Prenatal stress affects the rate of sexual maturation and attractiveness in bank voles

Field studies reveal that bank vole females' mobility and aggression increase during pregnancy. Here we investigated the reaction of pregnant females to social stress evoked by short but frequent meetings with another female at the same stage of pregnancy. The stress neither evoked pregnancy termination nor affected pregnancy duration but had a long-term effect on the reproductive activity of the offspring. Prenatal stress reduced the rate of sexual maturation of voles as estimated at the age of 20 days. Uterine weights of prenatally stressed females and testes weights of prenatally stressed males were significantly lower than in offspring born to nonstressed mothers. Olfactory signals are known to be important in the sexual preferences of bank voles. Adult prenatally stressed females were more attractive to other adult females than were nonstressed animals. For bank vole males, however, prenatal stress decreased the attractiveness of females; adult males selected nonstressed females over stressed partners, by odor. This study shows that prenatal conditions evoked by short but frequent encounters with another pregnant female lead to delayed puberty in females and males, and decrease sexual attractiveness in adult offspring. These two negative effects may significantly limit the reproduction of prenatally stressed offspring.     

Effects of pubertal timing on EEG coherence and P3 latency.

Neurodevelopmental approaches to schizophrenia emphasise the role of late brain maturational events. Abnormalities here may account for both the putative cortico-cortical underconnectivity in schizophrenia and its typical onset in late adolescence. Saugstad hypothesised that maturational rate at puberty may lead to an extension of normal maturational processes such as synaptic pruning. In extreme late maturers pruning was thought to be prolonged, leading to reduced numbers of synapses and an increased risk for schizophrenia. Here we assessed the effects of pubertal timing extremes on EEG coherence and P3 latency as putative measures of brain development in N = 37 healthy adults. During photic stimulation late maturing males showed increased left-hemispheric coherence compared with male early maturers. This was in line with earlier findings (Kaiser, J., Gruzelier, J.H., 1996. Timing of puberty and EEG coherence during photic stimulation. Int. J. Psychophysiol. 21, 135-149). As expected, P3 latency was shorter in late compared with early maturers. However, this was true only for females, whereas there was no difference in males. These results are consistent with the notion of an exaggeration of normal maturational changes in slow maturation, whereby the underlying process appears to be different for males and females.     

Post weaning high fat feeding affects rats' behavior and hypothalamic pituitary adrenal axis at the onset of puberty in a sexually dimorphic manner

Feeding adult rats with high fat (HF) diets can alter their hypothalamic pituitary adrenal (HPA) axis responsiveness. In the present study, we examined the effect of a high fat diet, applied in rats from weaning to puberty, on their behavior and HPA axis status at puberty onset. Wistar rats of both sexes were fed postweaning with two diets containing either 24% fat (high fat, HF) or 4.3% fat (normal chow) by weight. HF enhanced puberty onset in female rats, without increasing body weight gain in either sex, compared with chow-fed animals. In the forced swim test, HF males exhibited a more active behavioral response on the first day, whereas HF females a more passive response during the second day of the test, as compared with their chow-fed counterparts. In the open field test, HF females showed increased sniffing but reduced rearing, compared with chow-fed females and were less explorative than HF males in the central arena. All animals could learn and recall a water maze task though HF males spent more time in the opposite quadrant than chow-fed males during memory test. The HPA axis status of these animals was investigated under basal conditions. Pubertal fat-fed males had lighter adrenals, while females heavier ones, compared with their counterparts. In addition, plasma corticosterone levels of female rats were increased and glucocorticoid receptor levels in their hypothalamus were reduced due to fat diet, while in males no such changes were detected. We conclude that HF feeding during the prepubertal period can affect behavior and the HPA axis of rats at puberty onset, well before the appearance of the obese state, in a sexually dimorphic manner. Fat diet impacted more the female HPA axis, suggesting that their system is more sensitive to fat-induced nutritional imbalance during adolescence. Present data suggest that the fat-induced nutritional imbalance in young females may lead to neuroendocrine dysfunction that in turn may trigger the appearance of stress-related disorders during adolescence.     

Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats

In an attempt to develop an animal model to study the etiology of brain dysfunction in relation to early life experience, we tested the hypothesis that early-life stress during specific postnatal time windows affects long-term potentiation (LTP) reinforcement in adolescence. Male Wistar rat pups were stressed by separation from their dams for 24 h at postnatal day (PND) 4, 9, or 18. The animals were tested for reinforcement of LTP at adolescence (9 weeks old) by exposing them to a 2-min swim-stress. Here, we show that maternal separation during (at PND9) but not at the beginning (at PND4) or after (at PND18) the stress-hyporesponsive-period of the hypothalamic-pituitary-adrenal-axis impairs emotional LTP-reinforcement in adolescent animals. Thus, this in vivo model allows the investigation of physiological and pathophysiological emotional information processing at the cellular level in freely behaving adolescent animals.     

