Pair-housing of male and female rats during chronic stress exposure results in gender-specific behavioral responses

Social support has a positive influence on the course of a depression and social housing of rats could provide an animal model for studying the neurobiological mechanisms of social support. Male and female rats were subjected to chronic footshock stress for 3 weeks and pair-housing of rats was used to mimic social support. Rats were isolated or housed with a partner of the opposite sex. A plastic tube was placed in each cage and subsequently used as a 'safe' area in an open field test. Time spent in the tube was used as a measurement of anxiety levels. Chronic stress increased adrenal weights in all groups, except for isolated females who showed adrenal hypertrophy in control conditions. In isolated males, chronic stress resulted in an increase in the time the animals spent in the tube. While stress did not affect this parameter in socially housed males, males with a stressed partner showed a similar response as isolated stressed males. Even though adrenal weights showed that isolated females were more affected by stress, after chronic stress exposure, they spent less time in the tube than socially housed females. Socially housed stressed females spent less time in the 'safe' tube compared to control counterparts, indicating that stress has a gender-specific behavioral effect. In conclusion: pair-housing had a stress-reducing effect on behavior in males. Isolation of females was stressful by itself. Pair housing of females was not able to prevent stress-induced behavioral changes completely, but appeared to reduce the effects of chronic stress.     

Compensatory gastroprotective role of glucocorticoid hormones

Prostaglandings (PGs), nitric oxide (NO) and capsaicin-sensitive afferent neurons play a pivotal role in the defensive mechanisms against gastric mucosal injury. Glucocorticoid hormones released in response to ulcerogenic stimuli are naturally occurring gastroprotective factors and exert many of the same actions in the stomach as PGs, NO and capsaicin-sensitive afferent neurons. The results reviewed suggest that glucocorticoids exert a pivotal compensatory role in the maintenance of gastric mucosal integrity in the case of impaired gastroprotective mechanisms provided by PGs, NO and capsaicin-sensitive afferent neurons. The compensatory protective action of glucocorticoids may be provided by their maintenance of glucose homeostasis and gastric microcirculation.     

Timing of glucocorticoid administration determines severity of lipid metabolism and behavioral effects in rats

Glucocorticoids (GCs) are a group of steroid hormones secreted by the adrenal glands in circadian cycles, and the dysregulation of GC signaling has been suggested to cause metabolic syndrome. Even though prolonged GC exposure is associated with serious side effects such as metabolic syndrome and central nervous system disorders, the use of GCs in anti-inflammatory and immunosuppressive therapies has been continuously rising. Meanwhile, the exact mechanisms by which GCs can influence the lipid metabolism as well as behavior and how they are affected by time remain unknown. In this study, the effects of two different long-term GC dosing regimens on lipid metabolism and behavior were investigated. Male Wistar rats received daily administrations of the GC dexamethasone sodium phosphate (DEX, 0.5 mg/kg body weight) at either ZT0 (Dex0) or ZT12 (Dex12). After 6 weeks of treatment, DEX-treated rats, especially those treated at ZT0, had higher hepatic lipid accumulation and serum triglyceride levels and less locomotor activity than did control rats. In addition, serum levels of corticosterone, 5-hydroxy tryptamine and norepinephrine were decreased in the Dex0 group but not in the Dex12 group compared to the control group. Furthermore, quantitative real-time polymerase chain reaction analysis indicated that the chronic administration of GCs at ZT0 upregulated genes related to glycolysis and lipid synthesis and downregulated genes related to fatty acid β-oxidation in the liver more remarkably than administration at ZT12. Both DEX-treated groups displayed severely altered expression patterns of the core clock genes Bmal1 and Per2 in the liver and in fat. In addition, the expression of glutamate aspartate transporter, glial fibrillary acidic protein and glutamate transporter-1, astrocyte-related genes important for maintaining nervous system functions, was drastically decreased in the hippocampus of DEX-treated rats, especially when DEX was given at ZT0. In conclusion, our findings confirm that the severity of side effects, indicated by altered lipid metabolism and behavioral activity, depends on the timing of GC administration and is associated with the degree of glucocorticoid receptor dysfunction after dosing at disparate time points.     

Social dominance and reproductive behavior in male rhesus monkeys

Altmann's model describing the relationship of social dominance to breeding behavior in some non-human primate species has been tested using data from the Cayo Santiago rhesus colony. Although some of the model's assumptions are clearly not met by field observations, a good fit is often found for groups containing relatively few sexually mature, non-pregnant females. It is suggested that genetic change could be rapid under conditions described by this model. It is estimated that a “beneficial mutation” could spread through all the breeding males in as little as six generations regardless of group size. The speed at which an allele can spread through the group is discussed in terms of the mean length of female receptivity.     

