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Acute Stress Persistently Enhances Estrogen Levels in the Female Rat
Abstract
Here we tested whether exposure to either tailshock or swim stress alters ovarian hormone levels, estrogen and progesterone, in females and whether the effects are persistent. Adrenal hormone levels were also measured in males and females. Estradiol levels were elevated in unstressed females during proestrus relative to females in other stages of estrous, and exposure to the stressors enhanced estradiol beyond basal levels. For females stressed during diestrus 2, estradiol levels were elevated immediately after stressor cessation and up to 24 hrs. Exposure to tailshock, but not swim-stress, transiently enhanced progesterone in females stressed during the stage of proestrus and estrus. Glucocorticoid levels were elevated in response to both stressors and were supraelevated in females under both basal and stress conditions relative to males, particularly in blood from females exposed to acute swim stress. These results indicate that exposure to a relatively acute stressful event immediately and persistently enhances serum estradiol and are discussed in the context of reports that exposure to the same stressors immediately and persistently impairs associative learning in the female rat.
... Previous studies show no changes on estradiol after a mild acute stressor such as an elevated platform even 6 h after the offset of the stressor 48 . In contrast, other studies using swim stress found increased estradiol concentrations 6 h after stress inoculation in adult females 49 . From these results, it can be concluded that the nature and intensity of the stressor may be a key factor in the regulation of circulating estradiol. ...
... Corticosterone determination was performed 30 min after receiving osanetant or vehicle since these hormones have shown to be altered after fear conditioning procedures 57 . While we chose 330 min after treatments for estradiol assessment since previous studies have shown a long-term (4-6 h) regulation of this hormone after stress 48,49 . For Fig. 2, males and females' blood was collected by tail-nick as described in the CTT section. ...
Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and its pharmacogenetic temporal inhibition impair fear memory in male mice. Surprisingly, we demonstrate here the opposite effect of Tac2 blockade on enhancing fear memory consolidation in females. Furthermore, we show that CeA-testosterone in males, CeA-estradiol in females and Akt/GSK3β/β-Catenin signaling both mediate the opposite-sex differential Tac2 pathway regulation of fear memory. The Tachykinin 2 (Tac2) pathway in the central amygdala is sufficient and necessary for modulating fear memory consolidation. The authors show that silencing Tac2 neurons in the amygdala of male mice reduces fear expression, while fear expression in female mice is increased when manipulations are made during proestrus.
... 28 LEs might increase breast cancer risk by suppressing immune function and tumor surveillance, thus causing direct and indirect mutagenesis. 12,[29][30][31] Cortisol, the main glucocorticoid in humans, impairs the ability of the immune system to identify and neutralize cancer cells. 30 Cells treated with the stress hormones cortisol, epinephrine, or norepinephrine, showed a fivefold increase in DNA damage and impaired DNA damage repair. ...
... 30 Cells treated with the stress hormones cortisol, epinephrine, or norepinephrine, showed a fivefold increase in DNA damage and impaired DNA damage repair. 29 Additionally, a rat model of LE stress showed that exposure to tail shock increased serum estradiol levels, 31 which directly and indirectly contribute to breast carcinogenesis. 32 The results from the present study support the importance of a history of personal illness, defined as "serious illness or injury of oneself" as a major stress factor increasing breast cancer risk. ...
Background:
The influence of stress on breast cancer risk remains unknown. The goal of the present study was to determine the effect of stress in the form of salient positive and negative valence life events (LEs) on primary invasive breast cancer risk. We hypothesized that salient negative LEs would increase breast cancer risk and salient positive LEs would attenuate this increased risk.
Patients and methods:
We used a case-control design with 664 cases identified through the Cancer Surveillance Program of Orange County and 203 population-based controls. Participants completed a risk factor questionnaire, which included a LE section. Fourteen salient LEs of positive or negative valence were used to quantify stress exposure. A baseline model was constructed, and odds ratios (ORs) were calculated using multivariate unconditional logistic regression.
Results:
Negative LEs were associated with increased breast cancer risk. The OR for ≥ 4 negative LEs showed a 2.81-fold increase in breast cancer risk (OR, 2.81; 95% confidence interval [CI], 1.47-5.36). A significant dose-response relationship between lifetime negative valence LEs and breast cancer risk was found. Previous personal illness increased breast cancer risk by 3.6-fold (OR, 3.60; 95% CI, 2.50-5.20). In contrast, abortion was associated with a 45% decrease in breast cancer risk (OR, 0.55; 95% CI, 0.34-0.89). Salient positive LEs did not have a significant effect on breast cancer risk. However, they seemed to buffer the adverse effect of salient negative LEs on breast cancer risk.
Conclusion:
The findings from the present study support the role of salient negative LEs in promoting breast cancer development, with a possible buffering effect of salient positive LEs.
... Differential stress responses observed between the sexes and at variable hormonal states might further depend on the nature of the stressor. Estradiol levels rapidly and pervasively increase in response to acute stressors in animal models (Shors et al., 1999); however, interactions depend on the type, duration, and frequency of the stressor in a multi-phasic manner (Rivier and Rivest, 1991). One explanation is that each stressor has a different route by which it triggers the HPA-axis. ...
... The role of estrogen during acute stress is mixed in the stress reactivity literature. There is evidence that estradiol levels rapidly and pervasively increase in response to acute stressors in animal models (Shors et al., 1999) whereby interactions depend on the type, duration, and frequency of the stressor in a multi-phasic manner (Rivier and Rivest, 1991). ...
Sex differences in biobehavioral stress responses are related to diverse pathologies. Under
conditions of chronic stress, the hypothalamic-pituitary-adrenal axis’ production of glucocorticoids
(GCs) is linked to multi-systemic ‘wear and tear’ known as allostatic load (AL). To understand
inter-individual differences in stress-related disease trajectories in humans, researchers require
perspectives that account for both biological sex and socio-cultural gender. As an example of
gender, gender-roles represent our appropriation of stereotypically masculine (e.g., competitive)
and feminine (e.g., cooperative) behaviors linked to health and well-being. In addition, sexuality is
related to diverse spectrums of gendered behaviors, identities, and orientations that are uniquely
influenced by stigma, but that have yet to be extensively assessed using stress biomarkers.
This thesis explores how sex (male/female, sex hormones) and gender (gender-roles, sexual
orientation) factors relate to GC functioning and AL in three studies conducted among healthy
adults. First, we found that adjusting for sex hormones alters diurnal and stress reactive GC profiles
that are intermittingly sex-specific. Second, we show for the first time that sexual orientation
modulates stress reactive GC dynamics. Third, we identify a sex and gender-role interaction effect
related to allostatic load indexed using 20 neuroendocrine, immune, metabolic, and cardiovascular
biomarkers. Collectively, this thesis demonstrates the utility of applying sex- and gender-based
analyses when assessing inter-individual differences in stress physiology. By moving beyond sex as
a binary variable, stress scientists are better equipped to delineate vulnerability and/or resilience to
disease pathways that are not uniformly “sex-specific”.
... Both male and female rats exposed to ISS displayed similar behavioral differences in the FST, and female rats were more resilient in the MWM. Following exposure to acute stressors (other than inescapable swim or shock), memory is facilitated in females (Conrad et al., 2004), and estrogen appears to be a contributing factor for associative learning in female rats, as learning is improved by a stress-induced elevation of estrogen (Shors et al., 1999). Similar to ISS, inescapable shock causes escape learning deficiencies for males, but not females. ...
... Contrary to shock models (Muller et al., 2011), the current results showed that females differed in time of immobility for the FST following ISS. The role of estrogen could also be a contributing factor for the FST differences in response to swim or shock stress, as estrogen levels rise to a higher degree following swim stress compared to shock -most notably during the diestrus stage (Shors et al., 1999). ...
Abstract Various animal models of depression have been used to seek a greater understanding of stress-related disorders. However, there is still a great need for novel research in this area, as many individuals suffering from depression are resistant to current treatment methods. Moreover, women gave a higher rate of depression, highlighting the need to investigate mechanisms of sex differences. Therefore, we employed a new animal model to assess symptoms of depression, known as intermittent swim stress (ISS). In this model, the animal experiences 100 trials of cold water swim stress. ISS has already been shown to cause signs of behavioral depression in males, but has yet to be assessed in females. Following ISS exposure, we looked at sex differences in the Morris water maze and forced swim test. The results indicated a spatial learning effect only in the hidden platform task between male and female controls, and stressed and control males. A consistent spatial memory effect was seen for males exposed to ISS. In the forced swim test, both sexes exposed to ISS exhibited greater immobility, and the same males and females also showed attenuated climbing and swimming, respectively. The sex differences could be due to different neural substrates for male and females. The goal of this study was to provide the first behavioral examination of sex differences following ISS exposure, so the stage of estrous cycle was not assessed for the females. This is a necessary future direction for subsequent experiments. The current paper highlights the importance of sex differences in response to stress, which may have bearing on disease mechanisms.
... Moreover, the CORT response to footshock stress was higher in proestrus females than in males [10]. In contrast, others found that both basal levels of CORT and stress-induced increases in CORT were higher in female rats than males, independent of the phases of the female cycle [11]. ...
... These findings are in line with most of the literature [e.g. 1,4,[9][10][11]41], although not all [6,9]. ...
Sex differences in stress reactivity may be one of the factors underlying the increased sensitivity for the development of psychopathologies in women. Particularly, an increased hypothalamic-pituitary-adrenal (HPA) axis reactivity in females may exacerbate stress-induced changes in neuronal plasticity and neurogenesis, which in turn may contribute to an increased sensitivity to psychopathology. The main aim of the present study was to examine male-female differences in stress-induced changes in different aspects of hippocampal neurogenesis, i.e. cell proliferation, differentiation and survival. Both sexes were exposed to a wide variety of stressors, where after differences in HPA-axis reactivity and neurogenesis were assessed. To study the role of oestradiol in potential sex differences, ovariectomized females received low or high physiological oestradiol level replacement pellets. The results show that females in general have a higher basal and stress-induced HPA-axis activity than males, with minimal differences between the two female groups. Cell proliferation in the dorsal hippocampus was significantly higher in high oestradiol females compared to low oestradiol females and males, while doublecortin (DCX) expression as a marker of cell differentiation was significantly higher in males compared to females, independent of oestradiol level. Stress exposure did not significantly influence cell proliferation or survival of new cells, but did reduce DCX expression. In conclusion, despite the male-female differences in HPA-axis activity, the effect of repeated stress exposure on hippocampal cell differentiation was not significantly different between sexes.
... Surprisingly, we found that several of the adult behavioral and electrophysiological effects of MSEW persisted. While ovariectomy in adulthood substantially lowers levels of progesterone, progesterone production via the adrenal glands remains intact and is stress sensitive, with adult stress elevating peripheral levels of progesterone 48,49,74 , an effect we replicated in our study. We further found that these differences were even greater in vHIP where stress restored progesterone to shamoperated levels in ovariectomized mice. ...
Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.
... However, following precedent from the animal literature, we also examined changes in progesterone and the estradiol/progesterone ratio. Despite correlational evidence in humans (Roney and Simmons, 2015) and experimental evidence in nonhuman animals (Galea et al., 1997;Shors et al., 1999;Thorpe et al., 2013;Xiao et al., 1998), we did not find clear evidence for changes in estradiol levels. However, consistent with findings on the effects of stress and research on mechanisms for reproductive suppression, we found changes in women's mid-tolate follicular estradiol/progesterone ratio and progesterone levels. ...