Early-life stress and reproductive cost: A two-hit developmental model of accelerated aging?

Two seemingly independent bodies of research suggest a two-hit model of accelerated aging, one highlighting early-life stress and the other reproduction. The first, informed by developmental models of early-life stress, highlights reduced longevity effects of early adversity on telomere erosion, whereas the second, informed by evolutionary theories of aging, highlights such effects with regard to reproductive cost (in females). The fact that both early-life adversity and reproductive effort are associated with shorter telomeres and increased oxidative stress raises the prospect, consistent with life-history theory, that these two theoretical frameworks currently informing much research are tapping into the same evolutionary-developmental process of increased senescence and reduced longevity. Here we propose a mechanistic view of a two-hit model of accelerated aging in human females through (a) early-life adversity and (b) early reproduction, via a process of telomere erosion, while highlighting mediating biological embedding mechanisms that might link these two developmental aging processes.     

Hormonal and physical markers of puberty and their relationship to adolescent-typical novelty-directed behavior

The extent to which characteristic adolescent behaviors are associated with pubertal changes or driven by more general, puberty-independent developmental alterations is largely unknown. Using physiological and hormonal markers of puberty, this experiment characterized pubertal timing across adolescence and examined the relationships among these variables and novelty-directed behaviors. Males and females were tested for response to novelty at P28, P32, P36, P40, P44, P48, and P75, and examined for balano-preputial skinfold separation and sperm presence (males) or vaginal opening (females), followed by blood collection for hormonal assessments. Despite earlier pubertal maturation in females, with maturation generally completed by P36 in females and P44 in males, novelty-directed behavior peaked at P32 and P36 in both sexes, and was unrelated to pubertal measures. These data support the suggestion that the ontogenetic peak in this behavior during adolescence is not notably puberty dependent.     

Impact of mothers’ experience and early-life stress on aggression and cognition in adult male mice

The postnatal period is important for brain development and behavioral programming. Here, we hypothesized that females’ stressful experience early in life can lead to disruption of mother–offspring interactions with their own progeny. The objective of this study was to assess the effects of mothers’ stressful experience, early-life stress, or both on the behavior of adult male mice. In this study, female mice were allowed to raise their pups either without exposure to stress (normal rearing conditions, NC) or with exposure to maternal separation (3 hr/day, maternal separation, MS). Adult F1 female mice who had experienced MS (stressed mothers, SM) or had been reared normally (undisturbed mothers, UM) were used for generating F2 offspring, which was then exposed (or not exposed) to early-life stress. We assessed anxiety-like behavior, exploratory activity, locomotor activity, aggression, and cognition in four groups of adult F2 males (UM+NC, UM+MS, SM+NC, and SM+MS). We found that SM+MS males become more aggressive if agonistic contact is long enough; these results point to a change in their social coping strategy. Moreover, these aggressive males tended to show better long-term spatial memory. Overall, our findings suggest that mothers’ early-life experience may have important implications for the adult behavior of their offspring.     

Stress during adolescence alters behavioral sensitization to amphetamine

In humans, chronic intermittent and uncontrollable stress during adolescence is viewed as a key factor for vulnerability to drug abuse and development of psychopathologies later in life. Less is known about the long-term effects of chronic stress in animals during the juvenile period. Although there is evidence of cross sensitization during prenatal period and adulthood between chronic stress and amphetamine-induced behavioral sensitization in the rat, no studies have been conducted on cross sensitization between chronic variable stress in adolescence and behavioral sensitization to amphetamine. To address this question, at the onset of adolescence (28 days) male rats were subjected to 28 days of intermittent non-habituating social stress (isolation, novel environment, crowding, litter-shifting, subordination), or physical stress (restraint, swim, cold, ether, noise), or were handled as controls. Twenty-four hours after the last stressor or handling, all groups were exposed to a novel environment for 1 h, after which they underwent a regimen of behavioral sensitization to amphetamine. Our results showed that socially stressed rats have low locomotor activity in the novel environment, when compared to the control and physical groups who were identical in the same test. Even though socially stressed rats had lower locomotor activity in response to amphetamine injections, there were no significant differences during the training phase between the three groups at this dose of amphetamine. However, when tested for behavioral sensitization to amphetamine control and physically stressed rats showed a robust sensitization, socially stressed rats were significantly inhibited. We conclude that our chronic variable social stress protocol during adolescence inhibits behavioral sensitization to amphetamine during adulthood.     