Prenatal stress alters reproductive responses of rats in behavioral estrus and paced mating of hormone-primed rats

Adult female offspring of dams exposed to gestational stress (prenatal stress, PNS) may show altered reproductive behavior, exploration in novel environments, and/or social interactions than do their non-PNS counterparts. These behavioral differences may be more readily observed in a seminatural, paced mating paradigm, in which females have greater control of their sexual contacts, than in a standard mating situation. Adult offspring of dams exposed to restraint and lights for 45 min on Gestational Days 14-20 (PNS) were compared with those not subjected to stress (non-PNS, control condition). The motor, reproductive, and sociosexual behaviors of hormone-primed (Experiment 1) or cycling adult offspring in behavioral estrus (Experiment 2) were examined following 20 min of restraint stress under bright lights (postnatal stress). Hormone-primed PNS rats displayed less motor behavior in a novel arena than did non-PNS rats. In a standard mating test, hormone-primed PNS females tended to be more aggressive toward the male than were non-PNS rats. In a seminatural mating situation, hormone-primed PNS females showed increased avoidance behavior, such as longer latencies to the initial intromission, greater return latencies following mounts and intromissions, and more exiting subsequent to mounts and intromissions, than did non-PNS rats. PNS rats in behavioral estrus had decreased incidence and intensity of lordosis, and fewer solicitation behaviors, in both standard or paced mating situations, in which latency to and number of mounts were also increased. Thus, hormone-primed PNS rats exposed to restraint showed more avoidance behaviors in paced mating situations, while cycling PNS rats in behavioral estrus had greater disruption of reproductive responses in standard or paced mating paradigms than did non-PNS control rats.     

Thyroid hormone regulation by stress and behavioral differences in adult male rats

Thyroid hormones are essential regulators of growth, development and normal bodily function and their release is coordinated by the hypothalamic-pituitary-thyroid (HPT) axis. While the HPT axis has been established as an acutely stress-responsive neuroendocrine system, relatively little is known about the mechanisms of its stress regulation. The present study examined acute stress-induced changes in peripheral hormone levels [triiodothyronine (T3); thyroxine (T4), thyroid-stimulating hormone (TSH), reverse triiodothyronine (rT3)] and central mRNA levels of regulators of the HPT axis [thyrotropin-releasing hormone (TRH), somatostatin (SST), type II deiodinase (D2)] in response to an inescapable tail-shock, a rodent model of stress. Additionally, we examined whether individual differences in spontaneous exploratory behavior in an open field test predicted basal levels of TH or differential susceptibility to the effects of stress. The stress condition was associated with decreases in peripheral T3, T4 and TSH, but not rT3, when compared with controls. No changes were observed in TRH or SST mRNA levels, but there was a trend suggesting stress-related increases in D2 mRNA. We also found that an animal's exploratory behavior in an unfamiliar open field arena was positively related to peripheral thyroid hormone levels and predicted the magnitude of stress-induced changes.In conclusion, we found suggestive evidence for stress-induced decrease in central drive HPT axis, but the central mechanisms of its stress regulation remain to be elucidated. Additionally, we found that individual differences in animals' exploratory behavior were correlated with peripheral TH levels.     

Gonadal hormones masculinize and defeminize reproductive behaviors during puberty in the male Syrian hamster

Three experiments were conducted to test whether testicular hormones secreted during puberty masculinize and defeminize the expression of adult reproductive behavior. Experiment 1 tested the hypothesis that gonadal hormones during puberty masculinize behavioral responses to testosterone (T) in adulthood. Male hamsters were castrated either before puberty (noTduringP) or after puberty (TduringP). All males were implanted with a 2.5-mg T pellet 6 weeks following castration and tested once for masculine reproductive behavior 7 days after the onset of T replacement. TduringP males displayed significantly more mounts, intromissions, and ejaculations than noTduringP males. Experiment 2 tested the hypothesis that gonadal hormones during puberty defeminize behavioral responses to estrogen (EB) and progesterone (P). Eight weeks following castration, noTduringP and TduringP males were primed with EB and P and tested for lordosis behavior with a stud male. Behavioral responses of males were compared to that of ovariectomized (OVX) and hormone primed females. NoTduringP males and OVX females displayed significantly shorter lordosis latencies than TduringP males. Experiment 3 investigated whether prolonged T treatment or sexual experience could reverse the deficits in masculine behavior caused by the absence of T during puberty. Extending the T treatment from 7 to 17 days did not ameliorate the deficits in masculine behavior caused by absence of T during puberty. Similarly, when the level of sexual experience was increased from one to three tests, the deficits in masculine behavior persisted. These studies demonstrate that gonadal hormones during puberty further masculinize and defeminize neural circuits and behavioral responsiveness to steroid hormones in adulthood.     

