Mary E. Coussons-Read

Behavioral assessment of the Ts65Dn mouse, a model for down syndrome: Altered behavior in the elevated plus maze and open field

The Ts65Dn mouse carries a partial trisomy for mouse chromosome 16 in a region that has high homology to the Down syndrome (DS) region of human chromosome 21 and is, thus, a potential animal model of DS. The focus of the present study was to begin to characterize the behavioral phenotype of this mouse to assess its usefulness as a model of aspects of the DS phenotype. The behavior of Ts65Dn and littermate control mice was assessed in the elevated plus maze, lighted and dark open field, and a step-down passive avoidance task. The behavior of Ts65Dn mice in these tests differed considerably from the nontrisomic controls. In the elevated plus maze, Ts65Dn had more total arm visits than controls, showed a higher percentage of arm visits to the open arms than control mice, and showed no preference for the closed arms. Ts65Dn mice were more active in both open-field situations, regardless of light condition, and ventured into the center of the arena more than controls. Lighting in the open field had moderate effects on the activity of the Ts65Dn mice, but control mice were, as expected, much more active in the dark than the light. The trisomic mice learned and retained the step-down passive avoidance task in the same number of trials as the controls. Overall, these data indicate that Ts65Dn mice are more active than control mice in two testing situations. Most striking is the finding that the Ts65Dn mice were much less responsive to variations in environmental cues to which normal mice are quite sensitive. These data not only begin to characterize systematically the Ts65Dn phenotype, but also raise several interesting issues about the sources of the aberrant behaviors observed in these mice.

Prenatal stress alters cytokine levels in a manner that may endanger human pregnancy.

Objective: Recent data suggest that prenatal stress negatively affects pregnancy and infant outcome. Existing studies implicate dysregulation of the immune and endocrine systems in stress-related increases in premature labor and poor birth outcome, but no published studies have directly addressed the relationships among these variables during pregnancy. We sought to test the hypothesis that high levels of psychosocial stress and low levels of social support during pregnancy alter maternal cytokine profiles in a manner that contributes to poor birth outcomes. Methods: Psychosocial stress and social support were measured in 24 women with overtly normal pregnancies once during each trimester of pregnancy. Levels of interleukin-10 (IL-10), IL-6, and tumor necrosis factor-&agr; (TNF-&agr;) were assessed concurrently with stress and support measurements. Results: High social support was associated with low stress scores. Elevated stress scores were positively correlated with higher levels of the proinflammatory cytokines IL-6 and TNF-&agr;, and with low levels of the antiinflammatory cytokine IL-10. Conclusions: These findings provide initial support for our hypothesis that stress-related neural immune interactions may contribute to pregnancy complications and poor outcome, but require further study to determine the mechanism and significance of these effects. NK = natural killer; DMHA = Denver Maternal Health Assessment; SRR = Social Readjustment Rating; MCSD = Marlowe-Crowne Social Desirability; MRC = multiple linear regression and correlation.

The occurrence of preterm delivery is linked to pregnancy-specific distress and elevated inflammatory markers across gestation.

There is mounting evidence that stress during pregnancy can have detrimental effects on gestation and birth. Existing studies indicate that prenatal stress may increase levels of circulating inflammatory markers that are associated with prematurity and pregnancy complications, suggesting that stress-related changes in the cytokine milieu may increase the risk of poor pregnancy outcome. Previous studies, however, have not clearly connected stress during pregnancy to changes in inflammatory mediators and, in turn, to clinically-relevant outcomes such as premature delivery. The present study sought to directly connect prenatal stress and changes in inflammatory markers to preterm delivery and gestational age at birth (GAB). A sample of 173 women was recruited during the first trimester of pregnancy and followed through delivery. Overall stress, pregnancy-specific distress, and inflammatory markers were assessed early and later in pregnancy, and the predictive value of these measures for preterm birth and GAB was determined. There were significant differences in pregnancy-specific distress, IL-6, and TNF-α between women who delivered prematurely versus those who delivered at term, and elevated levels of pregnancy-specific distress, IL-6, and TNF-α were predictive of shortened GAB overall. Importantly, in many cases, the effects of overall stress and pregnancy-specific distress on GAB were mediated by levels of circulating inflammatory markers. Collectively, these data provide strong evidence that prenatal stress experiences can affect the timing of parturition via alterations in circulating inflammatory mediators, and underscore the need for ongoing research aimed at further understanding the mechanisms and effects of prenatal stress on maternal and infant health.