Maternal separation results in early emergence of adult-like fear and extinction learning in infant rats

Recent studies in rats have shown that extinction occurring early in life is resistant to relapse and may represent the erasure of fear memories. In the present study we examined the effects of early life stress on extinction in the developing rat, which could have important implications for the treatment of anxiety disorders in those who have experienced early life stress. In the present study, we used maternal-separation on postnatal days (P) 2-14 as an early life stressor. On P17, maternally separated and standard-reared animals were trained to fear a noise associated with a footshock. The fear of this noise was then extinguished (through repeated nonreinforced noise presentations) on P18. Animals were tested for contextually mediated, stress-mediated, and GABA-mediated fear relapse the day after extinction. We found that young animals exposed to maternal-separation were more likely to exhibit context- and stress-mediated relapse after extinction than standard-reared animals (Experiments 1 and 2). Further, unlike standard-reared animals, maternally separated rats exhibited a return of fear when the inhibitory neurotransmitter GABA was blocked at test (Experiment 3). These effects were not the result of maternal separation increasing rats' sensitivity to footshock (Experiment 5) and may in part be related to superior long-term memory for contexts in P17 maternally separated rats (Experiment 4). Taken together, these results suggest that early life adversity may prepare young animals to respond more cautiously toward fear signals in their environment.     

Prenatal stress feminizes juvenile play patterns in male rats.

Sexually dimorphic rough-and-tumble play patterns were compared in male and female rats derived from control mothers and mothers stressed from days 14-21 of pregnancy. Animals were weaned into groups of 8 consisting of 2 males and 2 females from each treatment. Play in the home cage was recorded at 25, 28, 31, 34, 37 and 45 days of age and was most intense on day 31. The overall level of play was significantly higher in control males than in females or stressed males. Control males showed higher levels of the pinning component of rough-and-tumble play than females or stressed males. No play partner preferences were detected in any group. In adulthood, a higher percentage of stressed than control males displayed the female lordotic pattern. No deficits in ejaculatory behavior occurred in the stressed males. Since maternal stress alters patterns of plasma testosterone in male fetuses, the data suggest that the sexual differentiation of social play begins during prenatal ontogeny in the rat. The present results show that sexually dimorphic behaviors displayed before puberty are incompletely masculinized in prenatally stressed males, a finding similar to that reported for a number of adult behaviors.     

Intermittent physical stress during early- and mid-adolescence differentially alters rats' anxiety- and depression-like behaviors in adulthood

Prior work showed that exposing rats to stress from weaning through to late adolescence (PD23-51) increased anxiety- and depression-related responses in adulthood. In the current study, we tested the hypothesis that the outcome of adolescent stress depends on the specific timing of adversity in adolescence. Male and female rats were exposed to intermittent, physical stress during either early (PD22-33) or mid -(PD35-46) adolescence, and then their anxiety- and depression-related responses to acute stressors were tested in adulthood. Early adolescent stress decreased rats' open-arm exploration in the elevated plus-maze in both male and female rats. Early adolescent stress also increased the duration of time rats spent burying in the shock-probe test and the duration of time they spent immobile in the forced swim test, but these effects were only seen in males. Stress in mid-adolescence did not increase rats' anxiety-related responding in adulthood. Instead, we observed paradoxical increases in open-arm exploration and only modest increases in shock-probe burying that failed to reach significance. Mid-adolescent stress also tended to increase depression-related immobility in the swim test. Thus, the current findings underscore the importance of timing of adolescent adversity to long-term outcomes. It appears that stress in early adolescence leads to a broader range of outcomes in adulthood, at least in male rats. By contrast, stress in mid-adolescence might have more predominant effects on risk-taking behavior (indexed by increases in open-arm activity), a possibility that merits further investigation.     

Effects of maternal stress on puberty, fertility and aggressive behavior of female mice from different intrauterine positions

We examined the effects of maternal stress (bright light and heat) during the last third of pregnancy on subsequent reproductive and behavioral characteristics of female mice from different intrauterine positions. Female mice that develop in utero between two male fetuses (2M females) differ from females that develop between two female fetuses (0M females) in their serum concentrations of both testosterone and estradiol during the fetal period of sexual differentiation. After birth, 0M and 2M females differ in a wide range of reproductive characteristics. We examined the effects of maternal stress on the response to social cues regulating the timing of first vaginal estrus and the length of the first postpubertal estrous cycle when 4 0M or 4 2M females were housed together next to an adult male. Maternal stress decreased the inhibitory effect of being housed with other females in terms of the length of the first postpubertal estrous cycle, but this only occurred in 0M females. We found no effect of maternal stress or intrauterine position on the capacity to mate and remain pregnant, regardless of whether 0M or 2M females were stressed or not stressed during early pregnancy prior to implantation. While there was no effect of prior intrauterine position on interfemale aggression or behavior toward young, maternal stress did tend to reduce the likelihood that females (in diestrus) would exhibit aggression toward other females.     