Low sexual desire in women: the role of reproductive hormones

The role of reproductive hormones in mediating sexual desire in healthy women is still unclear. Elucidation was sought in this study by comparing the hormonal milieu of two groups of subjects with markedly different levels of sexual desire. Seventeen women ages 27-39 who met DSM III-R criteria for severe, persistent, and generalized loss of desire (hypoactive sexual desire disorder, HSD), but had no other current psychological or medical problem, were compared to 13 healthy, sexually active women. All subjects and spouses were interviewed extensively to determine the women's sexual desire and responsiveness. Blood samples were drawn every 3 to 4 days for one menstrual cycle and were analyzed by RIA for testosterone, SHBG, estradiol, progesterone, prolactin, and luteinizing hormone. Results indicated that the HSD women's gonadal hormones fluctuated normally over the menstrual cycle, were within normal limits for each cycle phase, and were never significantly different from those of controls. Neither testosterone, non-SHBG bound testosterone, nor prolactin differentiated between the HSD women with the most and least severe HSD parameters (e.g., frequency of fantasy, masturbation, or female-initiated coitus), nor between women with lifelong and acquired HSD. The present findings did not provide evidence that reproductive hormones are important determinants of individual differences in the sexual desire of these eugonadal women.     

Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance

Life time prevalence of major depression disorder (MDD) is higher in women compared to men especially during the period surrounding childbirth. Women suffering from MDD during pregnancy use antidepressant medications, particularly Selective Serotonin Reuptake Inhibitors (SSRI). These drugs readily cross the placental barrier and impact the developing fetal brain. The present study assessed the effects of prenatal exposure to fluoxetine (FLX), an SSRI antidepressant drug, on corticosterone and behavioral responses to stress in female mice. In young females, prenatal FLX significantly elevated corticosterone response to continuous stress. In adults, prenatal FLX augmented corticosterone response to acute stress and suppressed the response to continuous stress. Additionally, prenatal FLX significantly augmented stress-induced increase in locomotion and reduced anxiety- and depressive-like behaviors in adult, but not young mice. The dexamethasone suppression test revealed that prenatal FLX induced a state of glucocorticoid resistance in adult females, indicating that the negative feedback control of the hypothalamic-pituitary-adrenal axis response to stress was disrupted. These findings provide the first indication of altered hormonal and behavioral responses to continuous stress and suggest a role for the development of glucocorticoid resistance in these effects. According to these findings, prenatal environment may have implications for stress sensitivity and responsiveness to life challenges. Furthermore, this study may assist in understanding the limitations and precautions that should be taken in the use of SSRIs during pregnancy.     

The role of AT1 receptor-mediated reproductive function in renovascular hypertension in male rats

There is an association between hypertension and reproductive dysfunction. Angiotensin II (Ang II) is involved in the pathogenesis of hypertension and the regulation of reproduction. The present study aimed to determine whether the angiotensinergic system mediates the effects of hypertension on reproductive function in male rats subjected to a two-kidney, one-clip (2K1C) model. Sexual behavior parameters, gametogenesis and plasma concentrations of Ang II, testosterone, prolactin and corticosterone were evaluated in male rats 28days after 2K1C or sham surgery and losartan (Los) treatment (a type 1 angiotensin II (AT1) receptor antagonist) or vehicle (V) treatment. The animals were divided into Sham+V, 2K1C+V, Sham+Los and 2K1C+Los groups. The 2K1C+V group showed a hypertensive response, inhibition of sexual behavior, spermatogenesis dysfunction, and increases in plasma Ang II and prolactin. Conversely, plasma testosterone decreased, and plasma corticosterone remained constant. Losartan treatment normalized blood pressure and prevented the changes in plasma testosterone and prolactin, sexual behavior and spermatogenesis in the 2K1C+Los group. In addition, losartan treatment caused an additional increase in circulating Ang ll in both groups (Sham+Los and 2K1C+Los). Together, these results suggest that Ang ll, acting through the AT1 receptor, modulates behavioral and endocrine parameters of reproductive function during renovascular hypertension. In addition, the effects of circulating Ang II on plasma testosterone and prolactin seem to contribute to the spermatogenic and sexual dysfunctions in hypertensive rats.     

