Marlies K. Ozias

Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: Interactions with reproductive status in female rats

Decreased tissue levels of docosahexaenoic acid (DHA; 22:6n-3) are implicated in the etiologies of non-puerperal and postpartum depression. With the aim of determining neurobiological sequelae of decreased brain DHA content, this study examined the effects of a loss of brain DHA content and concurrent reproductive status in adult female Long-Evans rats. An alpha-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 23-26% lower than virgin and parous rats fed a control diet containing adequate alpha-linolenic acid. Parous dams were tested/euthanized at weaning (postnatal day 20) of the second litter; virgin females, during diestrus. Decreased brain DHA was associated with decreased hippocampal BDNF gene expression and increased relative corticosterone response to an intense stressor, regardless of reproductive status. In virgin females with decreased brain DHA, serotonin content and turnover in frontal cortex were decreased compared to virgin females with normal brain DHA. In parous dams with decreased brain DHA, the density of 5-HT(1A) receptors in the hippocampus was increased, corticosterone response to an intense stressor was increased, and the latency to immobility in the forced swim test was decreased compared to parous dams with normal DHA. These findings demonstrate neurobiological alterations attributable to decreased brain DHA or an interaction of parous status and brain DHA level. Furthermore, the data are consistent with findings in depressed humans, and thus support a role for DHA as a factor in the etiologies of depressive illnesses, particularly postpartum depression.

Dopamine receptor alterations in female rats with diet-induced decreased brain docosahexaenoic acid (DHA): interactions with reproductive status

Abstract Decreased tissue levels of n-3 (omega-3) fatty acids, particularly docosahexaenoic acid (DHA), are implicated in the etiologies of non-puerperal and postpartum depression. This study examined the effects of a diet-induced loss of brain DHA content and concurrent reproductive status on dopaminergic parameters in adult female Long–Evans rats. An α-linolenic acid-deficient diet and breeding protocols were used to produce virgin and parous female rats with cortical phospholipid DHA levels 20–22% lower than those fed a control diet containing adequate α-linolenic acid. Decreased brain DHA produced a significant main effect of decreased density of ventral striatal D2-like receptors. Virgin females with decreased DHA also exhibited higher density of D1-like receptors in the caudate nucleus than virgin females with normal DHA. These receptor alterations are similar to those found in several rodent models of depression, and are consistent with the proposed hypodopaminergic basis for anhedonia and motivational deficits in depression.

Differential effects of modulation of docosahexaenoic acid content during development in specific regions of rat brain.

Variation in brain FA composition, particularly decreased DHA (22ŋ6n−3), affects neurodevelopment, altering visual, attentional, and cognitive functions, and is implicated in several neuropsychiatric disorders. To further understand how specific brain processes and systems are affected by variation in brain DHA content, we sought to determine whether specific brain regions were differentially affected by treatments that after brain DHA content. Adult male Long-Evans rats were raised from conception using diet/breeding treatments to produce four groups with distinct brain phospholipid compositions. Total phospholipid FA composition was determined in whole brain and 15 brain regions by TLC/GC. Brain regions exhibited significantly different DHA contents, with the highest levels observed in the frontal cortex and the lowest in the substantia nigra/ventral tegmental area. Increased availability of DHA resulted in increased DHA content only in the olfactory bulb, parietal cortex, and substantia nigra/ventral tegmental area. In contrast, treatment that decreased whole-brain DHA levels decreased DHA content in all brain regions except the thalamus, dorsal midbrain, and the substantia nigra/ventral tegmental area. Alterations in DHA level were accompanied by changes in docosapentaenoic acid (n−6 DPA, 22∶5n−6) content; however, the change in DHA and n−6 DPA was nonreciprocal in some brain regions. These findings demonstrate that the FA compositions of specific brain regions are differentially affected by variation in DHA availability during development. These differential effects may contribute to the specific neurochemical and behavioral effects observed in animals with variation in brain DHA content.