Puberty in female cavies (Cavia aperea) is affected by photoperiod and social conditions

In many environments, photoperiod is a reliable predictor of ecological conditions. Such predictability generally declines towards low latitudes as the yearly cycle becomes less marked. It has been claimed that photoperiodic effects are small in cavies and guinea pigs that reproduce throughout the year. We here investigated photoperiodic influences on the onset of puberty in female cavies (Cavia aperea) and show that photoperiod exerts a major influence. Female pups kept in groups of two matured at about 47 days when born into lengthening (from 10:14 to 12.5:11.5 L:D) and 79 days when born into shortening day length (from 14.5:9.5 to 12:12 L:D) and kept under identical short day conditions after weaning on day 20 of life (12.25:11.75 L:D). As shown previously, social conditions, especially the presence of an adult male, proved important modifiers of the onset of maturity in females. Differential stress cannot be responsible for the social effects on puberty as social conditions did not affect cortisol levels in young females. We conclude that photoperiod plays an important role in gearing the onset of cavy reproduction to the seasons and that specific male stimuli rather than unspecific effects of stressors accelerate female maturation.     

The sex‐shift in single disease and multimorbid asthma and rhinitis during puberty ‐ a study by MeDALL

Background

Cross‐sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex‐specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data.

Methods

In six European population‐based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero‐allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta‐analysis.

Findings

We included data from 19 013 participants from birth to age 14‐20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%‐confidence interval 0.73‐0.86) and 0.86 (0.79‐0.94), respectively (sex‐puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63‐0.81 and 0.81, 0.64‐1.02, respectively (sex‐puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female‐male‐OR 0.55, 0.46‐0.64) and a considerable shift towards a sex‐balanced prevalence after puberty onset (0.89, 0.74‐1.04); sex‐puberty interaction: P < .001.

Interpretation

The male predominance in prevalence before puberty and the “sex‐shift” towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.     

Social stress during adolescence in Wistar rats induces social anxiety in adulthood without affecting brain monoaminergic content and activity

Adolescence has been described as an important period to acquire social competences required for adult life. It has been suggested that early stress experiences could affect the development of the brain at different levels. These changes in the brain during adolescence may be related with the development of psychopathologies such as depression and social anxiety in adulthood. In the first experiment, we examined long-term effects of repeated social stress during adolescence on adult social approach-avoidance behavior. For that purpose, adolescent male Wistar rats were exposed twice at postnatal day (Pnd) 45 and Pnd48 to the resident-intruder paradigm followed by three times psychosocial threat with the same resident. Three weeks after the last psychosocial threat experience the animals were behaviorally tested in a social approach-avoidance test. Socially stressed animals spent less time in the interaction zone with an unfamiliar male adult rat. These data suggest that animals exposed to social stress during adolescence show a higher level of social anxiety in adulthood. In the second experiment, we investigated whether these long-term effects of social stress during adolescence on behavior draw a parallel with changes in brain monoamine content, biosynthesis and turnover. Using the same experimental design as in the first experiment, HPLC analysis of various brain regions showed that there were no differences in monoamine content, monoamine biosynthesis and monoamines activity in the prefrontal cortex, hippocampus, hypothalamus and striatum in adulthood. These results indicate that long-lasting changes in social behavior following social stress during adolescence are not accompanied by changes in brain monoamine content, biosynthesis and turnover.     

Social isolation in adolescence alters behaviors in the forced swim and sucrose preference tests in female but not in male rats

Social interactions in rodents are rewarding and motivating and social isolation is aversive. Accumulating evidence suggests that disruption of the social environment in adolescence has long-term effects on social interactions, on anxiety-like behavior and on stress reactivity. In previous work we showed that adolescent isolation produced increased reactivity to acute and to repeated stress in female rats, whereas lower corticosterone responses to acute stress and decreased anxiety-related behavior were noted in isolated males. These results indicate a sex specific impact on the effects of social stress in adolescence. However, little is known about whether social isolation impacts behaviors related to affect and whether it does so differently in male and female rats. The present study investigated the impact of adolescent social isolation from day 30-50 of age in male and female Sprague Dawley rats on behavior in the forced swim test at the end of adolescence and in adulthood and on behavior in the sucrose preference test in adulthood. Adult female rats that were isolated in adolescence exhibited increased climbing on the first and second day of the forced swim test and showed an increased preference for sucrose compared to adult females that were group-housed in adolescence. There were no effects in male rats. The results indicate that social isolation in adolescence produces a stable and active behavioral phenotype in adult female rats.     

