Effects of prenatal stress on reproduction in male and female mice

Pregnant mice were exposed to heat-restraint stress from Days 14 through 21 of gestation. Feminine receptivity quotients were significantly higher in prenatally-stressed male offspring than in unhandled males; however there were no differences in testes weights or masculine copulatory behavior. Prenatally stressed females exhibited vaginal opening at a later date, had longer estrus cycles and higher median quality receptivity scores than unhandled controls. Prenatal stress had no profound effects on pregnancy, parturition or survival of young. However there was a significantly smaller proportion of parturient postnatally stressed females compared to unhandled controls.     

Sex-specific susceptibility to cocaine in rats with a history of prenatal stress

Across species, maternal stress during prenatal life (prenatal stress [PS]) increases the expression of health complications in the developing offspring. While numerous reports indicate that male rats with a history of PS are vulnerable to psychiatric disease-like symptoms and drugs of abuse, comparable studies with females have been more limited. Here, the effects of PS in male and female rats were compared with the use of two well-validated tests of drug abuse susceptibility — the acquisition of cocaine self-administration and the expression of sensitization to the drug's psychomotor-activating properties. When a low dose (0.2 mg/kg/infusion) was available for self-administration across 15 1-hour test sessions, drug-taking behaviors were unaffected by an individual's early-life stress history. On an escalating-doses regimen (0.3-0.5 mg/kg/infusion) of self-administration, however, exposure to PS selectively facilitated the rate of acquisition and overall drug intake of males. Conversely, cocaine-induced psychomotor sensitization was augmented by PS in females, but not males. We conclude that exposure to PS enhances the reinforcing and psychomotor-sensitizing properties of cocaine male and female rats, respectively, later in life. Thus, these results suggest that gestational stress is a sex-specific risk factor for different aspects of substance abuse.     

Effects of prenatal stress on sexual partner preference in mice

Three-month old, male Swiss Webster mice were born to either control dams or dams who had been prenatally stressed with light, heat, noise and handling during the last week of gestation. As adults, male offspring were tested on sexual partner preference and sexual behavior (mounting, intromissions and lordosis) with a sexually experienced male stimulus animal and a stimulus estrous female. In comparison to males born to control dams, prenatally stressed males showed a sexual partner preference for the sexually active male as demonstrated by a negative partner preference score, more and longer visits to the male's compartment, fewer and shorter visits to the female's compartment and longer latencies to and lower frequencies of mounts and intromissions of females. In addition, stressed males showed a greater frequency of lordosis and a higher lordosis quotient than did control males. This study is the first to investigate the effects of prenatal stress alone, without hormonal manipulation, on sexual partner preference using both a partner preference paradigm and measures of sexual behavior such as mounting, intromissions and lordosis. These findings support the suggestion that prenatal stress alone is enough to significantly affect sexual partner preference in male mice.     

Effects of prenatal stress on avoidance acquisition, open-field performance and lordotic behavior in male rats.

Prenatal stress enhanced lordotic behavior potentials in male rats but did not feminize patterns of active avoidance acquisition or open-field performance. These results suggest that prenatal stress selectively feminizes some but not all behavior patterns shown to differentiate under the influence of perinatal gonadal hormones. In the rat, the critical period for the differentiation of active avoidance behavior appears to span prenatal and early neonatal ontogeny.     

Sex-dependent changes in anxiety, memory, and monoamines following one week of stress