Sex-specific effects of brain LC-PUFA composition on locomotor activity in rats

Insufficient availability of n-3 polyunsaturated fatty acids (PUFAs) during pre- and neonatal development decreases accretion of docosahexaenoic acid (DHA, 22:6n-3) in the developing brain and is associated with sub-optimal sensory and cognitive function in humans, altered behavior in animals, and may contribute to neurodevelopmental disorders such as attention deficit hyperactivity disorder and schizophrenia. This study examined the effects of variation in dietary availability of n-3 PUFAs on brain fatty acid composition and the consequent effects on locomotor activity in male and female Long-Evans rats. Rats were raised from conception using purified diets and breeding protocols designed to produce four groups with distinct brain phospholipid compositions varying in DHA content and/or the proportion of n-3 and n-6 PUFAs. Locomotor behavior was measured for a 2-h period on postnatal days 28, 42, 56, and 70. In males, decreased brain DHA produced alterations in activity that were most pronounced post-adolescence and with the greatest decrease in DHA. However, the behavioral effects in males were not linearly related to brain DHA level. In contrast, no significant effects of variation in brain fatty acid composition were observed in females. This suggests that variation in brain DHA content produces sex-specific alterations in locomotor activity and that the neurochemical alterations underlying the observed behavioral changes vary depending on the degree of DHA depletion.

Relationship of circulating adipokines to body composition in pregnant women.

Circulating adipokines are associated with physiological and pathophysiological processes in both obesity and pregnancy. Obesity in pregnancy increases the risk of pregnancy complications and the majority of research uses body mass index (BMI) to assess fatness. Specific fat compartments are associated with obesity-induced health risks yet it is not known how abdominal fat mass in pregnancy is related to circulating adipokines. Plasma leptin, resistin, visfatin, and adiponectin were measured by immunoassay in healthy pregnant women of normal weight (BMI 18.5–24.9; n = 17) and overweight/obese pregnant women (BMI 25.0–40, n = 21) in the third trimester. Total body and abdominal subcutaneous and visceral fat mass were measured at 1–3 weeks postpartum. Overweight/obese women had greater total body fat (t = −6.210, P < 0.001) and abdominal subcutaneous fat (t = −5.072, P < 0.001) than normal-weight women while there was no difference in abdominal visceral fat. Overweight/obese women had higher leptin (66.3 ± 34.2 vs. 35.7 ± 19.3 ng/mL, P < 0.001) compared to normal-weight women. Leptin was associated with total body fat (r = 0.782, P < 0.001) and resistin was associated with abdominal visceral fat (r = 0.452, P = 0.045). No significant correlations were observed between adiponectin or visfatin and any measure of body composition. In pregnant women, resistin has the potential to be a circulating biomarker for visceral fat, an ectopic fat compartment. These observational data may provide insight for the pathophysiological roles of adipokines and the impact of visceral fat in pregnant women.

Typical prenatal vitamin D supplement intake does not prevent decrease of plasma 25-hydroxyvitamin D at birth.

Objective: The objective of this longitudinal study was to determine what typical vitamin D predictors influence the change in vitamin D status from mid-pregnancy to birth. Methods: Plasma 25-hydroxyvitamin D [25(OH)D] was determined at mid-pregnancy (8–20 weeks gestation) and following birth (n = 193). Usual predictors of vitamin D status [body mass index (BMI), race, season] in addition to prenatal supplemental vitamin D intake and docosahexaenoic acid (DHA) status at delivery were assessed for their interaction on the change on plasma 25(OH)D concentration between the two time points. Results: Forty-nine percent of women had inadequate vitamin D status [categorized as deficient (<30 nmol/L) or insufficient (30–49.9 nmol/L) by IOM guidelines] at mid-pregnancy and 82% were deficient or insufficient at birth. Plasma 25(OH)D concentration dropped 61% from mid-pregnancy to birth. Season of birth (F = 7.86, P = 0.006) and mid-pregnancy plasma 25(OH)D concentration (F = 6.17, P = 0.014) were significant variables in the change of vitamin D status while BMI, race, DHA status, and typical vitamin D intake (334 IU/day) from prenatal supplements did not have an effect. Women who delivered in summer and fall had a 1.5-fold greater plasma 25(OH)D concentration than women who delivered in winter in spring (41.1 ± 23.1 and 40.7 ± 20.5 nmol/L summer and fall, respectively, versus 27.7 ± 17.9 and 29.3 ± 21.4 nmol/L in winter and spring, respectively). Conclusions: Typical supplemental vitamin D intake during pregnancy did not prevent precipitous drops in maternal plasma 25(OH)D concentration. Clinicians and dietitians should be aware of the risk of inadequate vitamin D status in pregnant women in the United States relative to their initial vitamin D status and the season of birth.