Neuroendocrine mechanisms that delay and initiate puberty in higher primates

This paper highlights a series of studies using the male rhesus monkey that has led to a model for the control of the onset of puberty in higher primates. The model proposes that the timing of puberty in these species is governed by the duration of a central brake that, during juvenile development, holds in check the hypothalamic network of gonadotropin-releasing hormone (GnRH) neurons, which, in the adult, drive the pituitary-gonadal axis. The neurobiology of this hypothalamic brake, and the physiological mechanisms that time its application and removal, are incompletely understood. Nevertheless, the pubertal resurgence of pulsatile GnRH release, which terminates the juvenile phase of primate development and triggers the initiation of puberty in man and monkeys, is associated with structural and molecular remodeling of the hypothalamus. A major component of this developmental plasticity appears to involve neuropeptide Y (NPY). NPY inhibits GnRH release, and NPY gene expression in the hypothalamus is elevated during juvenile development when GnRH release is restrained. Since the changes in hypothalamic function and morphology that trigger primate puberty unfold in the absence of gonadal steroid feedback, the possibility is raised that, in addition to activating the pituitary-gonadal axis at this stage of development, they may also contribute directly to the causation of behaviors and affective states that emerge at adolescence.     

Urinary chemosignals and puberty in female house mice: effects of photoperiod and food deprivation

Urinary chemosignals from male and female house mice alter the age of puberty in females and thus influence the onset of reproductive behavior. These chemosignal phenomena have been examined with respect to a variety of factors pertaining to the social and reproductive biology of the mice. The pair of experiments reported here tested whether two non-social, environmental factors might affect the presence of the chemosignals. Alteration in the photoperiod from the normal 12 hr light/day to 6 hr light/day and restricting food intake every other day significantly altered some of the chemosignal effects on puberty for urine from singly-caged adult male and female mice, but did not change the delay of puberty produced by treatment with urine from grouped females. The results conform with a general hypothesis that the urinary chemosignals in house mice that influence puberty in young females are effective in communicating the adequacy of conditions for reproduction to conspecifics.     

Effects of thymectomy on reproductive function and behavior.

The effects of thymectomy in perinatal Long-Evans rat pups on their reproductive function in early adulthood were examined. Thymectomized females had decreased lordotic responsivity to estrogen, while thymectomized males exhibited differences in mount latency or postejaculatory interval; these results suggest a possible influence of the thymus on the normal development of the neural substrates of sexual behavior. Gonadal histology appeared unperturbed in rats of either sex. No statistical abnormalities in luteinizing hormone or testosterone levels were seen in male animals. Likewise, no disturbances were observed in the ability of females to exhibit normal positive feedback after estrogen and progesterone administration; negative feedback after unilateral ovariectomy (as judged by ovarian compensatory hypertrophy) was also normal. The timing of puberty was not statistically delayed in females, even though slowed growth rates were observed. A heightened surgical stress response, as judged by progesterone levels in experimental females, suggests that perinatal thymectomy may possibly alter the sensitivity of adults to stress.     

Impact of gender on asthma in childhood and adolescence: a GA2LEN review

A number of studies have shown gender differences in the prevalence of wheeze and asthma. The aim of this review was to examine published results on gender differences in childhood and adolescent asthma incidence and prevalence, define current concepts and to identify new research needs.
A Medline search was performed with the search words (gender OR sex) AND (child OR childhood OR adolescence) AND (asthma). Articles that reported on abscence or prescence of gender differences in asthma were included and reviewed, and cross-references were checked. Boys are consistently reported to have more prevalent wheeze and asthma than girls. In adolescence, the pattern changes and onset of wheeze is more prevalent in females than males. Asthma, after childhood, is more severe in females than in males, and is underdiagnosed and undertreated in female adolescents. Possible explanations for this switch around puberty in the gender susceptibility to develop asthma include hormonal changes and gender-specific differences in environmental exposures. This aspect needs consideration of the doctors and allergists who diagnose and treat asthmatic individuals.
In conclusion, sex hormones are likely to play an important role in the development and outcome of the allergic immune response and asthma in particular. By obtaining functional data from appropriate models, the exact underlying mechanisms can be unravelled. To examine the effect of gender-specific differences in environmental exposures and changes of asthma prevalence and severity in puberty, larger populations may need to be investigated.