Chronic restraint stress alters performance of rats on cognitive tasks, and anxiety measurements, and these stress-induced behavioral alterations are sexually dimorphic. Following a long stress period (21 days restraint) males show cognitive impairments while females are either not affected or enhanced on the same tasks. The current study examined whether sexually differentiated responses are also induced following shorter restraint stress durations. Male and female Sprague Dawley rats, aged 2.5 months, served as controls or received restraint stress (6 h/day, 7 days) and were tested for anxiety (plus maze), non-spatial memory (object recognition), and spatial memory (object placement). Plus maze performance was altered by sex and stress exposure. Stress impaired male object recognition but did not affect female performance. Stress did not affect male spatial memory; however, control females could not significantly discriminate between the old and new locations, but stress exposure enhanced female performance. Following behavioral testing, monoamines and metabolites were measured in prefrontal cortex (PFC), hippocampus (CA1, CA3), and amygdala. Notably, PFC and CA3 indices for noradrenergic activity (MHPG levels and MHPG/NE ratios) were increased in stress females, but decreased in males, and similar changes were found in CA1 and BLA dopaminergic indices. Thus, these sexually dimorphic neurochemical changes following stress may underlie the behavioral differences. Current results show that short-term restraint elicits sex-dependent behavioral and neural changes different from those previously reported for longer term stresses and suggest that the temporal relationship between the change from adaptive to maladaptive responses to stress is shorter in male than female rats.     

性别对L-精氨酸诱发的昆明小鼠慢性胰腺炎的影响

目的:通过比较雌雄小鼠L-精氨酸诱发的慢性胰腺炎(CP)程度的差异,探讨性别对CP模型形成的影响。方法:健康昆明小鼠雌雄各42只,分为雌性对照组、雌性CP组、雄性对照组和雄性CP组(对照组n=18,每时点6只;CP组n=24,每时点8只)。CP模型组小鼠腹腔注射20%L-精氨酸(3 g/kg,每周1次,每次2轮,间隔1 h)诱发CP。分别于造模后第2、4、6周处死动物,取小鼠胰腺组织,HE及Masson染色检测各组小鼠胰腺形态学改变及纤维化程度;免疫组织化学观察胰腺组织F4/80的阳性染色率;real-time PCR检测胰腺组织白细胞介素6(interleukin-6,IL-6)、α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)及纤维连接蛋白(fibronectin,FN)的mRNA表达;Western blot检测胰腺组织α-SMA及FN蛋白的表达。结果:20%L-精氨酸腹腔注射后的第2、4和6周,HE及Masson染色显示雌雄CP组胰腺组织均可见病理损伤,但是同一时点雌雄小鼠胰腺损伤程度存在明显差异,雄性小鼠胰腺病变程度明显较重;胰腺F4/80染色显示雄性小鼠胰腺F4/80的表达水平在造模后各时点均明显高于同一时点的雌性小鼠;造模后第2和4周胰腺IL-6的mRNA表达在雌雄CP组均有所升高,但是雄性组表达水平明显高于雌性组(P0.05)。造模后α-SMA和FN在mRNA水平和蛋白质水平均可见高表达,但雄性小鼠表达时点更早,水平更高(P0.05)。结论:采用腹腔注射20%L-精氨酸可成功复制小鼠CP模型,但复制的模型在雌雄小鼠存在病变程度差异。L-精氨酸诱导的CP模型在雄性小鼠成模更早、纤维化程度更明显,其原因可能与雄性小鼠对L-精氨酸更敏感,引发的炎症反应程度更明显有关。雄性小鼠更适合于复制CP动物模型。     

