Proinflammatory activity and the sensitization of depressive-like behavior during maternal separation

When guinea pig pups are isolated for a few hours in a novel environment, they exhibit a distinctive passive behavioral response that appears to be mediated by proinflammatory activity. Recently, we observed that pups separated on two consecutive days show an enhanced (sensitized) passive response on the second day. In Experiment 1, pups receiving intracerebroventricular infusion of 50 ng of the anti-inflammatory cytokine interleukin-10 prior to a first separation failed to show a sensitized behavioral response to separation the next day. In Experiment 2, pups separated on Days 1 and 2, or just 2, showed an increase in passive responding during separation on Day 5. Pups injected with the bacterial antigen lipopolysacchride (LPS; 75 μg/kg body weight, intraperitoneal) prior to separation on Day 1 showed an increase in passive behavior several days later not shown by pups injected with saline prior to Day 1 separation. However, injection of LPS without separation on the first day did not enhance responding during an initial separation on the second day. These results suggest that immune activation is necessary, but not sufficient, to account for the sensitization of passive behavior of isolated guinea pig pups the following day, that boosting proinflammatory activity during an initial separation may promote sensitization several days later, and that the sensitized response persists for at least several days.     

Persistent sensitization of depressive-like behavior and thermogenic response during maternal separation in pre- and post-weaning guinea pigs

Early attachment disruption is thought to promote later onset of depressive illness through a process involving sensitization. Maternal separation in guinea pig pups produces depressive-like behavior and core body temperature fluctuations that appear to be mediated by proinflammatory activity. In pups near the age of weaning (~20 days of age), these responses are increased during repeated separations occurring over several days. Here, enhanced depressive-like behavior and core body temperature responses were observed during repeated separations in guinea pigs from ~10 to 30 days of age. The sensitization lasted for more than a week, with the greatest temperature response occurring during the final separation. These results demonstrate persisting sensitization of behavioral and thermogenic responses to maternal separation over the age range in which these responses are known to occur. The findings are consistent with the hypothesis that proinflammatory activity contributes to the sensitization response and provide further suggestion that the impact of early attachment disruption on susceptibility to depression may involve proinflammatory processes.     

Exhaustion is associated with reduced habituation of free cortisol responses to repeated acute psychosocial stress

We investigated the association between exhaustion and the habituation of free cortisol responses to repeated stress exposure. The study comprised 25 healthy male subjects (38-59 years) who were confronted three times with the Trier Social Stress Test. Mean cortisol responses showed the well-known general habituation effect. A two-way interaction day by exhaustion (p<0.05) indicated that mean cortisol responses vary across stress sessions depending on the extent of exhaustion. Linear regression revealed a negative dose-response relationship between exhaustion and the degree of habituation (p<0.02). We identified 19 individuals showing a response habituation (negative slope) and 6 individuals showing a response sensitization over the three sessions (positive slope) with the latter reporting higher exhaustion scores. It might be hypothesized that impaired habituation to repeated exposure to the same stressor could reflect a state of increased vulnerability for allostatic load. Absence of normal habituation might be one potential mechanism how exhaustion relates to increased disease vulnerability.     

Placental abruption is associated with decreased maternal plasma levels of soluble HLA-G

During pregnancy the fetus represents a semi-allograft. Both membrane-bound and soluble forms of the nonclassic human leukocyte antigen (HLA)-G protect the fetus from maternal immune attack. To assess the relevance of soluble HLA-G (sHLA-G) levels in the maternal circulation for the occurrence of characteristic pregnancy disorders, we analyzed sHLA-G plasma levels of women with normal and pathological pregnancies. Compared to normal pregnancy, significantly increased sHLA-G levels were detected in women delivered preterm because of intrauterine activation (uncontrollable labor, rupture of fetal membranes, cervical insufficiency) and women with Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome. Contrary to these disorders, the sHLA-G levels in women with placental abruption were more than three times lower than in normal pregnancy (p < 0.0001). Nonparametric discriminant analysis showed that women with sHLA-G levels below 9.95 ng/mL had a relative risk of 7.12 for the development of placental abruption during further course of pregnancy. These results suggest that the occurrence of pregnancy-associated diseases is strongly influenced by maternal sHLA-G plasma levels.     

