VBS model is useful to study the effect of intermittent and repeated exposure to psychosocial stress. Using this experimental paradigm, it has also been shown that subordinate rats lose weight even during the recovery period (21 days following the end of the period of VBS). Interestingly, during the recovery period subordinate rats increase food intake and body fat content (increased visceral fat and reduced subcutaneous fat) [25]. Taken together, these findings show that exposure to psy-. chosocial stress produces physiological changes in body weight, body composition, and in the endocrine system. These alterations in some cases are long lasting and may be associated with pathological conditions such as the metabolic syndrome [67].. Behavioral and neurochemical effects of chronic exposure to psychosocial stress The VBS stress paradigm also leads to alterations in the behavior and in brain neurochemistry of subordinate rats. For example, VBS decreases the consumption of a saccharin solution during periods of recovery [64] and changes in serotonergic and dopaminergic neurotransmission in brain regions involved in emotions and motivated behavior in subordinate rats [68–71]. In other models of subordination, dominant monkeys have increased expression of dopamine D2 receptors in the brain as measured by positron emission tomography and lower cocaine intake in a self-administration test compared to subordinate monkeys [72]. Chronic exposure to psychosocial stress causes changes in the expression of corticotropin-releasing factor (CRF) and its receptors CRF1 and CRF2. For instance, the expression of CRF mRNA levels increases in the central amygdala of subordinate rats [73]. CRF expression is also altered following exposure to other stressors. For example, immobilization stress increases CRF immunoreactivity in the central extended amygdala, an effect that is prevented by concomitant use of desipramine during the stress period [74]. The activation of the CRF system in the brain has been implicated in addictive behavior [75]. Periods of abstinence to drugs of abuse are highly susceptible to the effects of stress promoting relapse to drug use [75–77]. For example, during cocaine abstinence, stressin-I (a selective CRF1 agonist) does not produce the release of dopamine observed in control animals in the rat lateral septum, a brain region involved in anxiety and motivated behavior, suggesting alterations in the expression of CRF receptors or changes in its signaling cascades [78]. Chronic stress also alters the neurochemistry of other brain nuclei such as nucleus accumbens (NAc) and the ventral tegmental area (VTA). Repeated exposure to stress reduces basal and stimulated extracellular levels of dopamine induced by cocaine in the NAc of stressed rats [79], and inhibits somatodendritic release of dopamine induced by cocaine in the VTA [80]. Together, these results show that stress plays a major role in the addictive process, whether favoring relapse to drug seeking behavior or reducing the neurochemical effects of drugs of abuse. This effect may favor an increase in the dose of drugs of abuse used by abusers further increasing their vulnerability to addiction.. Conclusion. ▼. Exposure to chemical, biological, or physical insults (i. e., nutritional restriction, maternal stress), during critical periods of development, can exert permanent and long-term alterations on physiology, metabolism and body weight regulation, health, behavior, and responsiveness to gonadal hormones in adulthood. Exposure to stressors during the prenatal and postnatal periods can have an effect on mental health, sexual differentiation, behavior, metabolism, and gene expression in the brain. Male offspring are more vulnerable to the exposure to stressors during these periods. Importantly, the effects of prenatal stress are not limited to the exposed generation, but can also alter neurodevelopmental processes and stress responsivity in subseIsmail N et al. Stress, Gene, and Behavior … Horm Metab Res 2012; 44: 592–597.

(6) 596 Review. quent generations through the paternal lineage. Females, on the other hand, are more vulnerable to the exposure to stressors during the pubertal period. Like the prenatal and postnatal periods, exposure to stressors during the pubertal period can have an effect on mental health, behavior and responsiveness to gonadal hormones in adulthood. It is important to further pursue the investigation of sex differences in vulnerability to exposure to stressors during critical periods of development. 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