N-棕榈酰乙醇胺对慢性束缚应激小鼠焦虑抑郁样行为的影响

目的:采用慢性束缚应激小鼠模型,研究N-棕榈酰乙醇胺(N-palmitoylethanolamide,PEA)对小鼠焦虑抑郁样行为的影响,进一步探讨PEA抗小鼠焦虑抑郁作用的可能机制。方法:小鼠分为正常对照组、模型组、氟西汀(10 mg/kg)组和PEA 2.5、5、10 mg/kg组,每天灌胃给药后30 min,将小鼠(除了正常对照组)放置于有机玻璃管内接受4 h的慢性束缚应激,持续21 d。第22天采用旷场实验和强迫应激实验观察PEA对慢性束缚应激小鼠抑郁样行为的影响;高架十字迷宫实验探讨PEA对慢性束缚应激小鼠焦虑样行为的影响;水迷宫方法分析PEA对慢性束缚应激小鼠学习、记忆、空间定向和认知功能等方面的作用;ELISA方法检测慢性束缚应激小鼠血清促肾上腺皮质激素(adrenocorticotropic hormone,ACTH)、皮质醇(cortisol,CORT)及海马5-羟色胺(5-hydroxytryptamine,5-HT)含量的变化;可见分光光度法检测海马乙酰胆碱酯酶(acetylcholinesterase,ACh E)活性的改变。结果:与模型组相比,在小鼠强迫应激实验中,PEA及氟西汀组小鼠不动时间明显减少;旷场试验中,PEA及氟西汀明显增加小鼠水平移动距离及运动总时间,但只有PEA 10 mg/kg及氟西汀组增加了小鼠直立次数;在高架十字迷宫实验中,PEA及氟西汀明显增加小鼠开臂进入次数、开臂停留时间百分比及在臂总移动距离;在水迷宫实验中,PEA 5、10mg/kg及氟西汀组明显缩短小鼠寻台潜伏期,PEA 10 mg/kg及氟西汀组明显缩短小鼠搜寻距离。与应激模型组比较,PEA 2.5~10 mg/kg及氟西汀显著降低小鼠血清中ACTH水平,PEA 5、10 mg/kg及氟西汀显著降低小鼠血清CORT水平及小鼠肾上腺指数,PEA 10 mg/kg及氟西汀显著增高海马5-HT含量,降低海马ACh E活性,但PEA 2.5和5 mg/kg组海马组织中5-HT含量及ACh E活性则无明显改变。结论:PEA对束缚应激模型小鼠的焦虑及抑郁样行为具有一定的拮抗作用,其具体作用机制可能与调节下丘脑-垂体-肾上腺轴功能、增加海马单胺类递质5-HT水平及参与中枢胆碱系统的调节有关。     

产前应激对子代的影响及潜在作用机制

Inappropriate diet and stress in maternal pregnancy may affect the development of the offspring. Brain dysfunction and some chronic diseases such as obesity and diabetes in offspring are associated with the factors during maternal pregnancy. Many researches focused on how prenatal stress affected cognitive function and behavior of the offspring and how nutritional modulation might prevent the pathogenesis of such diseases. Here we summarize the effects of prenatal stress on the offspring and the potential mechanism, like hypothalamus-pituitary-adrenal axis(HPA), oxidative stress, apoptosis and inflammation, and the prevention of nutrient to offspring dysfunction by prenatal stress, based on our previous work and some existing references.     

中晚期孕期束缚应激对子代下丘脑多巴胺能神经元发育的影响

目的　研究中晚期孕期束缚应激对子代下丘脑多巴胺能神经元发育的影响。 方法　使用怀孕SD大鼠,实验组在孕期第15~21 d进行束缚应激,对照组则不受任何干扰。子代大鼠出生的当天为出生后的第0 天。在子代大鼠出生后的第1天（P1）,第7天（P7）和第30天（P30）,分别测子代大鼠的体重,通过免疫组织化学染色和Western Blotting,观察和比较下丘脑内合成多巴胺的关键酶酪氨酸羟化酶（TH）染色像素密度及TH蛋白水平变化。 结果　与正常对照组相比,中晚期孕期束缚应激子代大鼠在P1体重较低,下丘脑TH染色像素密度和TH蛋白水平上调, 这种异常在P7和P30消失。 结论　孕期应激使子代下丘脑多巴胺神经元早期发育异常, 可能是造成子代神经系统行为学异常的原因之一。     