When current conditions are probabilistically less suitable for successful reproduction than future conditions, females may prevent or delay reproduction until conditions improve. Throughout human evolution, social support was likely crucial to female reproductive success. Women may thus have evolved fertility regulation systems sensitive to cues from the social environment. However, current understanding of how psychological phenomena might affect female ovarian function is limited. In this study, we examined whether cues of reduced social support—social ostracism— impact women’s hormone production. Following an in-lab group bonding task, women were randomly assigned to a social exclusion (n = 88) or social inclusion (n = 81) condition. After social exclusion, women with low background levels of social support experienced a decrease in estradiol relative to progesterone. In contrast, socially-included women with low background social support experienced an increase in estradiol relative to progesterone. Hormonal changes in both conditions occurred specifically when women were in their mid-to-late follicular phase, when baseline estradiol is high and progesterone is low. Follow-up analyses revealed that these changes were primarily driven by changes in progesterone, consistent with existing evidence for disruption of ovarian function following adrenal release of follicular-phase progesterone. Results offer support for a potential mechanism by which fecundity could respond adaptively to the loss or lack of social support.
... However, mice in proestrus and metestrus presented differences in the regulation of progesterone, testosterone, and estradiol after stress. These differences have been previously characterized for progesterone and they have shown to vary depending on the type of stressor 64 . To note, the effects of IMO over FE and weight gain in females with cycle monitorization were attenuated compared to females without cycle monitorization. ...
Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP ( ADCYAP1 )-PAC1R ( ADCYAP1R1 ) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.
... rodents (Shors et al., 1999), but literature regarding stress-induced increases in male animal models or human participants is scant. A previous study on the SABPA cohort did however find that baseline cortisol hypo-activity, was related to higher baseline estradiol levels in DefS African men . ...
Ineffective stress-coping in Africans is associated with cardiac ischemia during acute mental stress. Ischemic conditions may be worsened by stress-induced release of glial-derived S100‑calcium-binding-protein β (S100B), which is pro-apoptotic for cardiomyocytes Whether estradiol as coping regulator and cardio-protective factor will protect against pro-apoptotic effects, remains unclear. Therefore, we aimed to investigate stress-induced associations between cardiac troponin T/cTnT (cardiac ischemic marker), S100B and estradiol in a bi-ethnic cohort of defensive copers of both sexes. The target population study included African and Caucasian teachers of both sexes (n = 344; aged 20–65 years). The Stroop-color-word-conflict-test was administrated for 1 min to induce acute mental stress in the participants. A chronic stress risk phenotype score was obtained. The Coping Strategy Indicator determined habitual defensive/avoidance/seeking social support coping scores. Fasting blood samples were obtained prior to and 10 min post-Stroop-stress to assess cTnT, S100B and estradiol levels. An interaction between ethnicity, sex and defensive coping (p˂0.05) was found for acute stress-induced percentage changes in estradiol. In defensive coping African men, the Stroop-color-word-conflict-test elicited decreases in S100B and increases in estradiol. Again, in this group, S100B decreases were related to unchanged cTnT, a chronic stress risk phenotype and acute estradiol increases (p < 0.05). No associations among main markers were apparent in the African women or the Caucasian defensive copers of both sexes. In the defensive coping African men, the markers studied may play a relevant role in the brain-cardiovascular system interaction during stress exposure. Further research is needed to elaborate on potential mechanisms and to establish clinical relevance.
... However, following precedent from the animal literature, we also examined changes in progesterone and the estradiol/progesterone ratio. Despite correlational evidence in humans (Roney and Simmons, 2015) and experimental evidence in nonhuman animals (Galea et al., 1997;Shors et al., 1999;Thorpe et al., 2013;Xiao et al., 1998), we did not find clear evidence for changes in estradiol levels. However, consistent with findings on the effects of stress and research on mechanisms for reproductive suppression, we found changes in women's mid-to-late follicular estradiol/progesterone ratio and progesterone levels. ...
When current conditions are probabilistically less suitable for successful reproduction than future conditions, females may prevent or delay reproduction until conditions improve. Throughout human evolution, social support was likely crucial to female reproductive success. Women may thus have evolved fertility regulation systems sensitive to cues from the social environment. However, current understanding of how psychological phenomena might affect female ovarian function is limited. In this study, we examined whether cues of reduced social support-social ostracism-impact women's hormone production. Following an in-lab group bonding task, women were randomly assigned to a social exclusion (n = 88) or social inclusion (n = 81) condition. After social exclusion, women with low background levels of social support experienced a decrease in estradiol relative to progesterone. In contrast, socially-included women with low background social support experienced an increase in estradiol relative to progesterone. Hormonal changes in both conditions occurred specifically when women were in their mid-to-late follicular phase, when baseline estradiol is high and progesterone is low. Follow-up analyses revealed that these changes were primarily driven by changes in progesterone, consistent with existing evidence for disruption of ovarian function following adrenal release of follicular-phase progesterone. Results offer support for a potential mechanism by which fecundity could respond adaptively to the loss or lack of social support.
... While chronic stress may have a detrimental impact on reproduction, there is evidence that acute stress may induce estrus in some species. Female rats subjected to a tail-shock exhibited an increase in estrogen concentration which persisted for over 24 hours (Shors et al. 1999). Increased estrogen can initiate the follicular phase of the estrous cycle subsequently releasing a preovulatory surge of LH (Moberg 1985). ...
African elephants (Loxodonta africana) are becoming increasingly endangered due to illegal poaching and ivory trade markets. Preservation of the species is imperative to maintain fully functioning ecosystems, for future studies of social behaviour, and to allow future generations to revel in their magnificence. Conservation/game reserves, sanctuaries and zoos are attempting to make suitable captive environments that would aid successful reproduction while re-establishing wild African elephant populations. Unfortunately, there has been very little success with breeding in captivity. The objective of this review is to evaluate sexual behaviours in wild and captive populations to distinguish what features and reproductive techniques should be implements in captive environments to potentially achieve an effective and successful breeding program. The results of this review are that captive environments are limiting in many factors that impede natural behaviours that may lead to copulation and successful reproduction: group sizes and composition, age and sex of groups, and endocrinological changes due to stress. Natural environments are difficult to mimic which has led to development of reproductive technologies which may improve reproductive success. There have been some advancements in spermatozoa extension and preparation for cryopreservation and use in artificial insemination. Extenders with increased cholesterol from egg yolk have proven beneficial in maintaining sperm viability through transport and storage providing a promising outlook into the future of population restoration projects in captive environments. ii ACKNOWLEDGEMENTS
... We first established the congruence of vaginal smears and estradiol levels (Fig. 2). Stress can alter cycle-dependent hormone fluctuations and estrous cycle duration (Galea et al., 1997;Shors et al., 1999;Liu et al., 2011;Wagenmaker and Moenter, 2017; Blume et al., 2019), but we excluded effects of the stressor used here on the duration of the estrous cycle. We focused on multiple acute concurrent stresses, such as those involved in mass shootings, assault, or natural disasters, events increasingly associated with the development of memory disorders. ...
Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events including mass shootings, assault, or natural disasters, events which consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain-network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examine synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory and fluctuating physiological levels of sex hormones may contribute to this effect.
... It is important to note that the current study examined the contribution of basal sex hormones to the effects of stress on mental rotation performance. However, given that acute stress is capable of enhancing the secretion of sex hormones [15,36,37], it is conceivable that the stress-induced increase in the levels of sex hormones has contributed to the enhancement of mental rotation performance. Nevertheless, these preliminary findings point to the need for more research on the interactive role of sex hormones and HPA-A and SNS activation as it relates to the effects of stress on visuospatial abilities. ...
The possible effects of stress and neurobiological stress mechanisms on visuospatial abilities
remain largely unknown. In the current study, we examined the combined effect of sex hormones
and both the hypothalamic–pituitary–adrenal axis (HPA-A) and the sympathetic nervous system
(SNS) on stress-induced changes in visuospatial performance. A total of 107 participants completed a
mental rotation task and were subsequently exposed to either to the Trier social stress test (TSST) or
to a control condition before completing the mental rotation task again. HPA-A and SNS reactivity
of the participants were evaluated by measuring salivary alpha amylase (sAA; an SNS activation
marker) and cortisol in four saliva samples. Pre-stress levels of sex hormones (progesterone, estradiol,
and testosterone) were also measured. The TSST enhanced mental rotation performance, and this
enhancement was negatively correlated with baseline estradiol levels and positively correlated
with the level of cortisol reactivity among men. In addition, controlling for baseline levels of
testosterone, estradiol, and progesterone diminished this effect of stress. These results imply that the
stress-induced facilitation of mental rotation performance is modulated by baseline sex hormones
and provide preliminary support to the notion that a complex interaction between sex hormones and
neuroendocrine stress mechanisms mediates the influence of stress on visuospatial performance.
... The role of estrogen or its production (aromatization from testosterone) in socially aggressive/dominant animals is well documented [61], whereas, its possible role in stressed/subordinate animals has scarcely been reported. In female rats, both acute and chronic stress increase plasma estrogen levels [62,63]. Therefore, higher levels of estrogen in subordinate males could be associated with social stress rather than social status. ...
Gonadotropin-releasing hormone (GnRH) is essential for the initiation and maintenance of reproductive functions in vertebrates. To date, three distinct paralogue lineages, GnRH1, GnRH2, and GnRH3, have been identified with different functions and regulatory mechanisms. Among them, hypothalamic GnRH1 neurons are classically known as the hypophysiotropic form that is regulated by estrogen feedback. However, the mechanism of action underlying the estrogen-dependent regulation of GnRH1 has been debated, mainly due to the coexpression of low levels of estrogen receptor (ER) genes. In addition, the role of sex steroids in the modulation of GnRH2 and GnRH3 neurons has not been fully elucidated. Using single-cell real-time PCR, we revealed the expression of genes for estrogen, androgen, glucocorticoid, thyroid, and xenobiotic receptors in GnRH1, GnRH2, and GnRH3 neurons in the male Nile tilapia Oreochromis niloticus. We further quantified expression levels of estrogen receptor genes (ERα, ERβ, and ERγ) in three GnRH neuron types in male tilapia of two different social statuses (dominant and subordinate) at the single cell level. In dominant males, GnRH1 mRNA levels were positively proportional to ERγ mRNA levels, while in subordinate males, GnRH2 mRNA levels were positively proportional to ERβ mRNA levels. These results indicate that variations in the expression of nuclear receptors (and possibly steroid sensitivities) among individual GnRH cells may facilitate different physiological processes, such as the promotion of reproductive activities through GnRH1 neurons, and the inhibition of feeding and sexual behaviors through GnRH2 neurons.
... Peripheral estradiol levels are similar between males and females (Adkins-Regan et al. 1990;Prior et al. 2014) despite the peripheral source from the ovaries in females and central source in males and females (Schlinger and Arnold 1992), indicating that alternative sources, such as brain-expressed aromatase, may be involved in compensating estrogen levels in males (De Vries 2004). Peripheral steroid hormones can have dynamic concentrations in other behavioral states such as stress and aggression (Shors et al. 2009;Heimovics et al. 2016), but in zebra finches, peripheral estradiol levels remain stable in acute timeframes when birds hear song despite concurrent robust changes in estradiol levels within the brain (Remage-Healey et al. 2008). Fecal estrogen analysis indicates elevation of peripheral estradiol in females during song playback (Tchernichovski et al. 1998) over a relatively long-term (several days) timescale. ...
Neuron-derived estrogens are synthesized by aromatase and act through membrane receptors to modulate neuronal physiology. In many systems, long-lasting hormone treatments can alter sensory-evoked neuronal activation. However, the significance of acute neuroestrogen production is less understood. Both sexes of zebra finches can synthesize estrogens rapidly in the auditory cortex, yet it is unclear how this modulates neuronal cell signaling. We examined whether acute estrogen synthesis blockade attenuates auditory-induced expression of early growth response 1 (Egr-1) in the auditory cortex of both sexes. cAMP response element-binding protein phosphorylation (pCREB) induction by song stimuli and acute estrogen synthesis was also examined. We administered the aromatase inhibitor fadrozole prior to song exposure and measured Egr-1 across several auditory regions. Fadrozole attenuated Egr-1 in the auditory cortex greater in males than females. Females had greater expression and clustering of aromatase cells than males in high vocal center (HVC) shelf. Auditory-induced Egr-1 expression exhibited a large sex difference following fadrozole treatment. We did not observe changes in pCREB expression with song presentation or aromatase blockade. These findings are consistent with the hypothesis that acute neuroestrogen synthesis can drive downstream transcriptional responses in several cortical auditory regions, and that this mechanism is more prominent in males.