Sleep disruption during pregnancy: how does it influence serum cytokines?

Women report their sleep to be disrupted during pregnancy. Sleep deprivation has been linked to elevations in pro-inflammatory cytokine levels. No information currently addresses the sleep-immune relationship during pregnancy. This study explores the relationship between subjectively reported sleep variables and circulating serum cytokine levels. Pregnant women (n=35; mean age=31.0+/-3.7 years) seen once a trimester completed sleep questionnaires, gave blood and recorded their sleep on a sleep diary at home for 2 weeks. Nonpregnant women (n=43; mean age=28.2+/-5.2 years) underwent the same protocol once. Subjective sleep variables were compared to serum cytokine levels for IL-4, -6, -10 and TNF-alpha as well as C-reactive protein (CRP) determined by ELISA. Nonparametric analyses and linear regression were performed to explore relationships between the sleep and immune variables. Pregnant women subjectively reported their sleep to be worse than in the nonpregnant group. Serum cytokine levels differed between the two groups and varied by trimester. As anticipated, IL-10 was significantly higher in all trimesters; however CRP, an indicator of systemic inflammation, was higher in all trimesters compared to the nonpregnant sample. Subjectively reported sleep disruption was associated with increases in TNF-alpha in the pregnant sample and CRP in the nonpregnant sample. These data confirm that disrupted sleep experienced during pregnancy, as well as during the nonpregnant state, is related to increases in inflammatory markers. Future exploration of these relationships should include functional assessments of immunity as well as polysomnographically recorded sleep.

Exploring the cytokine and endocrine involvement in narcolepsy

Narcolepsy is a disabling neurological sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep manifestations. Recently, the role of cytokines and growth hormone in the regulation of sleep and narcolepsy has been considered, and data suggest that proinflammatory cytokines may be involved in sleep and narcoleptic symptoms. Serum and clinical data were obtained from the Stanford Center for Narcolepsy Research for 39 Narcoleptics (22 Females, 17 Males, age 39+/-14.9) and 40 controls (13 Females, 27 Males, age 46+/-17.9). Plasma levels of TNF-alpha, IL-6, and human growth hormone (hGH) were measured by ELISA. TNF-alpha and IL-6 were significantly increased in narcoleptic subjects compared to controls (p=.001). Interestingly, hGH was significantly increased in narcoleptic subjects (p <.0001). There was also a significant difference in the epworth sleepiness scale (ESS) (17.7+/-4.6 vs. 5.5+/-3.2, p <.0001). These data indicate that narcoleptics, relative to controls, had higher serum levels of TNF-alpha, IL-6, and hGH. These data suggest that the dysregulation of sleep observed in narcoleptics correlates with the immune and endocrine dysregulation seen in these subjects, and the observed changes may in fact contribute to the higher likelihood of disturbed sleep and/or increased incidence of infection. Additional work is required to fully characterize connections between cytokines and narcoleptic symptomatology.

Sleep disturbances increase interleukin-6 production during pregnancy: implications for pregnancy complications.

Pregnant women experience disturbed sleep that varies throughout the gestational period. In clinical studies of nonpregnant cohorts, data link disturbed sleep with increases in inflammatory markers. Emerging evidence has also found associations between increased inflammation and medical morbidity, including various pregnancy complications. The authors have previously shown a correlation between sleep disturbances and serum cytokine levels. They extend this initial observation by evaluating the relationship between sleep during mid and late pregnancy and inflammatory cytokines in both serum and stimulated peripheral blood mononuclear cells. Subjective sleep during pregnancy, described by the Pittsburgh Sleep Quality Index and sleep diaries, and circulating and stimulated measures of interleukin (IL)—6 and tumor necrosis factor (TNF)—α were evaluated in 19 pregnant women. The authors found that greater sleep complaints in late pregnancy were associated with both increased circulating and stimulated IL-6 levels. Short sleep duration and poor sleep efficiency in both mid and late pregnancy were associated with higher stimulated levels of IL-6. No relationships were observed for TNF-α. These preliminary findings indicate that women who experience sleep disturbances as early as mid gestation are likely to have an increase in inflammation.

Disturbed sleep is associated with increased C-reactive protein in young women.