Rat sex and strain differences in responses to stress

Sensitivity to stress has been linked to the development of a variety of physical and psychological disorders. Studies to-date have focused on extreme stress phenotypes, have studied mostly male responses, have used limited dependent variables, and have included a limited number of measurement time points. The present experiment was designed to address these limitations. Feeding, body weight, open-field activity, acoustic startle reflex (ASR), and prepulse inhibition (PPI) responses of adult male and female Sprague-Dawley and Long-Evans rats to daily immobilization stress (20 min/day) were evaluated for 3 weeks. Stress significantly decreased feeding and body weight of males but generally not of females. Effects were greatest in Long-Evans males. Stress decreased 15-min activity levels for males on Stress Day 1, but not on other days. Stress did not affect 15-min activity levels of Long-Evans females but decreased 15-min activity levels of Sprague-Dawley females on every measurement day. ASR responses to stress differed based on rat strain; percent PPI responses differed based on rat strain and sex. Stress increased startle responses of Sprague-Dawley males and females but not of Long-Evans males and females. Stress reduced PPI of Long-Evans females on every measurement day but not of other groups. These findings indicate that strain and sex of rat is important to consider in evaluating behavioral and physiological responses to stress.     

Variation in infanticide and parental behavior in male mice due to prior intrauterine proximity to female fetuses: Elimination by prenatal stress

When sexually-naive male mice are placed together with newborn young, some males will commit infanticide (kill the young) while others will behave parentally (retrieve the young to a nest and keep them warm). The intrauterine position of male mouse fetuses, which is recorded at Cesarean delivery, has previously been found to influence the titers of estradiol that male fetuses are exposed to in utero. In adulthood, most male mice that developed in utero between male fetuses (2 M males) behaved parentally toward young, while most males that developed in utero between female fetuses (0 M males) committed infanticide. When 0 M and 2 M males were castrated at birth and tested with young in adulthood, few males committed infanticide. But, when these same males were tested with young after 25 days of treatment with testosterone, more 0 M than 2 M males committed infanticide and more 2 M than 0 M males behaved parentally. In contrast to the above findings, more 2 M than 0 M males that were castrated when 28 days old behaved parentally without treatment with testosterone; few of the non-parental males committed infanticide, but, instead, ignored the young. Finally, stressing pregnant mice by placing them under bright lights during the last third of pregnancy eliminated the effect of developing next to female fetuses in the male offspring, and all prenatally-stressed males resembled 2 M males in their behavior toward young: most prenatally-stressed males were parental rather than infanticidal when tested with young. The significance of these findings to models of hormonal effects on sexual differentiation is discussed.     

Psychological prenatal stress reduced the number of BrdU immunopositive cells in the dorsal hippocampus without affecting the open field behavior of male and female rats at one month of age

We examined whether prenatal psychological stress with little physical stress causes changes in the behavior and neurogenesis of the offspring of Sprague–Dawley rats at one month. Dams in the last trimester of gestation were psychologically stressed by placing them in a social communication box and shocking a rat on the other side of a transparent wall. They suffered little physical stress. Male and female offspring from the dams showed little change in an open field test at postnatal day (PND) 30. To evaluate neurogenesis in the brain, BrdU was intraperitoneally injected at PND 35 into offspring not used in the open field test. Immunohistochemical examinations of BrdU in their dorsal hippocampus at PNDs 42 and 112 revealed that the number of BrdU immunopositive cells in the offspring of prenatally stressed rats was significantly smaller than in the offspring of unstressed ones. These results together with our previous finding that prenatal psychological stress can alter specific behaviors suggest that prenatal psychological stress can suppress neurogenesis in the dorsal hippocampus of rats of both sexes at PND 35 even though impairment in the behavioral task has not yet appeared.     