Sex hormones and stress in the human male

Six blood samples were obtained from each of a group of 33 healthy males between the ages of 19 and 31, following which radioimmunoassays were used to determine the serum concentrations of testosterone (Tser), 5 alpha-dihydrotestosterone (DHT), and estradiol (E2). In addition, the free testosterone (Tsal) was also measured using saliva samples provided by 23 of the subjects. A questionnaire of our own design was administered together with the Sixteen Personality Factor Questionnaire (16 PF-Test) at the time of the first blood sample in order to check the long-term stress loads of our subjects as well as their abilities to deal with stress. During the investigational period, subjects kept daily records of their sleeping and working hours and noted the appearance of stressful situations. Weather data for Hamburg was also included as a variable in this study. A number of significant relationships between sex hormones and stress could be ascertained; however, it should be kept in mind that the correlation coefficients are low and explain only a small percentage of the variance between the variables. The stress variables "weather condition" and the "Q4" factor of the 16 PF-Test are significantly related to E2 (intersubject correlations). For all samples of all subjects, psychic stress correlates positively with the ratio of Tsal/Tser. There is a significant positive intersubject relationship between Tsal and long-term plus concurrent somatic stress, while somatic stressors on the day preceding a blood and saliva sample (acute somatic stress) correlate positively with Tsal and Tser.     

The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats

Attempts to determine the influence of testicular hormones on learning and memory in males have yielded contradictory results. The present studies examined whether testicular hormones are important for maximal levels of spatial memory in young adult male rats. To minimize any effect of stress, we used the Object Location Task which is a spatial working memory task that does not involve food or water deprivation or aversive stimuli for motivation. In Experiment 1 sham gonadectomized male rats demonstrated robust spatial memory, but gonadectomized males showed diminished spatial memory. In Experiment 2 subcutaneous testosterone (T) capsules restored spatial memory performance in gonadectomized male rats, while rats with blank capsules demonstrated compromised spatial memory. In Experiment 3, gonadectomized male rats implanted with blank capsules again showed compromised spatial memory, while those with T, dihydrotestosterone (DHT), or estradiol (E) capsules demonstrated robust spatial memory, indicating that T's effects may be mediated by its conversion to E or to DHT. Gonadectomized male rats injected with Antide, a gonadotropin-releasing hormone receptor antagonist which lowers luteinizing hormone levels, also demonstrated spatial memory, comparable to that shown by T-, E-, or DHT-treated males. These data indicate that testicular androgens are important for maximal levels of spatial working memory in male rats, that testosterone may be converted to E and/or DHT to exert its effects, and that some of the effects of these steroid hormones may occur via negative feedback effects on LH.     

Effect of acute and chronic psychogenic stress on corticoadrenal and pituitary-thyroid hormones in male rats

The effects of acute and chronic stress on serum corticosterone and pituitary-thyroid hormones were studied in male Wistar rats. Acute noise activated both the pituitary-adrenal and pituitary-thyroid axes. Chronic noise did not modify the basal serum levels of either corticosterone or pituitary-thyroid hormones. A decreased corticosterone response to noise was observed in chronically stressed rats, but the pituitary-thyroid response was the same in control and chronically stressed rats, suggesting that the mechanisms which control the responsiveness of both axes to a repeated stimulus are dissociated.     

Effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats

Diquat toxicity causes iron-mediated oxidative stress; however, it remains unclear how diquat affects iron metabolism. Here, we examined the effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats, with particular focus on gene expression. Hepatic nonheme iron content was unchanged until 20?h after diquat treatment. Hepatic free iron levels increased markedly in the early stages following treatment and remained elevated for at least 6?h, resulting in severe hepatotoxicity, until returning to control levels at 20?h. The level of hepatic ferritin, especially the H-subunit, increased 20?h after diquat treatment due to elevated hepatic ferritin-H mRNA expression. These results indicate that early elevated levels of free iron in the liver of diquat-treated rats cause hepatotoxicity, and that this free iron is subsequently sequestered by ferritin synthesized under conditions of oxidative stress, thus limiting the pro-oxidant challenge of iron. The plasma iron concentration decreased at 6 and 20?h after diquat treatment, whereas the level of plasma interleukin-6 increased markedly at 3?h and remained high until 20?h. In the liver of diquat-treated rats, expression of hepcidin mRNA was markedly upregulated at 3 and 6?h, whereas ferroportin mRNA expression was downregulated slightly at 20?h. Transferrin receptor 1 mRNA expression was significantly upregulated at 3, 6, and 20?h. These results indicate that inhibition of iron release from iron-storage tissues, through stimulation of the interleukin-6-hepcidin-ferroportin axis, and enhanced iron uptake into hepatocytes, mediated by transferrin receptor 1, cause hypoferremia.     