Evidence links disturbed sleep with an exaggerated inflammatory response and increased risk of adverse health outcomes. An emerging risk factor for many adverse health outcomes is chronic, low-grade inflammation. An exaggerated inflammatory response could provide a biological link between disturbed sleep and adverse health outcomes. The relationship between sleep and chronic, low-grade inflammation has been sparsely examined in otherwise healthy, young women. We evaluated cross-sectional relationships between self-reported sleep and three inflammatory markers. Participants were community dwelling nonpregnant women (N=43, 28.2+/-5.2 years of age). Measures included the Pittsburgh Sleep Quality Index (PSQI), sleep diaries, and serum levels of IL-6, TNF-alpha and C-reactive protein. Poor sleep quality and continuity were associated with higher CRP levels after controlling for covariates. No significant relationships were observed between PSQI scores and IL-6 or TNF-alpha; sleep duration was not related to any of the inflammatory markers. Poor sleep, in young adulthood, may contribute to the chronic, low-grade inflammation associated with an increased risk for future adverse health outcomes. Future work should longitudinally evaluate how these relationships may affect development of gender-specific diseases in apparently healthy young women.

Acculturation, maternal cortisol, and birth outcomes in women of Mexican descent.

Objective This study investigated the effects of acculturation on cortisol, a biological correlate of maternal psychological distress, and perinatal infant outcomes, specifically gestational age at birth and birth weight. Methods Fifty-five pregnant women of Mexican descent were recruited from a community hospital, and their saliva samples were collected at home for 3 days during pregnancy at 15 to 18 weeks (early), 26 to 32 weeks (mid), and more than 32 weeks (late) of gestation and once in the postpartum period (4–12 weeks). These values were used to determine the diurnal cortisol slope at each phase of pregnancy. Mothers also completed an acculturation survey and gave permission for a medical chart review to obtain neonate information. Results Multiple regression analyses determined that greater acculturation levels significantly predicted earlier infant gestational age at birth (R2 = 0.09, p = .03). Results from t tests revealed that mothers of low-birth-weight infants (<2500 g) had significantly higher acculturation scores than mothers of infants with birth weight greater than 2500 g (t = −2.95, p = .005). A blunted maternal cortisol slope during pregnancy was also correlated with low birth weight (r = −0.29, p = .05) but not gestational age (r = −0.08, p = .59). In addition, more acculturated women had a flatter diurnal cortisol slope late in pregnancy (R2 = 0.21, p = .01). Finally, diurnal maternal cortisol rhythms were identified as a potential mediator between increased acculturation and birth weight. Conclusions This study associated increased acculturation with perinatal outcomes in the US Mexican population. This relationship may be mediated by prenatal maternal diurnal cortisol, which can program the health of the fetus leading to several adverse perinatal outcomes. Abbreviations US = United States; HPA = hypothalamic-pituitary-adrenal; SASH = Short Acculturation Scale for Hispanics

High Altitude Residence During Pregnancy Alters Cytokine and Catecholamine Levels

Coussons‐Read ME, Mazzeo RS, Whitford MH, Schmitt M, Moore LG, Zamudio S. High altitude residence during pregnancy alters cytokine and catecholamine levels. AJRI 2002: 48:344–354

Acute morphine treatment alters cellular immune function in the lungs of healthy rats.

Previous work has shown that morphine suppresses the pulmonary immune response to infection and reduces pulmonary inflammation. No published studies have addressed the impact of morphine on lymphocyte function in the lungs without infection. This study addressed this question by assessing the impact of acute morphine treatment on proliferation, cytokine production, and natural killer (NK) cell activity in resident pulmonary lymphocytes from healthy rats. Male Lewis rats received either a single 15 mg/kg morphine sulfate or vehicle injection 1 h prior to sacrifice. Lungs were minced and passed through wire mesh following collagenase digestion. The resulting cell preparations were pooled (2 rats/pool) to yield sufficient cell numbers for the functional assays, and a portion of these suspensions were separated using a density gradient. Crude and purified cell suspensions were used in assays of NK cell activity and mitogen-induced proliferation and cytokine production. Morphine significantly suppressed lymphocyte proliferation and cytokine production in whole cell suspensions, but not in purified cultures. NK activity was enhanced by morphine treatment in purified treated cultures. Studies of nitrate/nitrite levels in crude and purified cultures suggest that macrophage-derived nitric oxide may be a mechanism of the suppression observed in whole cell suspensions following morphine treatment. These data are consistent with previous work showing that morphine suppresses mitogenic responsiveness and NK activity in the spleen and peripheral blood, and may do so through a macrophage-derived nitric oxide mechanism.