Effects of prenatal stress on stress-induced changes in behavior and macrophage activity of mice

The present study analyzed the effects of maternal stress on behavior and macrophage activity of mice. Pregnant mice received a daily footshock (0.2 mA) from gestational days 15 (GD15) to 19. Experiments were performed on male offspring, challenged or not with another footshock (0.2 mA) on postnatal day 30 (PND30) or 60. The following results were obtained for maternal stress: (1) increment in locomotor activity of juvenile but not of adult mice observed in both open-field and plus-maze; (2) increment in rearing frequency of juvenile but not of adult mice observed in the open-field; (3) decrement in macrophage spreading of adult but not of juvenile mice; (4) abolishment of postnatal footshock effects in both macrophage spreading on PND30 and macrophage nitric oxide (NO) production on PND60; (5) reversion of postnatal footshock effects on H(2)O(2) spontaneous and PMA-induced release by macrophage on PND30; (6) modification of postnatal stress effects on macrophage phagocytosis on PND60. These changes were unrelated to differences in gestational parameters and did not reflect altered maternal-pup interactions or nutritional factors. The observed data provide experimental evidence that maternal stress alters behavior, and macrophage activity at the same time and in the same litter. These data were discussed in the light of possible neuroimmune interactions that involve catecholaminergic pathways.     

RNASeq analysis reveals upregulation of complement C3 in the offspring gut following prenatal stress in mice

Dysregulated activation of inflammatory signaling by the immature neonatal immune system could lead to the development of many pediatric diseases including necrotizing enterocolitis (NEC). While the mechanism(s) of pathogenesis is unknown, NEC is believed to have multifactorial causes. Microbial dysbiosis and intestinal immaturity have been implicated as potential triggers for this disease. We hypothesized that psychological stress during pregnancy negatively impacts the development of intestinal tissues in offspring and contributes to development of NEC. Consistent with this hypothesis, we previously observed shorter villi and a decrease in total surface area in the small intestine of pups derived from mice that were chronically stressed during gestation. In this study, we performed RNASeq analysis to determine the gene expression changes in the offspring gut following prenatal stress in pregnant mice and identified several differentially expressed genes (DEGs) and biological pathways. Notably, C3 was upregulated in the small intestine and contributed to a higher tissue injury score in a mesenteric ischemia model compared to unstressed controls. We discuss the potential implications of these stress-induced genes expression changes and their contribution to development of intestinal inflammation.     

Effects of chronic postnatal drug administration on adult dominance behavior in two genera of mice

The experiments described examine the influence of early chronic treatment with amphetamine (AMPH) or chlorpromazine (CPZ) on the formation of adult dominance behavior in two genera of mice, i.e., Peromyscus maniculatus bairdi and a random bred, Swiss albino strain of Mus musculus. It was found that AMPH-pretreated Swiss albinos were significantly more dominant than either CPZ-pretreated or control animals. Early drug treatment had little effect on dominance behavior of adult bairdi. These results indicate that chronic administration of certain drugs to young animals is capable of producing a quantitative change in the formation of adult behavioral patterns. Moreover, the degree to which early drug treatment alters adult behavior is influenced by the genetic background of the organism.     

Quantitative trait loci associated with the behavioral response of B×D recombinant inbred mice to restraint stress: A preliminary communication

Quantitative trait loci (QTL) analysis was used to make provisional identification of loci containing genes influencing vulnerability to stress. The effect of restraint stress on openfield activity was measured in C57BL/6J and DBA/2J inbred strains of mice and in 22 B×D recombinant inbred strains of mice. QTL analyses were performed by correlating the behavioral delta scores for each group with the strain distribution pattern of 1300 markers for the B×D mice. A significant association was found between postrestraint rearings during min 5 through 8 in the open field and theLamb2 marker on chromosome 1 (r=.718,p<.0001). Significant associations at thep<.0001 level were also found between baseline open-field rearings of control mice during min 0 through 5 and theZp3, Ache, andMr66-1 markers on chromosome 5, baseline open-field rearings of control mice during min 5 through 8 and thePmv42 marker on chromosome 15, and open-field rearings of experimental mice during min 0 through 5 and theD11Ncvs61 marker on chromosome 11.     