... Our decision to use male rats for these studies was guided by our prior work demonstrating that the adrenal glands were the primary source of stress-induced PROG in plasma (Hueston & Deak, 2014b). In contrast, females tend to show a more variable stress-induced PROG release dependent type of stressor and estrous stage (Shors, Pickett, Wood, & Paczynski, 1999). All experiments were conducted between 0730 and 1130 unless otherwise specified. ...
In response to stressor exposure, expression of the inflammatory cytokine interleukin-1β (IL-1) is increased within the paraventricular nucleus of the hypothalamus (PVN). Surgical removal of the adrenal glands (ADX) potentiated stress-induced IL-1 expression, suggesting a role for adrenal-derived hormones in constraining stress-evoked increases in IL-1. While corticosterone (CORT) is a primary factor inhibiting IL-1 expression, progesterone (PROG) is also released by the adrenal glands in male rats in response to stress and also has potent anti-inflammatory properties. This series of studies first established doses of CORT and PROG that adequately recapitulate the normal stress-induced rise, and then tested for individual and combined roles of CORT and PROG in mitigating stress-induced expression of inflammatory genes. We found that CORT injection alone attenuated ADX-induced increases in IL-1 expression and normalized the HPA axis response to stress. In general, PROG replacement had little effect on changes in HPA axis responsivity or stress-induced inflammatory measures. When CORT and PROG were co-administered, a small effect on expression of the decoy receptor, IL-1R2 was observed, suggestive of an anti-inflammatory response. Overall, these results suggest that although CORT is likely to be the primary stress-related hormone responsible for constraining cytokine expression evoked by stress, CORT and PROG may exert certain combined actions that temper stress-induced neuroinflammation.
Lay Summary: Exposure to stress promoted expression of inflammation-related genes in the PVN and BNST. This inflammation was mainly suppressed by the adrenal hormone corticosterone, whereas progesterone had a smaller role in mitigating post-stress inflammation.
... 86 Differential stress responses observed between the sexes and at specific hormonal states might further depend on the nature of the stressor. Estradiol levels rapidly and pervasively increase in response to acute stressors in animal models 87 ; however, interactions depend on the type, duration, and frequency of the stressor in a multiphasic manner. 88 One explanation is that each stressor has a different route by which it triggers the HPA axis. ...
In this selective review, emerging literature linking biological sex, sociocultural gender, and sexual orientation to stress hormone functioning and multisystemic physiological dysregulations are summarized. Beyond sex as a binary biological variable, continuums of sex hormones, gender roles, gender identity, and sexual orientation each uniquely help delineate pathways and mechanisms linked to stress-related disease trajectories. This implicates glucocorticoid functioning and allostatic load, the “wear and tear” of chronic stress in synergy with unhealthy behaviors. Clinical considerations are also discussed for the field of gender medicine.
... In addition, studies specify that stress can alter the patterns of cortisol excretion during the estrous cycle which eventually affects the hormonal profile in critical phases of the reproductive process (Liu et al., 2012). In fact, female rats show decreased levels of estradiol in response to a chronic stressor (Shors et al., 1999), and high levels of estrogens are associated with the production of male offspring (James, 2008). Maternal predatory stress during the oocyte pre-maturation phase decreases oocyte developmental potential at both pre-and post-implantation stages (Liu et al., 2012). ...
This study aimed to investigate the effect of stress during spermatogenesis and oogenesis on reproductive performance in adult rats and sex ratio in offspring. The rats were subjected to predatory stress (exposed to a cat) twice a day for 50 (male) and 15 (female) consecutive days. At the end of the stress procedure, a number of control and stressed rats were considered to examine reproductive parameters and the rest was coupled as follows: both male and female control, male stressed/female control, male control/female stressed, and both male and female stressed. After parturition, the pups were counted, weighed, and gendered. Stress significantly increased the number of female pups in each litter (P = 0.034). In parents, stress reduced sperm quality (mobility, number, and morphology), testicular parameters (SI, STET, sloughing, and detachment), and thickness of vaginal epithelium in all phases of the estrous cycle. Serum testosterone and 17-B estradiol levels decreased significantly in stressed parents. These results emphasize the suppressive influence of stress during spermatogenesis and oogenesis on the performance of the organs of the reproductive system in parents and its consequence on sex ratio in offspring. © 2018 Faculty of Health and Social Sciences, University of South Bohemia in Ceske Budejovice
... In mice, milk insulin levels are increased in dams that underwent a combination of high-fat diet and unpredictable stress (compared with either condition alone this effect appeared to be cumulative) [36]. Oestrogen levels are affected by stress in rodent models [83] and luteinizing hormone is affected by stress in beef cows [84]. Furthermore, a variety of hormones is altered in a stressdependent manner in human breast-milk (see above). ...
More than 1 billion cattle are raised annually for meat and milk production. Dairy cows are repeatedly impregnated and separated from their calves, usually within the first 24 h after birth. Here, I suggest that dairy cows undergo a procedure comparable to the ‘Maternal separation combined with unpredictable maternal stress’ paradigm (MSUS), which is used to study the non-genetic inheritance (NGI) of phenotypes in rodents. I discuss what research on dairy cows may bring to the research field of NGI. The resulting research findings are likely to have benefits to our understanding of MSUS, NGI and consumer safety.
... Premenopausal women have higher average levels of estradiol [57,58]. In a mouse model of LE stress, tail shock and forced swim tests resulted in increased estrogen levels and persistently thereafter [59]. Consequently, decreased estrogen metabolism resulting from LE stress [60] likely more substantially contributes to increased premenopausal estrogen exposure. ...
... The type of stressor is also important when evaluating sexual dimorphism, as women had greater levels of cortisol in response to a social rejection challenge, while males had higher levels of cortisol in response to an achievement stimulus (116). Stress is able to alter plasma estradiol levels (117,118) and estrogens have been shown to dampen the HPA and sympathetic nervous system response in certain studies (113,119). However, other studies report a higher female HPA response independent of circulating gonadal hormone levels, suggesting either an innate difference in HPA mechanisms of action or an early developmental difference in response to sex hormone exposure (120). ...
Consequential differences exist between the male and female immune systems’ ability to respond to pathogens, environmental insults or self-antigens, and subsequent effects on immunoregulation. In general, females when compared with their male counterparts, respond to pathogenic stimuli and vaccines more robustly, with heightened production of antibodies, pro-inflammatory cytokines, and chemokines. While the precise reasons for sex differences in immune response to different stimuli are not yet well understood, females are more resistant to infectious diseases and much more likely to develop autoimmune diseases. Intrinsic (i.e., sex hormones, sex chromosomes, etc.) and extrinsic (microbiome composition, external triggers, and immune modulators) factors appear to impact the overall outcome of immune responses between sexes. Evidence suggests that interactions between environmental contaminants [e.g., endocrine disrupting chemicals (EDCs)] and host leukocytes affect the ability of the immune system to mount a response to exogenous and endogenous insults, and/or return to normal activity following clearance of the threat. Inherently, males and females have differential immune response to external triggers. In this review, we describe how environmental chemicals, including EDCs, may have sex differential influence on the outcome of immune responses through alterations in epigenetic status (such as modulation of microRNA expression, gene methylation, or histone modification status), direct and indirect activation of the estrogen receptors to drive hormonal effects, and differential modulation of microbial sensing and composition of host microbiota. Taken together, an intriguing question develops as to how an individual’s environment directly and indirectly contributes to an altered immune response, dysregulation of autoantibody production, and influence autoimmune disease development. Few studies exist utilizing well-controlled cohorts of both sexes to explore the sex differences in response to EDC exposure and the effects on autoimmune disease development. Translational studies incorporating multiple environmental factors in animal models of autoimmune disease are necessary to determine the interrelationships that occur between potential etiopathological factors. The presence or absence of autoantibodies is not a reliable predictor of disease. Therefore, future studies should incorporate all the susceptibility/influencing factors, coupled with individual genomics, epigenomics, and proteomics, to develop a model that better predicts, diagnoses, and treats autoimmune diseases in a personalized-medicine fashion.
... Therefore, given the inhibitory effect of glucocorticoids on GLUT2 protein levels (21) and insulin secretion (22,23), a stronger inhibitory effect on insulin secretion from pancreatic islets in the presence of stress is expected in females compared with males. On the other hand, concentrations of this hormone can change in response to stress or a high-fat diet (24)(25)(26). All of the aforementioned studies indicate that estrogens play a determining role in the female response to each of these factors. ...
This study was conducted to determine whether two estrus phases (proestrus and diestrus) in female rats may influence the metabolic response to a high-fat diet and/or stress, focusing on pancreatic insulin secretion and content. Animals were divided into high-fat and normal diet groups, then each group was subdivided into stress and non-stress groups, and finally, each one of these was divided into proestrus and diestrus subgroups. At the end of high-fat diet treatment, foot-shock stress was applied to the animals. Then, blood samples were taken to measure plasma factors. Finally, the pancreas was removed for determination of glucose transporter 2 (GLUT2) protein levels and assessment of insulin content and secretion of the isolated islets. In the normal and high-fat diet groups, stress increased plasma corticosterone concentration in both phases. In both study phases, high-fat diet consumption decreased estradiol and increased leptin plasma levels. In the high-fat diet group in response to high glucose concentration, a reduction in insulin secretion was observed in the proestrus phase compared with the same phase in the normal diet group in the presence and absence of stress. Also, high-fat diet decreased the insulin content of islets in the proestrus phase compared with the normal diet. High-fat diet and/or stress caused a reduction in islet GLUT2 protein levels in both phases. In conclusion, it seems possible that high-fat diet alone or combined with foot-shock, predispose female rats to impaired insulin secretion, at least in part, by interfering with estradiol levels in the proestrus phase and decreasing pancreatic GLUT2 protein levels.
... While there have been several reports of elevated glucocorticoids influencing plasma estradiol concentrations in other female vertebrates (Clearwater and Pankhurst, 1997;Coddington and Cree, 1995;Elsey et al., 1991;Mahmoud et al., 1989;Shors et al., 1999;Woodley and Moore, 2002;Zerani et al., 1991), plasma estradiol concentrations are typically low or undetectable in unmated female red-sided garter snakes during the spring and in females collected during the autumn pre-hibernation period (Garstka et al., 1985;Uhrig et al., 2012;Whittier et al., 1987). Not surprisingly, plasma estradiol was undetectable in the majority of females in this experiment, and therefore any effects of ACTH treatment on estradiol concentrations could not be determined. ...
Like many vertebrates, hormonal responses to stress vary seasonally in red-sided garter snakes (Thamnophis sirtalis parietalis). For example, males generally exhibit reduced glucocorticoid responses to a standard stressor during the spring mating season. We asked whether variation in adrenal sensitivity to adrenocorticotropic hormone (ACTH) explains why glucocorticoid responses to capture stress vary with sex, season, and body condition in red-sided garter snakes. We measured glucocorticoids at 0, 1, and 4 hours after injection with ACTH (0.1 IU/g body mass) or vehicle in males and females during the spring mating season and fall pre-hibernation period. Because elevated glucocorticoids can influence sex steroids, we also examined androgen and estradiol responses to ACTH. ACTH treatment increased glucocorticoids in both sexes and seasons. Spring-collected males had a smaller integrated glucocorticoid response to ACTH than fall-collected males. The integrated glucocorticoid response to ACTH differed with sex during the spring, with males having a smaller glucocorticoid response than females. Although integrated glucocorticoid responses to ACTH did not vary with body condition, we observed an interaction among season, sex and body condition. In males, ACTH treatment did not alter androgens in either season, but androgens decreased during the sampling period. Similar to previous studies, plasma estradiol was low or undetectable during the spring and fall and therefore any effect of ACTH treatment on estradiol could not be determined. These data provide support for a mechanism that partly explains how the HPA axis integrates information about season, sex, and body condition: namely, variation in adrenal responsiveness to ACTH.