Submicroscopic Plasmodium infection during pregnancy is associated with reduced antibody levels to tetanus toxoid

Submicroscopic Plasmodium infections in pregnancy are common in endemic areas, and it is important to understand the impact of these low-level infections. Asymptomatic, chronic infections are advantageous for parasite persistence, particularly in areas where the optimal eco-epidemiological conditions for parasite transmission fluctuate. In chronic infections, the persistence of the antigenic stimulus changes the expression of immune mediators and promotes constant immune regulation, including increases in regulatory T cell populations. These alterations of the immune system could compromise the response to routine vaccination. This study aimed to evaluate the effect of submicroscopic plasmodial infection with P. falciparum and P. vivax during pregnancy on the immune response to the tetanus toxoid vaccine in Colombian women. Expression of different cytokines and mediators of immune regulation and levels of anti-tetanus toxoid (TT) immunoglobulin (Ig)G were quantified in pregnant women with and without submicroscopic plasmodial infection. The anti-TT IgG levels were significantly lower in the infected group compared with the uninfected group. The expression of interferon (IFN)-γ, tumour necrosis factor (TNF) and forkhead box protein 3 (FoxP3) was significantly higher in the infected group, while the expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and transforming growth factor (TGF)-β was lower in the group of infected. In conclusion, submicroscopic Plasmodium infection altered the development of the immune response to the TT vaccine in Colombian pregnant women. The impact of Plasmodium infections on the immune regulatory pathways warrants further exploration.     

Sleep and temperature regulation during restraint stress in rats is affected by prior maternal separation.

During restraint stress, 30-day-old rats uniformly show an abrupt and persistent decrease in activity with a corresponding increase in quiet wakefulness. However, the effect of restraint on sleep and body temperature depends on whether maternal separation had previously occurred at the customary age (day 22) or 7 days earleir (day 15). If maternal separation took place on day 22, subsequent restraint on day 30 has no effect on the amount of time spend in sleep or on body temperature, relative to a comparison sgroup of unrestrained rats. But if maternal separation took place on day 15, restraint on day 30 elicits a marked initial increase in sleep and a later decrease in sleep and body temperature. The results are consistent with the interpretation that premature maternal separation retards the normal maturation of these behavioral and thermoregulatory responses to restraint stress.     

High maternal HIV-1 viral load during pregnancy is associated with reduced placental transfer of measles IgG antibody

BACKGROUND: Studies among HIV-1-infected women have demonstrated reduced placental transfer of IgG antibodies against measles and other pathogens. As a result, infants born to women with HIV-1 infection may not acquire adequate passive immunity in utero and this could contribute to high infant morbidity and mortality in this vulnerable population. METHODS: To determine factors associated with decreased placental transfer of measles IgG, 55 HIV-1-infected pregnant women who were enrolled in a Nairobi perinatal HIV-1 transmission study were followed. Maternal CD4 count, HIV-1 viral load, and HIV-1-specific gp41 antibody concentrations were measured antenatally and at delivery. Measles IgG concentrations were assayed in maternal blood and infant cord blood obtained during delivery to calculate placental antibody transfer. RESULTS: Among 40 women (73%) with positive measles titers, 30 (75%) were found to have abnormally low levels of maternofetal IgG transfer (<95%). High maternal HIV-1 viral load at 32 weeks' gestation and at delivery was associated with reductions in placental transfer (P < 0.0001 and P = 0.0056, respectively) and infant measles IgG concentrations in cord blood (P < 0.0001 and P = 0.0073, respectively). High maternal HIV-1-specific gp41 antibody titer was also highly correlated with both decreased placental transfer (P = 0.0080) and decreased infant IgG (P < 0.0001). CONCLUSIONS: This is the first study to evaluate the relationship between maternal HIV-1 viremia, maternal HIV-1 antibody concentrations, and passive immunity among HIV-1-exposed infants. These data support the hypothesis that high HIV-1 viral load during the last trimester may impair maternofetal transfer of IgG and increases risk of measles and other serious infections among HIV-1-exposed infants.     

