Differential effects of periodic maternal separation on adult stress coping in a rat model of extremes in trait anxiety

We studied interactions of genetic and environmental factors shaping adult emotionality and stress coping, and tested the hypothesis that repeated periodic maternal deprivation (PMD) exerts differential effects on adult behavioral and neuroendocrine stress responsiveness in dependence on the genetic predisposition to either hyper- or hypo-anxiety. Exposure of male Wistar rats bidirectionally bred for either high (HAB) or low (LAB) anxiety-related behavior to PMD between postnatal days 2 and 15 resulted in a behavioral approximation of the selected lines. This was reflected by test-dependent signs of reduced anxiety-related behavior in adult HAB rats and of enhanced levels of anxiety in LAB rats compared with their corresponding unstressed controls. In addition to behavioral parameters, differential effects of PMD were also seen with respect to the responsiveness of the hypothalamo-pituitary-adrenocortical axis to acute stressor exposure (novel environment) in adulthood. The corticotrophin (ACTH) and corticosterone hyper-responses seen in control rats of the HAB line compared with those of the LAB line became attenuated in PMD-HAB rats, whereas PMD did not significantly alter neuroendocrine responses in LAB rats. Thus, as a result of PMD, both ACTH and corticosterone responses became indistinguishable between HAB and LAB rats. Although HAB dams spent more time on the nest with the litter compared with LAB dams during the first 5 days postpartum, licking and grooming behavior did not differ between the lines prior to separation, and was found to be increased to the same extent in both HAB and LAB dams during the first hour immediately after reunion with the pups. In contrast to early life stress, exposure of adult HAB and LAB rats to a 10-day unpredictable stress schedule failed to alter their emotional measures. The mitigating effect of PMD on both behavioral and neuroendocrine parameters in rats representing extremes in trait anxiety might reflect an evolutionary benefit as the genetic variability among individuals of a species is sustained while allowing adequate responses to potentially dangerous stimuli in adulthood dependent on early life conditions.     

Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic–pituitary–adrenal axis and induces anxiety-like behavior in adult male rat offspring

We have reported that hypoxia affects the hypothalamic–pituitary–adrenal (HPA) axis and behavior by driving the expression of central corticotropin-releasing hormone (CRH) and its receptors in adult mammals, and this effect is modulated by other factors. Here, we address whether or not intermittent hypoxia (IH) or restraint (R) or a combination of both (IH+R) during gestation would result in differential alteration of the HPA axis and behavior of the adult male offspring. Gravid rats were exposed to IH in a hypobaric chamber (10.8% O₂, altitude of 5 km), R, or both, daily for 4 h for 21 days. Control parameters were set at sea level (20.9% O₂). All the stressors significantly and differentially increased CRH and corticotropin-releasing factor receptor type 1 (CRHR1) expression but decreased corticotropin-releasing factor receptor type 2 (CRHR2) in the paraventricular nucleus of the hypothalamus (PVN), enhanced CRHR1 mRNA and CRHR2 mRNA expression in the anterior pituitary, and increased plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels and adrenal weight in adult male offspring aged 120 days. Furthermore, norepinephrine (NE) and dopamine (DA) levels significantly increased in the locus coeruleus (LC), while the percentage of entries into the open arms of the elevated-plus maze test (EPM) markedly declined. In all the above effects, the combination-induced effect was stronger than each stressor alone. Confocal imaging showed a rich colocalization of CRHR1 with CRH or urocortin I (Ucn I), and CRHR2 with CRH or urocortin III (Ucn III) in the PVN, and CRHR1 with CRH in the LC in EPM-tested groups. In conclusion, IH or R alone or both in combination during gestation sensitize the HPA axis and induce anxiety-like behavior of the adult male offspring, and the combined effects are significantly great than IH or R alone. The CRH-NE neural circuit between the PVN and LC through CRH receptor driving might partly be involved in the effects. The differential colocalization of CRH with CRHR1 might be the neural basis of these effects.     

Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis

Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors.     

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus–pituitary–adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.     