... Because we collected blood samples following the FST, it is possible that drug and hormone interacted with stress of testing or anesthetic administration leading to an increase or different rate of recovery in estradiol concentrations in some groups. Indeed, acute stressors increase (Martinez-Mota et al., 2011;Shors et al., 1999), whereas chronic stressors decrease estradiol concentrations in nulliparae (Galea et al., 1997). In pregnant rats and mice, however, chronic stress increased estradiol concentrations (MacNiven et al., 1992;Misdrahi et al., 2005). ...
The postpartum confers considerable risk for developing depression. Depressed patients have elevated cortisol concentrations and impaired hypothalamic pituitary adrenal (HPA) axis negative feedback. Chronic stress or corticosterone (CORT) induces a depressive-like phenotype in rodents, including during the postpartum. The present study examined whether nulliparous and postpartum rats were differentially vulnerable to chronic high CORT and whether fluoxetine (FLX) would differentially alter the brain, behavior, and neuroendocrine function depending on reproductive experience. Nulliparous and postpartum female Sprague-Dawley rats were divided into 4 groups that received 21 d of injections of CORT or oil plus FLX or saline. CORT reduced maternal behaviors whereas FLX reversed CORT-induced decreases in maternal care. CORT increased immobility in the forced swim test (FST), but FLX did not significantly alter immobility in either nulliparous or postpartum rats. Dams spent less time immobile and had lower CORT concentrations after the FST compared with nulliparae, indicating that aspects of the postpartum period may provide resilience against a depressive-like phenotype. Both CORT and parity reduced neurogenesis (doublecortin expression) in the dentate gyrus. FLX-treated rats had lower CORT concentrations following the FST and more immature neurons, but only in the nulliparous, and not postpartum, groups. These data suggest that the postpartum may inherently protect against some deleterious effects of high CORT but also confer resistance to the neurogenic and endocrine effects of FLX. Our findings are important for understanding how females in different reproductive states respond to glucocorticoids and antidepressants.
... The role of estrogen during acute stress is mixed in the stress reactivity literature. There is evidence that estradiol levels rapidly and pervasively increase in response to acute stressors in animal models (Shors et al., 1999) whereby interactions depend on the type, duration, and frequency of the stressor in a multi-phasic manner (Rivier and Rivest, 1991). Moreover, testosterone is converted into estradiol in the brain through aromatization that exerts HPA-axis stimulation (Kudielka et al., 1998). ...
... Several studies on female rats, showed decreased [43,44], or increased plasma estradiol concentration [45] following stress exposure. Changes in plasma estradiol concentration subsequent to stress induction may be caused by the inhibitory effect of stress hormones on reproductive hormones secretion [46,47]. ...
... Acute (1 h) exposure of CF-1 mice to rats across a wire-mesh grid elevated adrenocortical corticosterone and P 4 right after exposure, and E 2 levels also rose 4 h after exposure [25]. Other acute stressors that can elevate E 2 include 20 min of swimming stress in rats [26] and lipopolysaccharide exposure in mice [27]. In other studies with pregnant animals, E 2 levels were elevated by chronic restraint stress in rats [28] and sequential exposure to various mild stressors in mice [29]. ...
... This may be explained in part in hormonal terms. It is known that exposure to acute stress (as the initial phases of the EE protocol) persistently elevates estrogen levels in female rats (Shors et al., 1999). Estrogen can exert protection against oxidative stress, either by acting as a direct antioxidant or by enhancing the expression of antioxidant enzymes (Chakraborti et al., 2007). ...
... Chronic EB5 injections produce physiological mean serum levels of estradiol of 102.2pg/ml, whereas chronic EB0.3 injections produce low physiological levels of estradiol of 23.81 pg/ml (Holmes, et al., in press). EB5 level produced levels similar to proestrus level while EB0.3 levels produced levels similar to diestrus level (Shors, Pickett, Wood, & Paczynski, 1999;Viau & Meaney, 1991). Chronic EB10 ...
... Subsequently, age related changes and higher estrogen may then account for enhancement in aged males displaying less anxiety (Luine et al, 2007). Acute stress enhances estrogen levels (Shors, Pickett, Wood & Paczynski, 1999) while levels decrease after longer periods of restraint stress (Galea, McEwen, Tanapat, Deak, Spencer & Dhabhar, 1997). Bowman, Zrull & Luine (2001) observed enhancing effects of chronic stress in female rats in the radial arm maze after a 21 day restraint stress exposure while performance degraded after a long stress exposure. ...
... However, early pregnancy can be disrupted by substantial doses of adrenocortical androgens (deCatanzaro et al., 1991;Harper, 1969) and moreover by minute amounts of exogenous estrogens, especially E 2 (deCatanzaro et al., 1991Thorpe et al., 2013). Major stressors can elevate females' endogenous E 2 in laboratory rodents (Shors et al., 1999;Thorpe et al., 2014), including during blastocyst implantation Thorpe et al., 2013). ACTH, which is released from the pituitary during stress and stimulates adrenocortical steroids, increases estrogen levels in pregnant ewes and their fetuses (Strott et al., 1974). ...
Whether from endogenous or exogenous sources, 17β-estradiol (E2) has very powerful influences over mammalian female reproductive physiology and behavior. Given its highly lipophilic nature and low molecular mass, E2 readily enters excretions and can be absorbed from exogenous sources via nasal, cutaneous, and other modes of exposure. Indeed, systemic injection of tritiated estradiol (3H-E2) into a male mouse or bat has been shown to produce significant levels of radioactivity in the reproductive tissues and brain of cohabiting female conspecifics. Bioactive E2 and other steroids are naturally found in male mouse urine and other excretions, and males actively direct their urine at proximate females. Very low doses of E2 can mimic the Bruce effect (disruption of peri-implantation pregnancy by novel males), the Vandenbergh effect (early reproductive maturation induced by novel males), and male-induced estrus and ovulation. Males’ capacities to induce the Bruce and Vandenbergh effects can both be diminished by manipulations that reduce their urinary E2. Uterine dynamics during the Bruce and Vandenbergh effects are consistent with the actions of E2. Collectively, these data demonstrate a critical role of male-sourced E2 in these major mammalian pheromonal effects.
... An inverse correlation between predator pressure and progesterone levels was found in elk (Cervus canadensis Erxleben, 1777) (Creel et al. 2007). In laboratory rodents, acute stress affects the levels of the primary sex hormone, estrogen (Shors et al. 1999); an increase of stress hormones disturbs the estrous cycle (Pollard et al. 1975). This effect, induced with predatory stress, was observed in bank voles (Koskela et al. 1996). ...
Research on mammals and birds has shown that predation may have indirect effects on prey reproduction. Some of the indirect effects may give prey an adaptive advantage. Females of several vole species respond to the presence of predators from the genus Mustela L., 1758 with suppressed breeding; this response increases females’ chances of survival. However, breeding suppression is observed only in a certain part of the female population; it is unclear whether predation risk affects the remaining females. We investigated this in a capture–mark–recapture experiment on reproductive effort of female common voles (Microtus arvalis (Pallas, 1778)) facing simulated presence of mustelid predators. We measured two parameters: the number of recruits per litter and the litter interval. Compared with control populations, the number of recruits per litter was not affected, but the litter interval was longer in females facing mustelid risk of predation. This indicates that predation risk affects females in a more complex way than originally proposed: it induces breeding suppression in some, but also influences litter frequency in others. Our result suggests that predatory stress deregulates the estrous cycle. Decreased frequency of litters can be a viable antipredatory adaptation in iteroparous organisms.
... Thus, in absence of MR, the impact of acute stress is larger with better performance in estrus and worse performance in diestrus. Whether this aggravation of the stress effect is because of altered stressinduced circulating sex steroid levels (Burgess and Handa, 1992;Shors et al., 1999) or because of dysregulation or a shift of the estrous cycle (Pollard et al., 1975;Herzog et al., 2009) remains to be investigated. ...
Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MR(CaMKCre)) and their wild type littermates (MR(flox/flox) mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MR(flox/flox) mice and neither did the acute stressor. However, the MR(CaMKCre) mutants needed significantly more time to find the exit and made more hole visit errors than the MR(flox/flox) mice, especially when in proestrus and estrus. In addition, stressed MR(CaMKCre) mice in estrus had a shorter exit latency than the control estrus MR(CaMKCre) mice. About 70% of the female MR(CaMKCre) and MR(flox/flox) mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MR(CaMKCre) mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones.
... However, throughout the estrous cycle, the ratio in plasma concentrations of gonadal hormones changes daily and we have not observed synchronization of the estrous cycle in females in our studies. Moreover, an additional complicating factor may be that stress has an effect on the plasma estradiol concentration [55,56]. Therefore, in our initial studies of gender differences in physiology and behavior after chronic stress [48,49] we have ignored individual variation in plasma sex hormone levels, enabling us to reduce the number of animals for the different experimental groups. ...
Women in the reproductive age are more vulnerable to develop affective disorders than men. This difference may attribute to anatomical differences, hormonal influences and environmental factors such as stress. However, the higher prevalence in women normalizes once menopause is established, suggesting that ovarian hormones may play an important role in the development of depression in women. Ovarian hormones such as estrogen can pass the brain-blood barrier and bind to cytoplasmatic estrogen receptor (ER)-alpha and ER-beta in different areas of the limbic system. During stress, estrogen can modulate the behavioral and neurobiological response depending on the concentrations of estrogen. In this review we present evidence for disparate effects of chronic stress on neuroplasticity and brain activity in male and female rats. Furthermore, we will demonstrate that effects of social support on coping with stress can be mimicked by social housing of rats and that this model can be used for identification of underlying neurobiological mechanisms, including behavior, phosphorylation of CREB and ERK1/2, and brain activity changes as measured with fos expression. Using cyclic administration of estrogen in ovariectomized female rats we could specifically address effects of different plasma estrogen levels and antidepressants on stress-induced neuroplasticity and activity changes. In this model we also studied effects of estrogen on recovery after chronic stress. We conclude that the female brain has a different innate strategy to handle stress than the male brain and that female animal models are necessary for studying the underlying mechanisms and options for treatment.
Rationale
Traumatic stress leads to persistent fear, which is a core feature of post-traumatic stress disorder (PTSD). Women are more likely than men to develop PTSD after trauma exposure, which suggests women are differentially sensitive to traumatic stress. However, it is unclear how this differential sensitivity manifests. Cyclical changes in vascular estrogen release could be a contributing factor where levels of vascular estrogens (and activation of estrogen receptors) at the time of traumatic stress alter the impact of traumatic stress.
Methods
To examine this, we manipulated estrogen receptors at the time of stress and observed the effect this had on fear and extinction memory (within the single prolonged stress (SPS) paradigm) in female rats. In all experiments, freezing and darting were used to measure fear and extinction memory.
Results
In Experiment 1, SPS enhanced freezing during extinction testing, and this effect was blocked by nuclear estrogen receptor antagonism prior to SPS. In Experiment 2, SPS decreased conditioned freezing during the acquisition and testing of extinction. Administration of 17β-estradiol altered freezing in control and SPS animals during the acquisition of extinction, but this treatment had no effect on freezing during the testing of extinction memory. In all experiments, darting was only observed to footshock onset during fear conditioning.