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

Prenatal stress has been widely associated with a number of short- and long-term pathological outcomes. Epigenetic mechanisms are thought to partially mediate these environmental insults into the fetal physiology. One of the main targets of developmental programming is the hypothalamic-pituitary-adrenal (HPA) axis as it is the main regulator of the stress response. Accordingly, an increasing number of researchers have recently focused on the putative association between DNA methylation at the glucocorticoid receptor gene (NR3C1) and prenatal stress, among other types of psychosocial stress. The current study aims to systematically review and meta-analyze the existing evidence linking several forms of prenatal stress with DNA methylation at the region 1_F of the NR3C1 gene. The inclusion of relevant articles allowed combining empirical evidence from 977 individuals by meta-analytic techniques, whose methylation assessments showed overlap across 5 consecutive CpG sites (GRCh37/hg19 chr5:142,783,607-142,783,639). From this information, methylation levels at CpG site 36 displayed a significant correlation to prenatal stress (r = 0.14, 95% CI: 0.05–0.23, P = 0.002). This result supports the proposed association between a specific CpG site located at the NR3C1 promoter and prenatal stress. Several confounders, such as gender, methylation at other glucocorticoid-related genes, and adjustment for pharmacological treatments during pregnancy, should be taken into account in further studies.     

Protein binding glucocorticoid hormones (transcortin) during peri-and postnatal ontogenesis and pregnancy in rats]

The constants of association and the energy of interaction between transcortin and cortisol, the binding ability and other characteristics of transcortin have been studied in the embryos, sexually immature and mature young and old females, females on the 14th and 21st days of pregnancy, immature and mature males. The constant of association in all the groups amounted to ca. 10(8) and the energy of interaction ca. 10 Cal/mole. The embryos and immature rats of both sexes are characterized by relatively low levels of the binding ability of transcortin. During the sexual maturation, the level of transcortin increased--insignificantly in males and markedly in females. The level of transcortin in the latter remained almost invariable during pregnancy and senescence. By the electrophoretic and sedimentation properties transcortin was the same in different groups. The high level of transcortin during pregnancy corresponded to the high level of hormones bound by transcortin, the level of these hormones in the embryos being much lower than in the mother.     

Membrane-initiated actions of thyroid hormones on the male reproductive system

The presence of specific nuclear receptors to thyroid hormones, described in prepubertal Sertoli cells, implies the existence of an early and critical influence of these hormones on testis development. Although the mechanism of action thyroid hormones has been classically established as a genomic action regulating testis development, our research group has demonstrated that these hormones exert several effects in Sertoli cells lacking nuclear receptor activation. These findings led to the identification of non-classical thyroid hormone binding elements in the plasma membrane of testicular cells. Through binding to these sites, thyroid hormones could exert nongenomic effects, including those on ion fluxes at the plasma membrane, on signal transduction via kinase pathways, on amino acid accumulation, on modulation of extracellular nucleotide levels and on vimentin cytoskeleton. The evidence of the participation of different K(+), Ca(2+) and Cl(-) channels in the mechanism of action of thyroid hormones, characterizes the plasma membrane as an important microenvironment able to coordinate strategic signal transduction pathways in rat testis. The physiological responses of the Sertoli cells to hormones are dependent on continuous cross-talking of different signal transduction pathways. Apparently, the choice of the signaling pathways to be activated after the interaction of the hormone with cell surface binding sites is directly related to the physiological action to be accomplished. Yet, the enormous complexity of the nongenomic actions of thyroid hormones implies that different specific binding sites located on the plasma membrane or in the cytosol are believed to initiate specific cell responses.     

Neonatal inhalatory anesthetic exposure: reproductive changes in male rats

We investigated the effects of an inhalatory anesthetic (ethyl ether) during the neonatal period of brain sexual differentiation on the later fertility and sexual behavior of male rats. Animals were exposed to ethyl ether immediately after birth. At adulthood, body weight, testes wet weight, and plasma testosterone levels were not affected; however, neonatal exposure to ether showed alterations on male fertility: a decrease in the number of spermatids and spermatozoa, an increase in the transit time of cauda epididymal spermatozoa and a decrease in daily sperm production. An alteration of sexual behavior was also observed: decreased male sexual behavior and appearance of homosexual behavior when the male rats were castrated and pretreated with exogenous estrogen. Probably, the ether delayed or reduced the testosterone peak of the sexual differentiation period, altering the processes of masculinization and defeminization of the hypothalamus. Our results indicate that perinatal exposure to ethyl ether during the critical period of male brain sexual differentiation, acting as endocrine disruptors, has a long-term effect on the fertility and sexual behavior of male rats, suggesting endocrine disruption through incomplete masculinization and defeminization of the central nervous system.