Enhanced stress responses in adolescent versus adult rats exposed to cues of predation threat, and peer interaction as a predictor of adult defensiveness

Development of the hypothalamic-pituitary-adrenal (HPA) axis is influenced by external factors during early life in mammals, which optimizes adult function for predicted conditions. We have hypothesized that adolescence represents a sensitive period for the development of some aspects of adult stress response regulation. This was based on prior work showing that repeated exposure of rats to a stressor across an adolescent period increases fearfulness in a novel environment in adulthood and results in lower levels of dopamine receptor subtype-2 protein in prefrontal cortex. Here, we further our investigation of both acute and long-term effects of repeated adolescent stressor exposure on physiological (i.e., corticosterone) and behavioral (i.e., defensive behavior) measures of stress responding in male and female rats. Furthermore, we compared outcomes with those following identical manipulations administered in early adulthood and found that animals exposed to cues of predation threat during adolescence showed the most robust defensive responses to a homotypic stressor encountered in adulthood. Peer interaction during control manipulation in adolescence was identified as an important individual characteristic mediating development of adult defensive strategies.     

Short periods of prenatal stress affect growth, behaviour and hypothalamo–pituitary–adrenal axis activity in male guinea pig offspring

Prenatal stress can have profound long-term influences on physiological function throughout the course of life. We hypothesized that focused periods of moderate prenatal stress at discrete time points in late gestation have differential effects on hypothalamo–pituitary–adrenal (HPA) axis function in adult guinea pig offspring, and that changes in HPA axis function will be associated with modification of anxiety-related behaviour. Pregnant guinea pigs were exposed to a strobe light for 2 h on gestational days (GD) 50, 51, 52 (PS50) or 60, 61, 62 (PS60) (gestation length ∼70 days). A control group was left undisturbed throughout pregnancy. Behaviour was assessed in male offspring on postnatal day (PND)25 and PND70 by measurement of ambulatory activity and thigmotaxis (wall-seeking behaviour) in a novel open field environment. Subsequent to behavioural testing, male offspring were cannulated (PND75) to evaluate basal and activated HPA axis function. Body weight was significantly decreased in adult PS50 and PS60 offspring and this effect was apparent soon after weaning. The brain-to-body-weight ratio was significantly increased in adult PS50 males. Basal plasma cortisol levels were elevated in PS50 male offspring throughout the 24 h sampling period compared with controls. In response to an ACTH challenge and to exposure to an acute stressor, PS60 male offspring exhibited elevated plasma cortisol responses. Plasma testosterone concentrations were strikingly decreased in PS50 offspring. Thigmotaxis in the novel environment was increased in PS50 male offspring at PND25 and PND70, suggesting increased anxiety in these animals. In conclusion, prenatal stress during critical windows of neuroendocrine development programs growth, HPA axis function, and stress-related behaviour in adult male guinea pig offspring. Further, the nature of the effect is dependant on the timing of the maternal stress during pregnancy.     

Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep

Epidemiological and experimental evidence suggests that maternal undernutrition during pregnancy may alter development of fetal organ systems. We have demonstrated previously that fetal hypothalamic-pituitary-adrenal (HPA) axis responses to exogenous corticotropin-releasing hormone (CRH) + arginine vasopressin (AVP), or adrenocorticotrophin hormone (ACTH), are reduced in fetuses of mildly undernourished ewes. To examine these effects further we tested HPA axis responses to acute isocapnic hypoxaemia in fetal sheep at 114-129 days gestation (dGA), following 15% reduction in maternal nutritional intake between 0 and 70 dGA. Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and plasma ACTH and cortisol responses were determined at 114-115, 120-123 and 126-129 dGA during hypoxaemia (1 h) induced by lowering the maternal inspired O2 fraction (FI,O2). Basal plasma cortisol concentrations and HPA axis responses at 114-115 and 120-123 dGA did not differ between C and R fetuses. At 126-129 dGA, both plasma ACTH (P < 0.01) and cortisol (P < 0.05) responses were smaller in R fetuses compared to C fetuses. Fetal blood gas status, fetal body weight, body proportions and organ weights did not differ between the groups. We conclude that mild maternal undernutrition alters development of the fetal HPA axis producing a reduction in pituitary and adrenal responsiveness to endogenous stimuli.     

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.     

Neuroendocrine and behavioral effects of CRH blockade and stress in male rats.