Conclusion
The results suggest multiple behaviors (or different behavioral paradigms) are needed to characterize the nature of traumatic stress effects on emotional memory in female rats and that nuclear estrogen receptor antagonism prior to SPS blocks SPS effects on emotional memory in female rats.
Anxiety and stress-related disorders are highly prevalent and are characterized by excessive fear to threatening and nonthreatening stimuli. Moreover, there is a large sex bias in vulnerability to anxiety and stress-related disorders—women make up a disproportionately larger number of affected individuals compared with men. Growing evidence suggests that an impaired ability to suppress fear in the presence of safety signals may in part contribute to the development and maintenance of many anxiety and stress-related disorders. However, the sex-dependent impact of stress on conditioned inhibition of fear remains unclear. The present study investigated sex differences in the acquisition and recall of conditioned inhibition in male and female mice with a focus on understanding how stress impacts fear suppression. In these experiments, the training context served as the “fear” cue and an explicit tone served as the “safety” cue. Here, we found a possible sex difference in the training requirements for safety learning, although this effect was not consistent across experiments. Reductions in freezing to the safety cue in female mice were also not due to alternative fear behavior expression such as darting. Next, using footshock as a stressor, we found that males were impaired in conditioned inhibition of freezing when the stress was experienced before, but not after, conditioned inhibition training. Females were unaffected by footshock stress when it was administered at either time. Extended conditioned inhibition training in males eliminated the deficit produced by footshock stress. Finally, exposing male and female mice to swim stress impaired safety learning in male mice only. Thus, we found sex × stress interactions in the learning of conditioned inhibition and sex-dependent effects of stress modality. The present study adds to the growing literature on sex differences in safety learning, which will be critical for developing sex-specific therapies for a variety of fear-related disorders that involve excessive fear and/or impaired fear inhibition.
Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic–pituitary–adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.
The effects of stress on memory performance, and the neuroendocrine mechanisms mediating such effects, are not well understood. Given the interrelationship between reproductive hormones and both the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal axis (HPA-A), we examined their combined effect on stress-induced modulation of declarative memory. Before and after exposure either to the Trier Social Stress Test (TSST) procedure or to a non-stress condition, 112 participants completed the Rey Auditory Verbal Learning Test. We analyzed participants’ HPA-A and SNS reactivity by measuring cortisol and salivary alpha-amylase (sAA, an SNS activation marker) in four saliva samples. In addition, testosterone, estradiol, and progesterone were sampled prior to the stress exposure. Exposure to the TSST attenuated memory recall after an introduction of an interference list during the declarative memory task. Importantly, controlling for testosterone, estradiol, and progesterone diminished this effect of stress, suggesting the importance of baseline reproductive hormones in stress-induced modulation of memory functions. Furthermore, a multiple regression model revealed that stress-induced declines in memory performance were negatively associated with participants’ stress-induced cortisol reactivity, but only among individuals with high testosterone levels. In addition, stress-induced declines in memory performance were negatively associated with participants’ stress-induced increases in sAA, but only in individuals with low progesterone levels. These findings suggest that the effects of stress on memory performance may be modulated by baseline reproductive hormones and provide a preliminary indication for specific modulatory interrelationships between reproductive hormones and neuroendocrine stress mechanisms in mediating the effects of stress on memory.
An unavoidable consequence of aerobic respiration is the generation of reactive oxygen species (ROS). ROS is a collective term that includes both oxygen radicals and certain oxidizing agents that are easily converted into radicals. They can be produced from both endogenous and exogenous substances. ROS play a dual role in biological systems, since they can be either harmful or beneficial to living systems. They can be considered a double-edged sword: oxygen-dependent reactions and aerobic respiration have significant advantages but overproduction of ROS, a consequence of oxygen-dependent reactions, has the potential to cause damage. Overproduction of ROS may negatively impact neonatal growth and contribute to the aetiology of many developmental disorders. During mitochondrial respiration, an inability to neutralize reactive oxygen species and free radicals leads to oxidative stress. The inner membrane of the mitochondria contains a large number of free radical scavengers including glutathione, vitamin C, and vitamin E, as well as anti-oxidant enzymes such as superoxide dismutase. The brain is particularly vulnerable to free radical attack for several reasons, including exposed to high oxygen concentrations, relatively low antioxidant protection, membranes with high levels of polyunsaturated fatty acids, and high iron and ascorbate content. The brain's high energy demand is primarily supplied by oxidative phosphorylation, the major producer of free radicals. When the level of free radicals overwhelms the cellular antioxidant defense system, a deleterious condition known as oxidative stress occurs. ROS has an intimate relationship with mitochondrial function and oxidative stress is believed to result from mitochondrial dysfunction. This review highlights the role of oxidative stress and mitochondrial dysfunction as key players in the neurodevelopmental pathophysiology. The mechanisms associating these two disease states can lead to neuronal death, neuroinflammation and impairment of energy metabolism. Biomarkers related to both aspects will be highlighted to demonstrate their importance in the early diagnosis of neurodevelopmental disorders like autism, cerebral palsy and others. Treatments trials for oxidative stress or mitochondrial dysfunction using nutritional supplements and antioxidants are reviewed in order to shed light on recent strategies for the early intervention for neurodevelopmental disorders.
Context:
Massage therapy is increasingly used to relieve physical and mental discomfort and is suggested as a safe therapeutic modality, without any significant risks or any known side effects. Although a multitude of complementary therapies, such as acupuncture, are applied in reproductive medicine, no information is available with regard to the application of massage as an adjuvant therapy in assisted-reproduction techniques (ARTs).
Objectives:
This study was intended to assess the effectiveness of a deep relaxation (andullation) therapy based on oscillating vibrations when used prior to embryo transfer (ET) in in vitro fertilization (IVF) cryo-cycles.
Design:
The research team designed a retrospective, observational study. Participants willing to undergo the massage treatment were allocated to the intervention (andullation) group.
Setting:
The study was performed at the IVF Centers Prof. Zech-Bregenz in Bregenz, Austria.
Participants:
A total of 267 IVF patients, with a mean age of 36.3 y, participated in this single-center study.
Intervention:
All patients receiving a transfer of vitrified and warmed blastocysts between January and December 2012 were included in the evaluation. Prior to ET, the andullation group received a standardized program of therapy-a 30-min, deep relaxation massage on an oscillating (vibrating) device, whereas the control group did not.
Outcome measures:
To determine efficacy, the primary outcomes that the study measured were (1) pregnancy rates (PRs), by testing urine and obtaining a positive β-human chorionic gonadotropin (β-hCG); and (2) ongoing, pregnancies (oPR), by observation of fetal heartbeat and birth rates (BR) as well as miscarriage rates. The patients' medical histories and types of infertility as well as the quality of the embryo transfers (ETs) were evaluated.
Results:
In patients using the massage therapy prior to ET, significantly higher PRs, oPRs, and BRs were observed compared with the control group-PR: 58.9% vs 41.7%, P<.05; oPR: 53.6% vs 33.2%, P<.01; and BR: 32.0% vs 20.3%, P<.05. No differences were detected among groups for patients' ages, hormonal substitution protocols, endometrium structures and buildups, quality of transferred embryos, or quality of transfers. No adverse effects were noted in the massage group.
Conclusions:
The research team's results suggested that andullation therapy prior to blastocyst transfer in a cryo-cycle improves embryo implantation, most likely due to a reduction in stress (ie, a relaxation effect on patients), a reduction in uterine contractions, and, probably, an enhancement of the blood flow in the abdominal region. These findings provide support for use of andullation as a complementary therapy for ART.
Gender related differences in stress induced neurobehavioral disorders have been reported although the mechanisms involved are not yet clear. The present study investigated the role of nitric oxide, an important biomodulator in the sex related differences in stress induced anxiety like behavior in rats. Restraint stress (RS for 1h) was used as the experimental stressor and the effects of NO modulators were assessed in the elevated plus maze (EPM) test in both male and female rats. No metabolites (NOx) and asymmetric dimethyl arginine (ADMA) were measured in brain homogenates of these rats for corroborative purposes. RS induced anxiogenesis in both male and female rats and such changes were greater in males as compared to females. The behavioral alterations were associated with enhanced levels of ADMA and reductions in levels of NOx) in brain homogenates - the effects being greater in intensity in males as compared to females. Pretreatment with NO precursor L-Arginine (500 mg/kg) reversed the RS induced behavioral and biochemical changes, while NO synthase inhibitor L-NAME (50 mg/kg), had opposite effects. Additionally, Formestane (50 mg/kg), an estrogen synthesis blocker aggravated stress induced anxiogenesis with a corresponding increase in ADMA and decrease in NOx levels in the females. To our knowledge, this is the first report indicating the involvement of ADMA, an endogenous nitric oxide synthase inhibitor in stress induced neurobehavioral changes. Furthermore, it is also evident that nitric oxide and its interactions with estrogens play a crucial modulatory role in the differential anxiogenic response to stress among males and females.
In studies of stress, it can be difficult to obtain blood rapidly enough to avoid confounding steroid measures. Noninvasive urinary steroid measures may provide an alternative insofar as they reflect systemic steroids. In Experiment 1, we profiled urinary corticosterone, progesterone, and estradiol in ovariectomized female mice following 1 h on an elevated platform. This increased urinary corticosterone for 3 h and progesterone for 4 h. In Experiment 2, blood and urine samples were obtained at 0-6 h following stressor offset. Females showed increased serum corticosterone and progesterone immediately after stressor offset. Urinary corticosterone was increased at both 0 and 2 h post-stress, while an increase in progesterone 2-6 h after stressor offset was not significant. Estradiol was not influenced by this mild stressor. In Experiment 3, mice were exposed to a more severe 1 h stressor, a rat across a wire-mesh grid. In serum, both corticosterone and progesterone were elevated immediately after stressor offset and returned to baseline within 2 h. In urine, this severe stressor elevated corticosterone immediately and 2 h after stressor offset, and in progesterone 2 h after stressor offset. Estradiol in serum was not dynamic, but it was significantly elevated in urine 4 h after stressor offset. Urinary measures generally reflected systemic measures; however, with a different time course resulting in a longer return to baseline. We suggest that the relative value of serum or urinary steroid measures in mice depends upon the experimental design, and that estradiol may only respond when the stressor is severe.
Diverse stressors can disrupt blastocyst implantation in inseminated female mammals. Stress-induced implantation failure can be mimicked by minute doses of exogenous estradiol, and some evidence indicates that it may be mitigated by exogenous progesterone. In Experiment 1, we showed that acute exposure to a rat across a wire-mesh grid caused elevation of corticosterone and progesterone. In Experiment 2, we showed that exposure of inseminated mice to rats across a grid during gestation days 1-5 was associated with avoidance of proximity to the grid and a significantly reduced number of implantation sites on gestation day 6. Rat-exposure also resulted in elevated progesterone levels in females that maintained their pregnancies, and elevated estradiol levels in females that lost their pregnancies. In Experiment 3, we investigated whether exogenous progesterone, estradiol, or a combination of both could influence implantation failure induced by rat-exposure stress. Treatment with 100ng estradiol per day on gestation days 1-5 induced a complete absence of implantation sites on gestation day 6, regardless of the presence or absence of the stressor. Administration of 500μg progesterone per day was insufficient to prevent the stress-induced pregnancy loss. However, 500μg progesterone plus 10ng estradiol per day did prevent implantation failure in rat-exposed females. These findings are consistent with the hypothesis that estradiol elevations contribute to stress-induced pregnancy loss, but show paradoxically that low doses of estradiol can act together with progesterone to mitigate stress-induced pregnancy loss.