Social housing conditions around puberty determine later changes in plasma cortisol levels and behavior

A recent study found that male guinea pigs raised in large, mixed age/sex groups exhibited an unexpected suppression of their cortisol response at 4 mo of age. The present study examined the effect of social experience around the time of puberty on cortisol response suppression and social behavior at 4 mo of age. Males reared in large, mixed age/sex groups were either pair-housed with a female or moved to another large colony at 55 days of age. When tested at 4 mo, pair-housed males exhibited much higher levels of courtship and sexual behavior than did colony-housed males, and a shorter latency to begin courtship when with an unfamiliar adult female. In addition, pair-housed males showed much higher levels of agonistic behavior and a shorter latency to escalated aggression with an unfamiliar adult male. Pair-housed males also had lower basal cortisol concentrations and exhibited a greater increment in cortisol levels when isolated in a novel cage than did colony-housed males. Finally, pair-housed males showed a smaller increment in cortisol levels when with the stimulus female or male than when isolated, but colony-housed males did not. The findings demonstrate that social housing conditions around the time of puberty can have pervasive effects on social behavior and hypothalamic-pituitary-adrenal (HPA) activity in 4-mo-old males. Further, these findings are consistent with the notion that changes in HPA activity contribute to social behavior development beyond the time of sexual maturity.     

Depression-like state in maternal rats induced by repeated separation of pups is accompanied by a decrease of cell proliferation and an increase of apoptosis in the hippocampus

Stressful experiences, such as an unsatisfactory mother–infant relationship after delivery, can induce depressive disorders, and it is well-known that stressors impair memory function. The hippocampus plays a crucial role in memory processes. In the present study, we determined whether a depressed-like state induced by repeated separation of pups affects the memory capability of the maternal rats. We also determined the effects of repeated separation from pups on cell proliferation, apoptosis, and serotonin expression in the brains of maternal rats. In the present results, the immobility time in the forced swim test was increased and the climbing time was decreased in the mothers separated from their pups. The latency in the step-down avoidance task was increased in the mothers separated from their pups. Also, the expressions of serotonin (5-hydroxytryptamine) and tryptophan hydroxylase in the dorsal raphe were decreased in the mothers separated from their pups. The number of Ki-67-positive cells was decreased, while the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in the hippocampal dentate gyrus was increased in the mothers separated from their pups. Based on the present results, it is suggested that separation of pups might induce a depressed-like state in the maternal rats with reduced cell proliferation and increased apoptosis in the hippocampus, resulting in memory impairment of maternal rats.     

Severe chronic urticaria is associated with elevated plasma levels of D-dimer

Background:  Patients with chronic urticaria (CU) frequently show signs of thrombin generation as a result of the activation of the extrinsic pathway of coagulation and signs of fibrinolysis as shown by slightly increased mean D-dimer plasma levels. Here, we studied patients with severe CU to see whether the activation of coagulation and fibrinolysis parallels the severity of the disease.
Methods:  Eight consecutive patients with severe exacerbations of CU and 13 with slight CU were studied. Plasma prothrombin fragment F₁₊₂ as well as D-dimer were measured by ELISA. Serum histamine-releasing activity was assessed by basophil histamine release assay. Seventy-four normal subjects were used as controls.
Results:  In patients with severe CU, median levels of both D-dimer (11.20 nmol/l) and F₁₊₂ (592 pmol/l) largely exceeded those found in patients with slight CU [D-dimer: 2.66 nmol/l ( P  = 0.001) and F₁₊₂: 228 pmol/l ( P  = 0.003)] and in normal subjects [D-dimer: 1.41 nmol/l ( P  = 0.0001) and F₁₊₂: 159 pmol/l ( P  = 0.0001)]. Sera from 25% of patients with severe CU and 31% of those with slight CU, but from none of normal subjects, showed in vitro histamine-releasing activity. D-dimer and F₁₊₂ levels were significantly correlated each other ( r  = 0.64, P  = 0.002) and with CU severity score ( r  = 0.80–0.90, P  = 0.0001), but no correlation was observed between serum histamine-releasing activity and coagulation parameters or severity score.
Conclusions:  Severe exacerbations of CU are associated with a strong activation of coagulation cascade and fibrinolysis. Whether this activation is the cause of CU or acts as an amplification system is still a matter of debate.     