Our previous data have shown that restraint (RT), a mild nonpainful stressor, acutely impairs nonsocial and social behavior in male rats. Corticotropin-releasing hormone (CRH) is a regulator of these behavioral responses. To evaluate whether CRH mediates the neuroendocrine and behavioral alterations present 24 h after restraint stress, we administered the CRH antagonist alpha-helical CRH(9-41) (alpha-hCRH) intracerebroventricularly to male rats and we compared its effects with those of saline. Twenty-four hours after treatment, nonsocial behaviors were significantly decreased by alpha-hCRH, this effect being independent of RT. Among social behaviors, only introductory activity showed significant differences as a result of both RT and alpha-hCRH. The concentrations of ACTH in the plasma and those of beta-endorphin in the anterior and neurointermediate lobes of the pituitary were affected by alpha-hCRH treatment. The effect on ACTH was simply related to the administration of the alpha-hCRH, while for beta-endorphin, significant interactions between alpha-hCRH and RT were found. On the whole, these results point to the role played by CRH in the control of neuronal mechanisms involved in the stress-induced effects.     

褪黑素对SD大鼠下丘脑-垂体-肾上腺皮质的影响

目的 研究褪黑素对正常和糖尿病大鼠下丘脑-垂体-肾上腺皮质功能和超微结构的影响.方法 应用放射免疫法分别观察了低、中、高剂量(0.5mg/kg、10mg/kg、50mg/kg)褪黑素及对照药物硫辛酸(100mg/kg)连续腹腔注射3周,对SD大鼠血浆促肾上腺皮质激素释放激素(CRH)、促肾上腺皮质激素(ACTH)、皮质酮(COR)水平的影响.并运用电镜观察用药前后大鼠垂体、肾上腺皮质超微结构的变化.结果 1.正常和糖尿病大鼠低、中、高剂量褪黑素处理组CRH水平与相应对照组相比显著降低;正常大鼠低、中、高剂量褪黑素及硫辛酸处理组和糖尿病大鼠低剂量(0.5mg/kg)褪黑素、硫辛酸处理组ACTH水平比相应对照组明显降低(P＜0.05);正常大鼠低、中、高剂量褪黑素处理组和糖尿病大鼠中高剂量褪黑素处理组皮质酮水平比相应对照组显著降低(P＜0.05).2.褪黑素对正常大鼠下丘脑-垂体-肾上腺皮质超微结构无明显影响.糖尿病大鼠垂体细胞和肾上腺皮质细胞出现功能受抑制状态,褪黑素(50mg/(kg·d))处理21d后垂体促肾上腺皮质细胞和肾上腺皮质细胞代谢较处理前明显活跃.结论 褪黑素能在不同层次直接或间接地发挥对正常和糖尿病大鼠下丘脑-垂体-肾上腺(HPA)轴的抑制作用.     

Attenuated hypothalamo-pituitary-adrenal axis responses to immune challenge during pregnancy: the neurosteroid opioid connection.

In late pregnancy maternal hypothalamo-pituitary-adrenal (HPA) axis responses to emotional and physical stressors are attenuated. This is expected to minimize the detrimental programming effects of glucocorticoid exposure on the fetuses. We have utilized a model of immune challenge, systemic administration of interleukin-1beta (IL-1beta), to investigate the underlying mechanisms. Intravenous IL-1beta activates corticotropin-releasing hormone (CRH) neurones in the parvocellular division of the paraventricular nucleus (pPVN) via noradrenergic (A2 cell group) neurones in the nucleus tractus solitarii (NTS). Despite comparable activation of these brainstem neurones by IL-1beta in virgin and in late pregnant rats, pPVN CRH neurones are activated only in virgin rats. As a consequence IL-1beta fails to evoke ACTH and corticosterone secretion in late pregnant rats, in contrast to virgin rats. Suppressed responsiveness of the CRH neurones, and hence the HPA axis, following IL-1beta in late pregnancy is explained by presynaptic inhibition of noradrenaline release in the pPVN, due to increased endogenous enkephalin and mu-opioid receptor production in brainstem NTS neurones. The factor that signals to the brain the pregnancy status of the animal and stimulates opioid production in the brainstem is allopregnanolone, a neurosteroid metabolite of progesterone. The supporting evidence for these mechanisms is discussed.     