O estresse pode alterar a sensibilidade da resposta cronotrópica às catecolaminas em vários tecidos. O objetivo deste estudo foi avaliar a sensibilidade à norepinefrina (NE) em átrios direitos de ratas submetidas ao estresse agudo por natação nas fases de estro e proestro. Ratas Wistar em estro ou proestro foram submetidas a uma sessão de 50 min de natação, após a qual foram anestesiadas e sacrifícadas. Os átrios direitos destes animais e de ratas controle foram isolados para obtenção de curvas concentração-efeito à NE antes e após o bloqueio dos sistemas de metabolização das catecolaminas (fenoxibenzamina + estradiol). Os dados foram analisados por ANOVA ou teste t de Student. Não houve diferenças de sensibilidade à NE entre as fases de estro e proestro nos tecidos isolados de animais controle (p>0,05). No proestro, a natação induziu supersensibilidade à NE (p
O objetivo do trabalho foi testar a hipótese de que a interpretação do tempo de imobilidade (desamparo aprendido ou adaptação) pode variar conforme o modelo utilizado (teste da natação forçada ou estresse por natação). Foram analisados o tempo de imobilidade (TI) e a mobilização de glicogênio de ratos submetidos à natação em dois protocolos: estresse por natação (EN) e teste da natação forçada (TNF). Também comparamos os efeitos da desipramina e diazepam. Os experimentos foram filmados para análise do TI. Os ratos, após a sessão de natação, foram sacrificados e amostras do fígado e músculos foram preparadas para quantificação do glicogênio. O TI foi menor no EN comparado ao TNF (p=0,001). As concentrações de glicogênio hepático dos grupos foram diferentes entre si (controle>EN>TNF; p<0,05). Nos músculos gastrocnêmio e sóleo, as concentrações de glicogênio foram menores no EN comparado ao controle e TNF (p<0,05). O TI do grupo tratado com desipramina e diazepam também foi mensurado. A desipramina diminuiu o TI no TNF, sem alterá-lo no EN. O diazepam aumentou o TI no EN sem alteração no TNF. Concluímos que o EN e o TNF induziram respostas fisiológicas e comportamentais distintas e representam situações diferentes para o animal.
This article is part of a Special Issue "Puberty and Adolescence". Many endocrine changes are associated with pubertal and adolescent development. One such change is the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to physical and/or psychological stressors. Recent human and non-human animal studies have shown that hormonal stress reactivity increases significantly throughout puberty and adolescence. Specifically, exposure to various stressors results in greater adrenocorticotropic hormone (ACTH) and glucocorticoid responses in peripubertal compared to adult animals. This review will focus on how stress reactivity changes throughout puberty and adolescence, as well as potential mechanisms that mediate these changes in stress responsiveness. Though the implications of these pubertal shifts in stress responsiveness are not fully understood, the significant increase in stress-related mental and physical dysfunctions during this stage of development highlights the importance of studying pubertal and adolescent maturation of HPA function and its reactivity to stress.
Stress induces a switch in learning strategies of male C57BL/6J mice from predominantly spatial to more stimulus-response learning. To study generalization of these findings over sex, we investigated female C57BL/6J mice at three phases of the estrous cycle under non stress and acute (10min) restraint stress conditions. On a circular hole board (CHB) task, about half of the naive female mice used spatial and stimulus-response strategies to solve the task. Under stress, female mice favored spatial over stimulus-response strategies, with 100% of female mice in the estrus phase. Performance expressed as latency to solve the task is only improved in stressed female mice in the estrus phase. We conclude that the use of learning strategies is influenced by sex and this difference between sexes is aggravated by acute stress.
The first clinical observation of brain–gut interactions dates back to Beaumont’s classical monograph published in 1833 that detailed alterations of gastric mucosa in relation with the mental state of his fistulous subject, Alexis St. Martin (1). Seminal reports by Cannon at the beginning of the last century brought experimental proof of the impact of emotion (fear, rage, and hunger) on gastric secretory and motor function in cats (2). However, Selye deserves much of the credit for introducing the term “stress” which he defined as “the adaptive bodily changes to any demands” (3). In his 1936 landmark publication, he identified the gut, immune systems, and endocrine systems as primary targets altered by various physical and chemical challenges (4). Since then, over 200,000 articles are listed in PubMed related to stress and cell or body responses. However, the impact of stress on visceral pain has emerged only recently, largely driven by the early clinical recognition that stressful events exacerbate or even trigger abdominal pain episodes in nearly half of patients with irritable bowel syndrome (IBS) (5) and increase pain response to colorectal distension (CRD) (6,7). Now growing clinical reports document that the manifestations of IBS symptoms, including visceral pain, are modulated by stress (8–10) and that disorders of the brain-gut axis are part of the underlying mechanisms involved in visceral hypersensitivity in IBS patients (11–13). Recently, several laboratories have developed experimental models of visceral pain that recapture some features of IBS symptoms to gain insight into the pathophysiology of this functional bowel disorder.
O estresse representa a resposta do organismo a estímulos aversivos ou a situações desconhecidas, cuja finalidade é a adaptação do indivíduo à nova condição. O agente estressante pode ser físico, químico, emocional e social. Diferentes estressores estão presentes no cotidiano dos seres humanos e podem favorecer o desenvolvimento de doenças degenerativas e acelerar o processo de envelhecimento, afetando o funcionamento de todo o organismo. Os principais mediadores da reação de estresse são as catecolaminas (norepinefrina e a epinefrina) liberadas pelo sistema nervoso simpático e pela medula da glândula supra-renal, e os glicocorticóides liberados pelo córtex da supra-renal. As catecolaminas e os glicocorticóides iniciam eventos celulares que promovem mudanças adaptativas em células e tecidos, com a função de proteger o organismo e garantir a sua sobrevivência. Essa resposta a agentes estressores pode ser modificada pelas características do estímulo estressor e do indivíduo. Entre estas merecem destaque a idade, o sexo e, em fêmeas, a fase do ciclo reprodutivo. As variações nos níveis dos esteróides sexuais estradiol e progesterona, características do ciclo reprodutivo, modulam a secreção de CRH, ACTH e glicocorticóides que ocorrem na reação de estresse e estão envolvidos nas diferenças de resposta entre homens e mulheres. Vários estudos demonstraram que a exposição a estímulos estressores pode induzir alterações de sensibilidade às catecolaminas no tecido cardíaco, as quais têm sido relacionadas com processos adaptativos. Estas alterações incluem mudanças na atividade dos sistemas de metabolização das catecolaminas, na afinidade ou no número dos adrenoceptores, no acoplamento entre o receptor e a proteína G e em processos enzimáticos, que medeiam etapas intracelulares após a ativação do receptor. O estudo de tais alterações pode auxiliar na compreensão das alterações cardíacas observadas na espécie humana após exposição à água e à natação.
Stress has been shown to impair subsequent learning. To determine whether stress would impair classical conditioning, rats were exposed to inescapable, low-intensity tail shock and subsequently classically conditioned under freely moving conditions with a brief periorbital shock unconditioned stimulus and a white noise conditioned stimulus. Unexpectedly stressed rats exhibited significantly more conditioned eyeblink responses and the magnitude of their individual responses was also enhanced. These results stand in contrast to the learning deficits typically observed and suggest that stress can enhance the acquisition of discrete conditioned responses.
Recent evidence has demonstrated that there are fluctuations in both the anatomy and physiology of the hippocampus across the estrous cycle of the female rat. In the present study we examined the behavioral implications of these changes by testing females on either a hippocampal or nonhippocampal version of the Morris water maze during the various phases of the estrous cycle. Males were also tested on these tasks. Although there was little variance on the nonhippocampal cue task, females in proestrus performed significantly better than those in estrus. Optimal female performance on the spatial version of the task occurred during the phase of estrus, whereas the least efficient performance occurred during proestrus. These results do not support the traditional view that hippocampal long-term potentiation is positively correlated with spatial learning.
The present study examined the proactive effects of inescapable stress on aversive Pavlovian conditioning. Stressed rats were restrained and exposed to 90 1-mA tailshocks. Twenty-four hours later, all rats were exposed to IO conditioned stimuli (CS; 350 ms of white noise at 85 dB). Rats then received either paired training in which the CS coterminated with a 100-ms, 0.7-mA periorbital shock or the same stimuli presented in an explicitly unpaired fashion. After the unpaired exposures, these rats were also exposed to paired training. Previously stressed rats exhibited persistent sensitization to the white-noise stimulus. Stressed rats exposed to unpaired stimuli, and no longer exhibiting a sensitized response, acquired the eyeblink conditioned response at a facilitated rate when these stimuli were presented in a paired fashion. These results also demonstrate that the effect of stress on classical conditioning is long-lasting, in excess of 48 hr.
Objectives:
We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers.
Design:
A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable.
Setting:
Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.
Subjects:
Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n=143) or met criteria for nondemented control status (n=92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses.
Main Outcome Measures:
Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n=10) and nonusers (n=128) for whom this information was available.
Results:
Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5).
Conclusions:
Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.
It is clear that male and female animals have distinct cognitive capacities and emotional responses. For instance, exposure to a fearful and stressful event of restraint and intermittent tail-shocks impairs instrumental learning in male rats, but has minimal consequence in female rats. Conversely, exposure to a similar stressor facilitates classical conditioning in male rats and dramatically impairs conditioning in female rats. Many such sex differences in learning and responses to stress are attributable to the effects of sex hormones on brain morphology and physiology. Indeed, the stress-induced facilitation of classical conditioning in male rats is dependent on activation of the NMDA type of glutamate receptor in the amygdala, whereas the impaired conditioning in female rats is dependent on activational influences of the ovarian hormone estrogen. The role of estrogen and progesterone in the diametrically opposed effects of stress on learning are discussed, as are neuronal mechanisms that underlie sex differences in memory formation.
: Acute swim stress (3-min swim at 32°C) in female, but not in male, mice results in substantial changes in the characteristics of GABA binding to membranes prepared from the forebrain. These changes were larger when measured in a relatively crude membrane preparation than in a well-washed membrane preparation commonly used in GABA binding assays, consistent with the loss of endogenous modulators of GABA binding in the latter preparation. These changes may be related to stress-induced alterations in part in the modulation of the characteristics of GABA binding by endogenous steroids, as the acute swim stress produced a larger increase in plasma corticosterone levels in female than in male mice.
The effects of chronic estrogen treatment on radial arm maze performance and on levels of central monoaminergic and amino acid neurotransmitters were examined in ovariectomized (Ovx) rats. In an eight arms baited paradigm, choice accuracy was enhanced following 12 days but not 3 days of treatment. In addition, performance during acquisition of the eight arms baited maze task was better in estrogen-treated Ovx rats than in Ovx rats. Performance of treated rats was also enhanced in win-shift trials conducted 12 days postestrogen treatment. Working, reference, and working-reference memory was examined when four of the eight arms were baited, and only working memory was improved by estrogen and only after long-term treatment. Activity of Ovx rats on an open field, crossings and rearings, was increased at 5 but not at 35 days following estrogen treatment. In medial prefrontal cortex, levels of NE, DA, and 5-HT were decreased but glutamate and GABA levels were not affected following chronic estrogen treatment. Basal forebrain nuclei also showed changes in monoamines following estrogen. Hippocampal subfields showed no effects of estrogen treatment on monoaminergic or amino acid transmitters. Levels of GABA were increased in the vertical diagonal bands following chronic estrogen. Results show that estrogen enhances learning/memory on a task utilizing spatial memory. Effects in Ovx rats appear to require the chronic (several days) presence of estrogen. Changes in activity of both monoaminergic and amino acid transmitters in the frontal cortex and basal forebrain may contribute to enhancing effects of estrogen on learning/memory.