Maternal Vitamin D Status and Infant Infection

Maternal vitamin D status during pregnancy may modulate fetal immune system development and infant susceptibility to infections. Vitamin D deficiency is common during pregnancy, particularly among African American (AA) women. Our objective was to compare maternal vitamin D status (plasma 25(OH)D concentration) during pregnancy and first-year infections in the offspring of African American (AA) and non-AA women. We used medical records to record frequency and type of infections during the first year of life of 220 term infants (69 AA, 151 non-AA) whose mothers participated in the Kansas University DHA Outcomes Study. AA and non-AA groups were compared for maternal 25(OH)D by Mann–Whitney U-test. Compared to non-AA women, AA women were more likely to be vitamin D deficient (<50 nmol/L; 84 vs. 37%, p < 0.001), and more of their infants had at least one infection in the first 6 months (78.3% and 59.6% of infants, respectively, p = 0.022). We next explored the relationship between maternal plasma 25(OH)D concentration and infant infections using Spearman correlations. Maternal 25(OH)D concentration was inversely correlated with the number of all infections (p = 0.033), eye, ear, nose, and throat (EENT) infections (p = 0.043), and skin infection (p = 0.021) in the first 6 months. A model that included maternal education, income, and 25(OH)D identified maternal education as the only significant predictor of infection risk in the first 6 months (p = 0.045); however, maternal education, income, and 25(OH)D were all significantly lower in AA women compared to non-AA women . The high degree of correlation between these variables does not allow determination of which factor is driving the risk of infection; however, the one that is most easily remediated is vitamin D status. It would be of value to learn if vitamin D supplementation in this at-risk group could ameliorate at least part of the increased infection risk.

Abdominal visceral adiposity influences CD4+ T cell cytokine production in pregnancy

Women with pre-gravid obesity are at risk for pregnancy complications. While the macrophage response of obese pregnant women categorized by body mass index (BMI) has been documented, the relationship between the peripheral CD4(+) T cell cytokine profile and body fat compartments during pregnancy is unknown. In this study, third trimester peripheral CD4(+) T cell cytokine profiles were measured in healthy pregnant women [n=35; pre-pregnancy BMI: 18.5-40]. CD4(+) T cells were isolated from peripheral blood mononuclear cells and stimulated to examine their capacity to generate cytokines. Between 1 and 3weeks postpartum, total body fat was determined by dual-energy X-ray absorptiometry and abdominal subcutaneous and visceral fat masses were determined by magnetic resonance imaging. Pearsons correlation was performed to assess relationships between cytokines and fat mass. Results showed that greater abdominal visceral fat mass was associated with a decrease in stimulated CD4(+) T cell cytokine expression. IFN-gamma, TNF-alpha, IL-12p70, IL-10 and IL-17A were inversely related to visceral fat mass. Chemokines CCL3 and IL-8 and growth factors G-CSF and FLT-3L were also inversely correlated. Additionally, total body fat mass was inversely correlated with FGF-2 while abdominal subcutaneous fat mass and BMI were unrelated to any CD4(+) T cell cytokine. In conclusion, lower responsiveness of CD4(+) T cell cytokines associated with abdominal visceral fat mass is a novel finding late in gestation.