Attenuated hypothalamo-pituitary-adrenal axis responses to immune challenge during pregnancy: the neurosteroid–opioid connection

In late pregnancy maternal hypothalamo-pituitary-adrenal (HPA) axis responses to emotional and physical stressors are attenuated. This is expected to minimize the detrimental programming effects of glucocorticoid exposure on the fetuses. We have utilized a model of immune challenge, systemic administration of interleukin-1β (IL-1β), to investigate the underlying mechanisms. Intravenous IL-1β activates corticotropin-releasing hormone (CRH) neurones in the parvocellular division of the paraventricular nucleus (pPVN) via noradrenergic (A2 cell group) neurones in the nucleus tractus solitarii (NTS). Despite comparable activation of these brainstem neurones by IL-1β in virgin and in late pregnant rats, pPVN CRH neurones are activated only in virgin rats. As a consequence IL-1β fails to evoke ACTH and corticosterone secretion in late pregnant rats, in contrast to virgin rats. Suppressed responsiveness of the CRH neurones, and hence the HPA axis, following IL-1β in late pregnancy is explained by presynaptic inhibition of noradrenaline release in the pPVN, due to increased endogenous enkephalin and μ-opioid receptor production in brainstem NTS neurones. The factor that signals to the brain the pregnancy status of the animal and stimulates opioid production in the brainstem is allopregnanolone, a neurosteroid metabolite of progesterone. The supporting evidence for these mechanisms is discussed.     

Personality, manual preference and neuroendocrine reactivity in hirsute subjects

Behavioral and neuroendocrine differences may be postulated in hirsute subjects since central effects of gonadal steroids are well established. We conducted a controlled clinical study with 25 consecutive young hirsute participants compared with 20 consecutive controls. Neuropsychological evaluation included the Minnesota Multiphasic Personality Inventory (MMPI) and the Edinburgh Inventory of Manual Preference (EIMP). Neuroendocrine reactivity was assessed by the adrenocorticotropic hormone (ACTH) and cortisol responses to corticotropin releasing hormone (CRH). Hirsute participants presented a flattened personality profile with lower neurotic triad scores--146 +/- 20 versus 166 +/- 28. Left-hand preference was more common in hirsute participants--4/21 versus 0/20. Decreased ACTH [area under the curve (AUC)--36 +/-2 8 vs. 72 +/- 63 pg/ml h] and cortisol (AUC--18 +/- 4 vs. 25 +/- 10 microg/dl h) responses to CRH were found in the hirsute group. In the hirsute group, higher manual preference scores were associated with lower ACTH responses to CRH, while the opposite association was found in the control group. In the hirsute group, the hyporeactive hypothalamic-pituitary-adrenal (HPA) axis was associated with lower behavior-deviant scores, while in the control group, the hyporeactive HPA axis was associated with more psychopathology. We conclude that personality and HPA axis reactivity are different in hirsute female participants when compared with controls, with a trend for differences regarding handedness. Personality and handedness are differently associated with HPA reactivity. Distinctive features in hirsute participants are probably established very early during ontogenic development.     

Hypothalamo-pituitary-adrenocortical dysregulation in aging F344/Brown-Norway F1 hybrid rats

Hypothalamo-pituitary-adrenocortical (HPA) axis aging was studied in young (3 mo), middle aged (15 mo) and aged (30 mo) F344/Brown Norway hybrid rats. This strain was selected to obviate HPA-relevant pathologies found in other aging models. Aged, unstressed rats showed enhanced central HPA drive, marked by elevated ACTH release and decreased pituitary proopiomelanocortin and corticotropin-releasing factor receptor 1 (CRH-R1) mRNAs. Acute corticosterone responses to spatial novelty were exacerbated in aged rats; however, responses to restraint or hypoxia were not affected. Chronic stress exposure also differentially increased HPA drive in aged animals, marked by elevated paraventricular nucleus CRH peptide levels and pituitary proopiomelanocortin mRNA. Plasma ACTH and pituitary POMC and CRH-R1 mRNA expression in middle-aged rats were intermediate those of young and aged animals. Middle-aged animals responded to chronic stress with disproportionate increases in CRH mRNA levels, and increased corticosterone secretion following hypoxia but not novelty. The results suggest a gradual increase in HPA tone across the aging process, culminating in marked hyperresponsivity to both acute and chronic stress in senescence.     