Exposure to restraint and brief intermittent tailshocks facilitates associative learning of the classical conditioned eyeblink response in male rats. Based on evidence of sex differences in learning and responses to stressful events, we investigated sexually dimorphic effects of a stressor of restraint and intermittent tailshock on classical eyeblink conditioning 24 h after stressor cessation. Our results indicate that exposure to the acute stressor had diametrically opposed effects on the rate of acquisition of the conditioned response in male vs. female rats. Exposure to the stressor facilitated acquisition of the conditioned response in males, whereas exposure to the same stressful event dramatically impaired acquisition in females. We further demonstrate that the stress-induced impairment in female conditioning is dependent on the presence of ovarian hormones. Conditioning of stressed sham-ovariectomized females was significantly impaired relative to the unstressed controls, whereas conditioning in stressed ovariectomized females was not impaired. We present additional evidence that estrogen mediates the stress-induced impairment in female acquisition. Females administered sesame oil vehicle and then stressed were significantly impaired relative to their unstressed controls, whereas females administered the estrogen antagonist tamoxifen prior to stress were not impaired. In summary, these results indicate that exposure to the same aversive event can induce opposite behavioral responses in males vs. females. These effects underscore sex differences in associative learning and emotional responding, and implicate estrogen in the underlying neuronal mechanism.
Exposure to a stressful event facilitates classical eyeblink conditioning in male rats and impairs conditioning in females. The contribution of stages of estrous to the stress-induced impairment of eyeblink conditioning was evaluated. Females in proestrus, estrus and diestrus were either exposed to an acute stressor of intermittent tailshocks or swim stress and compared to unstressed females in the three stages. Females in proestrus, when estrogen levels are high, acquired the conditioned response at a facilitated rate relative to females in other stages. However, exposure to a stressor of either intermittent tailshocks or inescapable swim stress severely impaired acquisition in females during proestrus. These results suggest that the enhancing effect of estrogen on procedural memory formation is disrupted by previous exposure to a stressful event.
To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (O'), 10 micrograms of E2 (E') 24 h before stress testing, or with E2 and 500 micrograms P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E2 and P occurring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity.
With respect to the ovarian status and the estrous cycle as expressed by the vaginal cytology, it was emphasized that there is only a rough correspondence between the vaginal stages and the days of the cycle. The 4-day cycle tends to be the most frequent, with the 5-day cycle a normal variant. Spontaneous persistent vaginal estrus (SPE), an acyclic state occurring in older adult rats, reflects the presence in the ovaries of large vesicular follicles failing to luteinize and, hence, the absence of corpora lutea once the condition becomes well established. Pseudocyclic fluctuations in the vaginal smear during SPE resemble those in ovariectomized rats treated chronically with estrogen. The age of onset of SPE varies among different rat strains, appearing as early as 5 or 6 months in the DA and CD strains, but rarely before 12 months in the O-M strain. O-M/DA hybrids were intermediate. In the DA strain there was also a marked influence of length of daily illumination on the occurrence of SPE: exposure to 10 hours or less of light per day restored cycling to rats that had already shown SPE while exposed to longer days. An hereditary influence of age was also apparent in the rapidity with which continuous illumination induced persistent estrus (LLPE). Young DA females rapidly entered LLPE within 10 days, while young O-M females remained cyclic for 5 weeks. Hybrids again were intermediate. At middle age. O-M rats became as responsive as young rats of the DA strain. Like SPE in DA rats. LLPE was reversible, for estrous cycles returned after daily exposure to light was reduced. The special sensitivity of DA rats to lighting may have been a trait acquired from outcrossing with wild gray rats in years past. Normal cycling could be restored in SPE rats by daily injection of progesterone at low dosage. The same effect followed isolated treatments with progesterone upon return of proestrus/estrus after interruption of SPE. This was the first demonstration of positive feed-back of progesterone, the first sign of its biphasic action, and an indication that progesterone facilitates the action of estrogen in promoting ovulation. When progesterone treatment was delayed after proestrus/estrus there was progressively lower effectiveness during the next 10 days. Indirect support of regular ovulatory cycles resulted from treating DA SPE rats with prolactin (PRL) daily at low doses, provided that an initial set of corpora lutea was first induced by other means.(ABSTRACT TRUNCATED AT 400 WORDS)
1. The amount of progesterone contained in both adrenal glands of a rat was similar to or larger than the amount of progesterone in the ovaries of the same rat. This was found in unstressed rats, in stressed rats and also in pregnant rats.2. After ether anaesthesia and exsanguination the adrenal progesterone content was increased by 75%; the ovarian progesterone content remained unchanged.3. In contrast, prolonged operative stress resulted in a rise in the ovarian content of progesterone and 20-dihydroprogesterone whereas the adrenal progesterone content of these rats was lower than that of unstressed rats.4. The rate at which progesterone was secreted by the adrenal glands of stressed rats was similar to the ovarian progesterone secretion rate. Rats which were kept under mild stress conditions before the experiment showed higher adrenal progesterone secretion rates.
Three potent stressors (forced running, immobilization, and footshock) were found to increase levels of cyclic AMP in the pituitaries of both female and male rats. The pituitary cyclic AMP response in females was generally similar to that observed in males. The tested stressors elevated both plasma corticosterone and prolactin and decreased plasma growth hormone. Plasma corticosterone rose more rapidly in females than in males following stress. Control growth hormone levels were higher in male rats. There was no clear cause and effect relationship between elevations of pituitary cyclic AMP and changes in plasma levels of prolactin, corticosterone, and growth hormone.
Exposure to an inescapable stressor facilitates acquisition of a classically-conditioned eyeblink response in the freely-moving rat. Here, we tested the hypothesis that the facilitation is mediated via activation of the N-methyl-D-aspartate (NMDA) type of glutamate receptor. Rats were injected with the competitive NMDA antagonist CGP-37849 (5 mg kg-1) or vehicle 2 h prior to exposure to restraint and 90, 1 mA, 1 s tail shocks. In contrast to the dramatic facilitation exhibited in stressed rats injected with the vehicle, rats whose NMDA receptors were blocked during exposure to the stressor did not exhibit any facilitation 24 h later. The antagonist alone had no effect on learning. These results demonstrate that the stress-induced facilitation of classical conditioning is dependent on NMDA receptor activation and support the hypothesis that stress is inducing a phenomenon similar in mechanism to that of long-term potentiation (LTP).
The present study examined the association between hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls. (iii) Cytosol binding assays revealed an oestradiol-induced decrease in hippocampal MR capacity. This decrease appears to be due to an effect of the steroid on MR transcription as in situ hybridisation analysis of MR mRNA showed an oestradiol-induced decrease in MR transcript in all hippocampal subfields. (iv) Treatment of oestradiol-primed animals with progesterone reversed the oestradiol-induced decrease in hippocampal MR capacity. Data from MR mRNA hybridisation in situ experiments indicate that this reversal may be due to an antagonism of the oestradiol effect on MR transcription. (v) Progesterone treatment with or without prior oestradiol-priming induced a significant decrease in the apparent binding affinity of hippocampal MR. We show that progesterone and its 11 beta-hydroxylated derivative have a high affinity for the hippocampal MR. (vi) Neither oestradiol nor progesterone affected GR binding parameters in the hippocampus. In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus.
Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability. Search accuracy on probe trials, when the platform was unavailable, was also equivalent for the male and female groups. These results contrast with previous studies of rodents at younger ages, which have reported a male advantage in spatial learning. It is suggested that the age at which rats are assessed may be an important factor, possibly reflecting a different course in the relatively protracted maturation of the hippocampus in male and female rats. The results of this investigation are also discussed with reference to studies of sex differences for spatial abilities in humans.
The present study examined the proactive effects of inescapable stress on aversive Pavlovian conditioning. Stressed rats were restrained and exposed to 90 1-mA tailshocks. Twenty-four hours later, all rats were exposed to 10 conditioned stimuli (CS; 350 ms of white noise at 85 dB). Rats then received either paired training in which the CS coterminated with a 100-ms, 0.7-mA periorbital shock or the same stimuli presented in an explicitly unpaired fashion. After the unpaired exposures, these rats were also exposed to paired training. Previously stressed rats exhibited persistent sensitization to the white-noise stimulus. Stressed rats exposed to unpaired stimuli, and no longer exhibiting a sensitized response, acquired the eyeblink conditioned response at a facilitated rate when these stimuli were presented in a paired fashion. These results also demonstrate that the effect of stress on classical conditioning is long-lasting, in excess of 48 hr.
Exposure to an acute stressor of restraint and intermittent tailshock facilitates acquisition of the classically conditioned eye-blink response 24 h after stressor cessation. The contribution of stressor intensity, duration, and context was determined. Male rats exposed to 90 or 30 1-mA tailshocks exhibited sensitization to an auditory cue of 86 dB and facilitated acquisition of the conditioned response, whereas rats exposed to 90 0.5-mA tailshocks or restraint alone only exhibited sensitization. Rats exposed to the 5 1.0-mA tailshocks (and 5 min of restraint) exhibited neither sensitization nor facilitated acquisition. Rats stressed in the same context 48 and 96 h earlier exhibited sensitization and facilitated acquisition relative to those stressed in a different context. Neither stressed group exposed to unpaired stimuli responded to the CS, and thus there was no pseudodconditioning. Together, these results dissociate the stress-induced sensitization from the facilitated learning. They also indicate that the facilitated learning is particularly sensitive to stressor intensity and contextual cues.
Sexual dimorphism in the rat hypothalamic-pituitary-adrenal axis was investigated by determination of plasma corticosterone and immunoreactive (I-) ACTH in males and in females at each stage of the estrous cycle. A serial blood-sampling technique enabled assessment of covariation of the two hormones across the full circadian range of their concentrations within individual animals. Distinct diurnal rhythms in plasma corticosterone were evident in all rats, and the degree and timing of this rhythmicity, determined by cosinor analyses, did not vary with gender or cycle stage. There were, however, marked differences in absolute levels of corticosterone across the estrous cycle, with the average daily concentration (mesor) increasing progressively from a minimum at estrus (129 +/- 11 ng/ml) to a maximum 3 days later at proestrus (246 +/- 14 ng/ml). The mesor corticosterone value in male rats (102 +/- 21 ng/ml) was not different from that in estrous females, but was lower than that in females at all other stages of the cycle. In contrast, no gender- or cycle-related differences were detected in absolute levels of I-ACTH, although distinct diurnal rhythms, synchronous with those for corticosterone, were evident in all groups. Accordingly, a strong and positive within-rat relationship between plasma corticosterone and I-ACTH was observed in all groups, but there was a clear shift in the nature of this relationship across the estrous cycle, such that the slope (i.e. concentration of plasma corticosterone per unit concentration of I-ACTH) was minimal in males and estrous females and maximal in proestrous females. In conclusion, this study shows that the extent of sexual dimorphism in resting plasma corticosterone levels is dependent on estrous cycle stage, being absent at estrus and maximal at proestrus. Moreover, this variation in plasma corticosterone was not accompanied by corresponding changes in plasma I-ACTH, suggestive of cycle-related changes in responsiveness of the adrenal cortex to trophic stimulation.
The present study investigated the effects of 21 days of chronic restraint stress on neural and endocrine parameters in male and female rats. Consistent with previous results, repeated restraint stress induced apical dendritic atrophy (a decrease in the number of apical branch points and dendritic length) of the CA3c pyramidal neurons in male rats. In contrast, female rats did not show significant dendritic atrophy in the apical field in response to repeated restraint stress. Female rats did show a decrease in the number of branch points in the basal dendritic tree compared to male rats in response to repeated restraint stress. Baseline and stress levels of plasma corticosterone were higher in female rats compared to male rats. Females exhibited slightly longer increases in corticosterone levels throughout the 21 days of restraint stress than males, indicating that the male corticosterone response to stress exhibited greater habituation. Plasma corticosteroid-binding globulin levels of female rats were also higher than those of male rats throughout the experiment. There was no change in plasma corticosteroid-binding globulin levels in male rats during the restraint stress, while there was a decrease in plasma corticosteroid-binding globulin levels in female rats during the restraint stress. Plasma estradiol levels in female rats also decreased in response to the chronic stress. In view of the qualitatively different dendritic atrophy found in males and females in appears unlikely that sex differences in the corticosteroid-binding globulin and corticosterone response can account for these morphological differences.