C57BL/6J及NIH Swiss小鼠在抑郁模型中的行为学表现

目的 探讨两种不同遗传背景的小鼠C57BL/6J及NIH Swiss在抑郁模型中的行为学差异,为抗抑郁药物研究的实验动物选择提供参考,为研究遗传学因素在抑郁症发病过程中的作用提供有用的动物模型.方法 C57BL/6J、NIH Swiss小鼠各14只,利用强迫游泳实验和悬尾实验检测两种小鼠在应激条件下的抑郁样行为表现;利用旷场实验检测两种小鼠的自主运动能力.结果 强迫游泳实验中,C57BL/6J小鼠的不动时间明显长于NIH Swiss小鼠[(133.198±5.749)s比(80.265±10.939)s,P=0.000].悬尾实验中,C57BL/6J小鼠的不动时间高于NIH Swiss小鼠[(151.315±12.161)s比(95.107±14.649)s,P=0.007].而在旷场实验中,两种品系的小鼠运动总路程、站立次数、运动时间、边缘区运动路程、边缘区运动时间、中央区运动路程、中央区运动时间差异均无统计学意义.结论 C57BL/6J小鼠在急性应激的情况下更容易表现出抑郁样行为,而NIH Swiss小鼠则表现出一定的抑郁抗性,两种不同品系小鼠的不同行为学表现可能由于遗传因素导致.     

Effects of light environment on emotionality and endocrine system of inbred mice

Eighty mice from two emotionally divergent inbred strains, C57/Alb and Balb/Alb were reared in either a dark or light environment. At 50 days of age, half the animals in each rearing condition were administered a battery of tasks consisting of 19 measures of emotionality. At 58 days of age all animals were dissected and pituitary, adrenal, spleen, and gonad weight recorded. Factor scores were computed for all animals on six factors of emotionality previously obtained. Strain differences were found on all factors and rearing differences on 2 factors: autonomic balance and motor discharge. Strain and sex affected all organ weights, light rearing affected adrenal, spleen and ovary weight, and emotionality testing affected pituitary and adrenal weight. The results were interpreted that light rearing affects maturation of the hypothalamic-pituitary-adrenal axis and response to stress.     

Development of open-field behavior in mice: Effects of age and experience

Offspring from each of two inbred strains of mice (BALB/cJ and C57BL/6J) and their reciprocal crosses were tested in an open-field apparatus at 10 ages, from 15 to 120 days. Cross-sectional and longitudinal analyses were performed to assess separately the effects of age and prior test experience on open-field activity and defecation. Increased activity was associated with increased age in both strains and their F₁ reciprocal hybrids; however, the magnitude of this effect was a function of the genotype. Defecation also increased initially in all groups as a function of age; but, at later ages, different groups exhibited rather dissimilar defecation patterns. Prior experience was found to decrease activity in the open field in inbred strains and their reciprocal hybrids. The effect of prior experience on defecation was more complex: Within the two inbred strains, prior experience had relatively little effect on the pattern of defecation; for the F₁ hybrids, however, prior experience led to a significant increase in defecation at most ages. It was suggested that the differential effect of test experience on open-field activity and defecation represents a separation of two components of open-field behavior, “exploration” and “emotionality.”     

Effects of retention interval and gonadectomy on sex differences in passive avoidance behavior

Female rats show more response suppression in aversively motivated learning when the effect of presentation of an aversive stimulus upon subsequent responding is measured immediately, whereas males show more suppression in procedures in which the effect of an aversive stimulus is measured after longer intervals. To test whether this divergence can indeed be attributed to temporal parameters, step through passive avoidance was studied using various intervals between shock and retention trial. In contrast to the hypothesis, males showed more response suppression than females when tested directly after shock presentation. This sex difference was also observed at longer intervals. The highest levels of passive avoidance was observed at a 15 minute interval in all groups. Ovariectomy had no effect on the performance of females, but castration of males significantly decreased their performance. These findings demonstrate that the presence of testosterone in adulthood is critical for the masculine pattern of this behavior.