Impact of maternal morphine and saline injections on behavioral responses to a cold water stressor in adult male and female progeny

The purpose of the present study was to test the effects of maternal morphine and saline injections on chronic cold water stress responses in three groups of adult male and female rats: prenatally morphine-exposed adult progeny, prenatally saline-exposed adult progeny, and control groups. All male rats were gonadally intact, and female rats were ovariectomized (OVX) in adulthood, and half of them were injected with estradiol benzoate (EB). All animals were exposed to a cold water stressor daily for 2 weeks and tested before (baseline) and after (stress effects) the chronic cold water stressor in a swim test and an open field test. In the swim test, both adult males and OVX, EB-treated adult females born to mothers injected with morphine or saline displayed more floating behavior during the swim test than their controls, both before and after the cold water stressor. Male rats exposed to morphine or saline prenatally also spent more time struggling during the swim tests than controls, and this was further increased after the cold water stressor. In the open field test, males and OVX, EB-treated females born to morphine- or saline-injected mothers were less active and displayed fewer rearings than controls. No differences were observed in OVX females as a result of prenatal injections. Thus, the present study demonstrates that maternal injections, regardless of injection content, induce long-lasting effects on stress responsiveness in adult progeny.     

Evidence for a lack of phasic inhibitory properties of habituated stressors on HPA axis responses in rats

This experiment tested the hypothesis that habituation to repeated stressor exposures is produced by phasic inhibitory influence on the neural circuitry that normally drives the paraventricular nucleus of the hypothalamus and subsequently the adrenocortical hormone response to psychological stress. Such a process would be expected to lower the acute response to a novel stressor when experienced concurrently with a habituated stressor. Rats were exposed to restraint or no stress conditions for 14 consecutive days. On the 15th day, the rats were exposed to the control condition (no stress), acute restraint, loud noise, or restraint and loud noise concurrently. Blood was taken and assayed for ACTH and corticosterone and brains were collected to examine c-fos messenger RNA expression in several brain areas. As predicted, the rats that received the same (homotypic) stressor repeatedly and again on the test day displayed low levels of ACTH and corticosterone, similar to the control conditions (i.e., showed habituation). All rats that received a single novel stressor on the test day, regardless of prior stress history, exhibited high levels of ACTH and corticosterone. The rats that received two novel stressors also displayed high levels of ACTH and corticosterone, but little evidence of additivity was observed. Importantly, when a novel stressor was concurrently given with a habituated stressor on the test day, no reduction of HPA axis response was observed when compared to previously habituated rats given only the novel stressor on the test day. In general, c-fos mRNA induction in several stress responsive brain areas followed the same patterns as the ACTH and corticosterone data. These data suggest that habituation of the adrenocortical hormone response to psychological stressors is not mediated by phasic inhibition of the effector system.     

Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor

The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem structures that regulate anxiety-related behavior and hypothalamic-pituitary-adrenal (HPA) activity, but its role in regulating anxiety-related behaviors is equivocal, and evidence for its role in regulating HPA activity is limited. Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these issues. Behavior in the elevated plus maze, open field, light-dark box and after Pavlovian fear conditioning was examined in addition to HPA activity under basal and acute stress conditions. Compared to age-matched adult male wild-type (WT) controls, adult male KO mice exhibited increased distance traveled in the open arms of the elevated plus maze, consistent with decreased measures of anxiety. There were no differences between the two genotypes in exploratory behavior in the open field or light-dark test. KO mice displayed enhanced fear conditioning indexed by fear-induced freezing behavior. KO mice displayed lower adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In addition, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the central amygdala were observed in KO compared to WT mice. Therefore, deletion of the 5-HT-3A receptor revealed an important role for this receptor in regulating HPA responses to acute stress and a potential interaction between the 5-HT-3A receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A receptor does not have a unitary role in the regulation of anxiety- and fear-related behaviors but has a potentially substantial role in the regulation of HPA activity.     