Juvenile rats show reduced c-fos activity in neural sites associated with aversion to pups and inhibition of maternal behavior

Juvenile rats (18-23 days old) interact avidly with pups as novel stimuli and show maternal behavior after only 1-3 days of pup exposure; adults initially avoid pups and require 3-9 days of pup exposure. Upon exposure to pups as novel stimuli, adults had more c-Fos-immunoreactive neurons in the hypothalamus and amygdala--regions associated with aversion to pups--than adults exposed to familiar pup stimuli (maternal) or not exposed to pups (p < .05). In juvenile rats exposed to pups as novel stimuli, only the medial amygdala had a small significant increase of c-Fos neurons. In juveniles, this blunted engagement of c-Fos neurons may reflect the diminished activation of inhibitory neurons, facilitating the interaction of juveniles with pups as novel stimuli and onset of maternal behavior.     

Microbiota of newborn meconium is associated with maternal anxiety experienced during pregnancy

Little is known about whether a mother's psychological state during pregnancy influences her offspring's microbiome. This study examined whether maternal anxiety, depression, and stress during pregnancy is associated with the diversity of meconium microbiome, the first internal discharge, in 75 newborns from an existing birth cohort study. The meconium microbiome was profiled using multibarcode16S rRNA sequencing at V3-V4 hypervariable region followed by taxonomic assignment to the green gene 16S references at 97% similarity and diversity analysis at the genus level. Results showed that the meconium contained diversified microbiota, and greater pregnancy-related anxiety was significantly associated with a less diverse meconium microbiota community (p = 0.001). At the specific taxa level, greater pregnancy-related anxiety was correlated with a lower level of the Enterococcaceae family (p = 2e-4, Spearman rho = −0.43). These findings support a significant role of prenatal maternal mood in the early-life bacteria colonization of their offspring.     

Poor sleep the night before an experimental stress task is associated with reduced cortisol reactivity in healthy women

Sleep disruption is a growing problem that may have serious health effects. As stress-induced increases in cortisol are thought to be a key adaptive process it is important to examine how this response is affected by sleep. The current study investigated the association of four sleep parameters (objective/subjectively measured sleep quality and quantity) and subsequent salivary cortisol reactivity (maximal change from baseline) to an experimental stressor in 53 healthy women. Objective actigraphy monitoring and self-report diaries were used to assess sleep. Results revealed that individuals with lower objective sleep quality (wake percentage during sleep) had a blunted response to the experimental stressor. No associations were found between cortisol reactivity and actigraphy-derived sleep quantity, or either of the self-reported sleep variables. Results are discussed with regard to the possible adverse health effects that may result from poor sleep quality and a blunted cortisol response to stress.     

Total cortisol,free cortisol,and growth hormone associated with brief social separation experiences in young macaques

Many behavioral, immunological, and physiological consequences of brief maternal separation in bonnet (Macaca radiata) and pigtail monkeys (Macaca nemistrina) have been documented. However, the impact of social separation on plasma cortisol and growth hormone is unknown for these particular species. In the present study, the behavioral and endocrinological consequences of a 2-week maternal separation in socially housed infant bonnet and pigtail monkeys were followed. In seven pairs (separated and matched control) of bonnet and six pairs of pigtail infants, plasma was obtained under baseline, separated, and reunion conditions twice weekly for the duration of the study. Blood samples were obtained from both infants of the pair in approximately 10 min. Plasma total cortisol, free cortisol, and growth hormone were measured in these samples. Focal animal behavioral observations were made on all subjects twice daily throughout the study period. In both species, total cortisol and free cortisol rose immediately following maternal separation in comparison to the matched nonseparated controls and returned to basal levels (e.g., that of matched non-separted controls) following reunion with the mother. In contrast, plasma growth hormone rose only in the pigtail infants over a time course that peaked around the time of reunion. Multiple regression techniques indicated for the first week of separation, in the separated but not control subjects, that mean plasma free and total cortisol was positively related to distress behaviors (vocalization and postural slouch) observed during this week and negatively related to social behaviors (play and proximity to others) noted during the same period. In contrast, plasma growth hormone was related to both species and sex of the subjects but unrelated to behavioral variables. © 1995 John Wiley & Sons, Inc.     

Higher luteal progesterone is associated with low levels of premenstrual aggressive behavior and fatigue

Contradictory findings show both positive and negative effect of progesterone on the premenstrual mood changes in women. Here we present the study investigating this relationship on the large sample of premenstrual women. 122 healthy, reproductive age women collected daily morning saliva samples and recorded intensity scores for the mood symptoms: irritability, anger, sadness, tearfulness, insomnia, and fatigue. Saliva samples were assayed for progesterone concentrations and mood intensity scores were used to calculate behavioral indices. Women with low Aggression/Irritability and Fatigue had consistently higher progesterone levels during the luteal phase than women with high Aggression/Irritability and Fatigue. Additionally, Aggression/Irritability and Fatigue correlated negatively with maximal progesterone value during the luteal phase. Our results demonstrated a negative effect of low progesterone level on the premenstrual mood symptoms such as aggressive behavior and fatigue in healthy reproductive age women. This supports a previously proposed model of biphasic action of progesterone metabolites on mood.     