Forty years ago, Lerner and coworkers (1958) discovered the first nonsteroidal antiestrogen and Jensen (Jensen and Jacobson, 1960) identified a target for drug action, the ER. This knowledge opened the door for the clinical development of tamoxifen which we now know provides a survival advantage in both node-positive and node-negative patients with ER-positive disease (Early Breast Cancer Trialists Collaborative Group, 1992, 1998). The drug has been studied extensively, and the results have provided an invaluable insight into possible ancillary advantages of "antiestrogens", i.e., maintenance of bone density and the prevention of coronary heart disease, and possible disadvantages, i.e., rat liver carcinogenesis and an increased risk of endometrial cancer. Most importantly, the identification of the target site-specific actions of tamoxifen caused a paradigm shift in the prospective uses of antiestrogens from a direct exploitation of the antitumor properties to the broader application as a preventative for osteoporosis, but with the beneficial side effects of preventing breast and endometrial cancer. Raloxifene, a second-generation SERM, has all the properties in the laboratory that would encourage development as a safe preventative for osteoporosis (Jordan et al., 1997). As a result, raloxifene has been evaluated in more than 11,000 postmenopausal women and found to maintain bone density with significant decreases in breast cancer incidence and no increase in endometrial thickness. Raloxifene is now available as a preventative for osteoporosis in postmenopausal women. There is every reason to believe that a multifaceted agent like raloxifene will find widespread use, and there will be continuing interest by the pharmaceutical industry in the development of new agents with even broader applications. The extensive clinical effort is augmented by past molecular innovations in the laboratory and the future promise of new discoveries. The cloning and sequencing of the ER (Green et al., 1986; Greene et al., 1986) has allowed the development of an ER knock-out mouse (Lubahn et al., 1993) that compliments Jensen's pioneering work (Jensen and Jacobson, 1962) and describes the consequences of the loss of ER alpha. However, ER beta (Kuiper et al., 1996), the second ER, has provided an additional dimension to the description of estrogen and antiestrogen action. For the future, the development of ER beta monoclonal antibodies, the classification of target sites for the protein around the body, and the creation of ER beta and ER alpha, beta knock-out mice will identify new therapeutic targets to modulate physiological functions. Clearly, the successful crystallization of ER alpha with raloxifene (Brzozowski et al., 1997) must act as a stimulus for the crystallization of ER beta. The central issue for research on antiestrogen pharmacology is the discovery of the mechanism (or mechanisms) of target site-specificity for the modulation of estrogenic and antiestrogenic response. The description of a stimulatory pathway for antiestrogens through an AP-1 ER beta signal transduction pathway (Paech et al., 1997), although interesting, may not entirely explain the estrogenicity of antiestrogens. The model must encompass the sum of pharmacological consequences of signal transduction through ER alpha and ER beta with the simultaneous competition from endogenous estrogens at both sites. This is complicated because estradiol is an antagonist at ER beta through AP-1 sites (Paech et al., 1997), so this is clearly not the pathway for estrogen-induced bone maintenance in women. Estrogen is stimulatory through ER alpha, but antiestrogens are usually partial agonists and may either block or stimulate genes. However, we suggest that the ER alpha stimulatory pathway could be amplified through selective increases in coactivators. The principle is illustrated with the MDA-MB-231 cells stably transfected with the cDNAs for the wild-type and the amino acid 351 mutan
Roles of glucocorticoids in the direct regulation of ovarian function are poorly understood. This opinion paper highlights: (1) the inflammatory nature of the ovulatory process; (2) the contributions of cytokines and prostaglandins (hence inflammation) to ovulation; (3) the development-related pattern of 11beta-hydroxysteroid (11beta HSD) isoform expression (hence glucocorticoid metabolism) that occurs in ovarian follicles; and (4) the attribution of general anti-inflammatory properties of glucocorticoids to their interference with prostaglandin synthesis. We interpret the evidence cited to hypothesise that corticosteroids serve an anti-inflammatory role during ovulation, thereby promoting rapid healing of the wound left by follicular rupture. Other possible levels of glucocorticoid action in the ovaries are also considered.
The association between administered estrogen and performance on verbal memory and other cognitive tasks was examined. Male-to-female transsexuals undergoing estrogen treatment for sex reassignment (n = 29) scored higher on Paired Associate Learning (PAL) compared to a similar transsexual control group, awaiting estrogen treatment (n = 30) (P < 0.05). No differences between groups receiving and not receiving estrogen were detected on a control memory task (Digit Span) or on other cognitive tasks including Mental Rotations and Controlled Associations. There were no group differences in age. Group differences in mood or in general intellectual ability also did not explain the findings. Results suggest a specific influence of estrogen in men on verbal memory tasks, similar to that seen in prior studies of women. They are discussed in terms of differential processing demands of the two memory tasks and possible differences between estrogenic influences on Mental Rotations and Controlled Associations in men versus women.
The present paper provides a review of recent research carried out in this laboratory investigating the effects of posttraining peripheral and intrahippocampal injection of estradiol on memory in rats, and estradiol-acetylcholine interactions in memory modulation. Ovariectomized rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Immediately following training, rats received a posttraining peripheral or intrahippocampal injection of estradiol-cyclodextrin complex or vehicle. Twenty-four hours later rats were returned to the maze for a retention test session, and latency to escape was used as a measure of memory for the previous day's training. Peripheral posttraining injection of estradiol enhances memory relative to vehicle-treated rats. Injections of estradiol given 2 h posttraining has no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes. A time-dependent memory enhancing effect of posttraining intrahippocampal injections of estradiol has also been observed in both male and ovariectomized female rats. The memory enhancing effect of peripheral posttraining injection of estradiol in ovariectomized rats is blocked by a subeffective dose of the acetylcholine muscarinic receptor antagonist scopolamine, suggesting that estradiol interacts with cholinergic systems in memory modulation. Concurrent peripheral posttraining injection of a subeffective dose of estradiol and a subeffective dose of the cholinergic agonist oxotremorine produces a synergistic memory enhancing effect. The findings suggest that: (1) estradiol selectively influences memory storage independent of an effect on nonmnemonic processes, (2) the hippocampus is a potential neuroanatomical site of action mediating estrogenic effects on memory, and (3) estradiol interacts with cholinergic systems in memory modulation.
Exposure to a brief, stressful event is reported to facilitate classical eyeblink conditioning in the male rat (Rattus norvegicus) by use of a delay paradigm in which the conditioned stimulus (CS) and unconditioned stimulus (US) overlap and coterminate. This study examined the effects of stress on trace conditioning, a task in which the CS and US were separated by 500 ms. Experiment 1 showed that exposure to brief (1 s), low-intensity (1 mA) tailshocks facilitated acquisition 24 hr later. Experiment 2 showed that stressor exposure did not affect retention or extinction of trace conditioning in rats that were stressed after acquisition. Experiment 3 showed that exposure to the same stressor opposed acquisition of inhibitory conditioning. These results suggest that exposure to a stressful event persistently facilitates acquisition of trace conditioning and enhances a bias toward acquiring positive versus negative associations.
Exposure to an acute stressful event facilitates classical eye-blink conditioning in the male rat. The facilitation persists for days after the stressor and its induction is prevented by antagonism of the N-methyl-D-aspartate (NMDA) type of glutamate receptor. To determine whether NMDA receptor antagonists prevent the facilitated conditioning by activity in the amygdala, a competitive antagonist, AP5, was injected bilaterally into the lateral/basolateral versus central nuclei of the amygdala. Local injection of D,L-2-amino-5-phosphonovaleric acid (AP5) into the lateral/basolateral nucleus before stressor exposure prevented the facilitated learning 24 hr later, whereas antagonism in the central nucleus before stressor exposure did not. To determine when the necessary activation occurs, AP5 was injected into the lateral/basolateral nucleus before versus after exposure to the acute stressful event. Blockade of NMDA receptors before but not after stressor exposure prevented the facilitated acquisition of the conditioning in response to stress. These results suggest that exposure to a stressful event transiently activates NMDA receptors in basolateral/lateral nuclei of the amygdala and thereby induces a persistent enhancement of associative learning.
Ether anesthesia administered as a standardized stress produced higher and more persistently elevated plasma corticosterone concentrations in female rats than in male animals. Similar effects were obtained following administration of ACTH. The biological half-life of corticosterone in female rats was found to be 13 minutes compared to 20 minutes in male animals. Female rat liver homogenates metabolized the A ring of corticosterone and that of cortisone more rapidly in vitro than did male tissue. No sex difference was observed in the rate of metabolism of the sidechain of corticosterone although male liver homogenates reduced the sidechain of cortisone more rapidly than did female tissue. The concentration of corticosterone in the adrenal vein of the female rat is 2.5 times that in the male. These findings are interpreted to signify increased sensitivity of the female adrenal gland to stimulation by ACTH. The higher plasma corticosterone levels observed after ACTH or stress in female rats are not explained by the sex differences in the rate of clearance and metabolism of the steroid. An additional possibility to be considered is that the female pituitary gland is more responsive to stress with respect to ACTH release.
Gonadectomy in male rats impaired growth but increased pituitary and adrenal weight and adrenal RNA and DNA content. Pituitary ACTH content increased also. Testosterone replacement lowered both ACTH content and adrenal weight to control levels. Estradiol administration increased pituitary ACTH without a further increment in adrenal weight. Gonadectomy and adrenalectomy together increased pituitary ACTH content compared with adrenalectomy alone. Under these conditions, testosterone replacement reduced pituitary ACTH and estradiol administration increased it further. Plasma corticosterone (Cpd. B) concentrations in castrated males at rest, after stress or after ACTH injection did not differ from those observed in intact controls. Biological half-life in vivo was shortened and hepatic inactivation of steroid in vitro was increased. Steroid production by adrenal slices in vitro was diminished by castration, and the output of steroid in adrenal venous blood also decreased. Increased steroid secretion was produ...
Spatial and nonspatial leam-ing across the rat estrous cycle Stress facilitates classical condi-tioning in males but impairs conditioning in females through activational influences of ovarian hormones
- S G Warren
- J M Juraska
- G E Wood
- T J Shors
Warren, S.G. & Juraska, J.M. (1997). Spatial and nonspatial leam-ing across the rat estrous cycle. Behavioral Neuroscience, 111, Wood, G.E. & Shors, T.J. (1998). Stress facilitates classical condi-tioning in males but impairs conditioning in females through activational influences of ovarian hormones. Proceedings of the National Academy of Sciences, 95,40664071. 259-266. Stress Downloaded from informahealthcare.com by Freie Universitaet Berlin on 11/04/14 For personal use only.
Pituitary adrenal function in the rat after gona-dectomy and gonadal hormone replacement Estra-diol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters
- J I Kitay
- Endocrinology
- V N Luine
- S T Richards
- V Y Wu
- K D &beck
Kitay, J.I. (1963). Pituitary adrenal function in the rat after gona-dectomy and gonadal hormone replacement. Endocrinology, Luine, V.N., Richards, S.T., Wu, V.Y. &Beck, K.D. (1998). Estra-diol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters. Hormones and Behavior, 34, 149-162.
- Atkinson H. C.
- Beylin A. V.
Stress and sex effects on associative learning : For better or for worse
- T J Shors
Estrogen replacement therapy in older women
- V W Henderson
- A Paganini-Hill
- C K Emaluel
- M E Dunn
- J G Buckwalter
Stages of estrous mediate the stress-induced impairment of associative learning in the female rat
- T J Shors
- C Lewczyk
- M Paczynski
- P R Mathew
- J Pickett