Hormonal and behavioral responses to stress in lactating and non-lactating female common marmosets (Callithrix jacchus)

In several mammalian species, hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors are down-regulated in lactating females, possibly preventing stress-induced disruptions of maternal care. Experimental elevations of HPA axis hormones have been found to inhibit maternal behavior in lactating common marmoset monkeys (Callithrix jacchus), raising the question of whether lactating female marmosets also have blunted endogenous responses to stress. Therefore, we compared HPA and behavioral responses to standardized stressors in reproductively experienced female common marmosets that were undergoing ovulatory cycles and that either were (N = 7) or were not lactating (N = 8). Each marmoset underwent (1) a restraint stressor during the early follicular phase of the ovarian cycle (approximately 5 weeks postpartum for lactating females) and (2) exposure to a simulated hawk predator during the early to mid-luteal phase (approximately 7 weeks postpartum for lactating females). Lactating females were tested in the presence of one of their infants. Blood samples were collected before, during, and immediately after each test for determination of plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Both stressors caused significant elevations in plasma ACTH and cortisol levels, and significant decreases in cortisol:ACTH ratios; however, lactating and non-lactating females showed no significant differences in their endocrine or behavioral responses to either stressor, or in baseline ACTH or cortisol levels. These findings suggest that in contrast to several other mammalian species, lactating female marmosets maintain full behavioral and HPA responsiveness to stress, at least in the presence of their infants.     

Anxiety-like behavior in the elevated-plus maze tests and enhanced IL-1β, IL-6, NADPH oxidase-1, and iNOS mRNAs in the hippocampus during early stage of adjuvant arthritis in rats

We studied anxiety-like behavior in the elevated plus-maze (EPM) tests in male Lewis rats on days 2 and 4 of adjuvant arthritis (AA). In plasma we analyzed C-reactive protein (CRP), albumin, ACTH, corticosterone, in the hippocampus the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), corticotrophin releasing factor (CRH), NADPH oxidases NOX1 and NOX2, and inducible NO-synthase (iNOS). EPM tests showed a higher anxiety index in AA rats on days 2 and 4 and reduction of total entries. On days 2 and 4 we found reduced plasma albumin, enhanced CRP, ACTH and corticosterone, and in the hippocampus enhanced mRNA for NOX1 and IL-1β in AA rats, on day 4 we found enhanced mRNAs for iNOS and IL-6, and reduced mRNA for CRH. The mRNA for NOX2 did not change on any experimental day. These results suggest enhanced anxiety, as well as locomotor impairment during the early phase of AA that correlate with enhanced mRNA expressions of parameters of oxidative stress NOX1, iNOS, and inflammatory cytokines IL-1β and IL-6 in the hippocampus.     

Swimming exercise ameliorates depression-like behaviors induced by prenatal exposure to glucocorticoids in rats

Prenatal exposure to glucocorticoids (GCs) leads to affective dysfunction in adulthood, which may be associated with the alterations in hypothalamic–pituitary–adrenal (HPA) axis. Physical exercise has been shown to ameliorate depressive symptoms. The objectives of present study were to investigate whether prenatal exposure to GCs induces depression-like behaviors in adult offspring rats, and determine whether swimming exercise alleviates the depression-like behaviors induced by this paradigm. Pregnant rats received dexamethasone (DEX) (0.1 mg/kg/day) in the last third of pregnancy or vehicle. DEX treatment reduced body weight in 1, 3, 6, 9-week old male offspring, and 3, 6, 9-week old female offspring. DEX treatment resulted in an elevated level of serum corticosterone in adult offspring (9 weeks). Female and male adult offspring rats exhibited decreased number of poking into holes and rearing and decreased central distance traveled in open field test (OFT), and reduced sucrose consumption, suggesting prenatal DEX exposure increase depression-like behaviors in the adult offspring rats. Four-week swimming exercise reduced serum corticosterone levels, and alleviated the depressive behavior by reversing the decreased number of poking into holes and rearing as well as decreased central distance traveled, and reversing the reduced sucrose consumption in male and female adult offspring. These findings suggested prenatal exposure to GCs increase the activity of HPA axis and depression-like behaviors of adult offsprings. Swimming exercise decreases HPA activity and ameliorates depression in rats exposed to DEX prenatally.