Higher luteal progesterone is associated with low levels of premenstrual aggressive behavior and fatigue

Contradictory findings show both positive and negative effect of progesterone on the premenstrual mood changes in women. Here we present the study investigating this relationship on the large sample of premenstrual women. 122 healthy, reproductive age women collected daily morning saliva samples and recorded intensity scores for the mood symptoms: irritability, anger, sadness, tearfulness, insomnia, and fatigue. Saliva samples were assayed for progesterone concentrations and mood intensity scores were used to calculate behavioral indices. Women with low Aggression/Irritability and Fatigue had consistently higher progesterone levels during the luteal phase than women with high Aggression/Irritability and Fatigue. Additionally, Aggression/Irritability and Fatigue correlated negatively with maximal progesterone value during the luteal phase. Our results demonstrated a negative effect of low progesterone level on the premenstrual mood symptoms such as aggressive behavior and fatigue in healthy reproductive age women. This supports a previously proposed model of biphasic action of progesterone metabolites on mood.     

Changes in heart rate and body temperature during passive avoidance behavior in rats

Heart rate, core temperature and gross locomotor activity during passive avoidance behavior in rats were recorded by a telemetry system connected to a computer data acquisition program. Passive avoidance latency and approach to the dark compartment were evaluated. Rats were assigned to five different groups, i.e., the shock groups that received different intensities of footshock (0.15, 0.25 and 1.0 mA, respectively, for 3 sec), a no footshock control group and a group that had no access to the dark compartment (i.e., no dark compartment control group). Retention tests were carried out 24 and 120 hr after the learning trial. Rats exposed to footshock showed a decrease in heart rate during the first 10 sec of the observation period in both retention tests. An average bradycardia was found in the lowest shock intensity group (0.15 mA) at both the 24- and 120-hr retention test whereas the other two groups (0.25 and 1.0 mA) showed a gradual increase in heart rate. This increase was more pronounced the longer the rats stayed on the platform. Similarly, a gradual rise in core temperature was observed in these rats as well as in the no dark compartment control group. The number of approaches to the dark compartment was significantly depressed in the group exposed to 1.0 mA footshock intensity. Gross locomotor activity was reduced in animals that exhibited maximum avoidance latency. Exposure of rats to the above-described behavioral paradigms induced autonomic activation resulting in changes in heart rate and temperature. These changes were not caused by gross locomotor activity and may thus be related to the various behavioral states.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ingestive behavior and body temperature of pigeons during long-term cold exposure.

Pigeons well adapted to living in 21 degrees C ambient temperature (T(a)) were continuously exposed to cold T(a) for 6 days (Experiment 1) or 30 days (Experiment 2). The pigeons lived on a 12:12 L:D cycle where they could obtain short access to food and water at any time in the light phase by making 12 keypeck responses. Across the two experiments, the levels of cold exposure were 6 degrees C, 1 degrees C, and 0.6 degrees C. In cold, total daily food intake increased gradually across the first few days of the exposure, and the new level of food intake was inversely related to T(a). The daily ratio of total water drunk to total food eaten averaged approximately 1.3 in 21 degrees C, fell to approximately 1.0 on day 1 of cold exposure, and remained at that level for as long as 30 days. The day-night cycle in core body temperature was not changed by cold exposure. The bimodal temporal pattern of feeding in the light phase, which is characteristic of pigeons in moderate T(a), was preserved in the cold although the absolute level of feeding activity was enhanced. An analysis of the ways individual pigeons achieved total daily food intake by combining a number of feeding episodes with an average amount eaten per episode revealed considerable variation between birds, but a relatively constant feeding style within bird over time. In the colder temperatures used, however, the pigeons all increased the number of feeding episodes per day. The results provide the first detailed analysis of cold-induced changes in ingestive behavior in the pigeon and raise several questions about the behavioral expression of cold-sensitive regulatory processes.