Direct and indirect effects of estrogen on rat hippocampus

Estrogen-induced synaptic plasticity was frequently shown by an increase of spines at apical dendrites of CA1 pyramidal neurons after systemic application of estradiol to ovariectomized rats. Recent findings question this direct endocrine regulation of synaptogenesis by estradiol. We have shown, for the first time, that estrogens are synthesized de novo in rat hippocampal neurons. By using letrozole, an inhibitor of aromatase, estradiol levels in hippocampal dispersion cultures as well as in hippocampal slice cultures were significantly suppressed. Letrozole treatment resulted in a significant decrease in the density of spines and spine synapses and in the number of presynaptic boutons. Quantitative immunohistochemistry revealed a dose-dependent downregulation of spinophilin, a spine marker, and of synaptophysin, a presynaptic marker, in the hippocampus. Surprisingly, exogenous application of estradiol to the cultures had no effect. Indirect effects of estrogens, mediated via subcortical nuclei, may help to explain this phenomenon. Implantation of estrogen-filled cannulae into the median raphe, which projects to the hippocampus, resulted in a significant increase in spine density in the hippocampus after seven days of treatment. This increase was paralleled by a decrease in the density of serotonergic innervation of the strata lacunosum moleculare and radiatum of the CA1 region. Apart from direct endocrine mechanisms our findings suggest that estradiol-induced spinogenesis in the hippocampus is also mediated by indirect mechanisms and is furthermore regulated endogenously, in a paracrine manner.     

The effects of prenatal stress, and of prenatal alcohol and nicotine exposure, on human sexual orientation

BACKGROUND: Studies of rats have shown that mothers who are subjected to stress during pregnancy are more likely than mothers who are not stressed during pregnancy to have male offspring who exhibit female-typical sexual receptivity postures (lordosis) in the presence of other males following the onset of puberty. More recent animal experiments have indicated that prenatal exposure to alcohol affects the sexual preferences of male offspring in ways that are similar to the effects of prenatal stress. Research with human subjects have thus far yielded inconsistent findings regarding the effects of prenatal stress on male sexual orientation, and no research has yet addressed the possible involvement of prenatal exposure to alcohol or other widely used recreational drugs, such as nicotine. PURPOSE: The present study was undertaken to determine if prenatal stress could be one of the causes of variations in sexual orientation in humans, both singularly and in conjunction with prenatal exposure to alcohol and nicotine. METHODS: Over 7500 offspring and their mothers provided information regarding the offspring's sexual orientation and the mother's stressful experiences and use of alcohol and nicotine during pregnancy. RESULTS: Findings indicate that prenatal stress has a modest but significant effect on the sexual orientation of male offspring, particularly when the stress occurred during the first trimester of pregnancy. Regarding prenatal exposure to alcohol, no evidence was found to suggest that it impacted offspring sexual orientation of either males or females. Prenatal nicotine exposure, however, appears to significantly increase the probability of lesbianism among female offspring, especially if the exposure occurred in the first trimester along with prenatal stress in the second trimester. CONCLUSION: The present study is consistent with animal models suggesting that prenatal stress disrupts the typical sex hormonal milieu within which male fetal brains are sexed, thereby feminizing/demasculinizing the male's sexual orientation. However, little support was found for similar effects of prenatal alcohol exposure. In the case of prenatal nicotine, this study is the first to suggest that this drug has masculinizing/defeminizing effects on the sexual orientation of female offspring.     

Direct and indirect effects of P2O5 glass reinforced-hydroxyapatite composites on the growth and function of osteoblast-like cells

Human osteoblast-like cells were plated on hydroxyapatite and P2O5-glass reinforced hydroxyapatite composite discs. They were also cultured in the presence of media obtained by incubating the discs in the absence of cells. The effects of these direct and indirect interactions were examined by measuring cell proliferation and the expression of certain key extracellular matrix antigens. One composite was found to initially delay cell growth, while the extract of a different composite appeared to down-regulate DNA synthesis. Flow cytometry analysis showed that growth directly on the discs had little effect on collagen type I, but reduced fibronectin and osteocalcin levels. The extracts of the materials generally had less effect, although one extract obtained from the glass-reinforced hydroxyapatite significantly down-regulated fibronectin. These in vitro studies thus suggest that there were only few differences overall in the growth of the cells directly on the glass-reinforced compared with the hydroxyapatite discs and also only relatively small effects of the extracts on the cells. However, the flow cytometry results suggest that both the materials and the extracts may have a potentially important influence on connective tissue production, and that these effects are both material- and antigen-specific.     

Direct and indirect effects of parenting and children's goals on child aggression.

This study tested a dual-mediation model of the relations among harsh parenting, hostile social information processing, and level of child aggression in a sample of 239 (150 male, 89 female) 2nd- to 4th-grade children. The theoretical model posited that harsh parenting has both direct and indirect effects on child level of aggression, with the indirect effects mediated through children's social goals. The model further posited that the impact of social goals on aggression is mediated through other social cognitive processes (i.e., attributions of hostile intent, hostile solution generation, and positive outcome expectancies for aggression). We tested the dual-mediation model with structural equation modeling and found it to be a good fit to the data. Results were consistent with the view that parenting affects children's goal orientation and that children's goal orientation affects their behavior via online processing in social situations.     

Neurological and neuropsychological effects of low and moderate prenatal alcohol exposure

Several explanations for the diverse results in research on foetal alcohol spectrum disorders or alcohol‐related neurodevelopmental disorder might be at hand: timing, amount and patterns of alcohol exposure, as well as complex epigenetic responses. The genetic background of the offspring and its interaction with other prenatal and post‐natal environmental cues are likely also of importance. In the present report, key findings about the possible effects of low and moderate doses of maternal alcohol intake on the neuropsychological development of the offspring are reviewed and plausible mechanisms discussed. Special focus is put on the serotonergic system within developmental and gene–environment frameworks. The review also suggests guidelines for future studies and also summarizes some of to‐be‐answered questions of relevance to clinical practice. Contradictory findings and paucity of studies on the effects of exposure to low alcohol levels during foetal life for the offspring's neuropsychological development call for large prospective studies, as well as for studies including neuroimaging and multi‐omics analyses to dissect the neurobiological underpinnings of alcohol exposure‐related phenotypes and to identify biomarkers. Finally, it remains to be investigated whether any safe threshold of alcohol drinking during pregnancy can be identified.     

Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function

The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo-pituitary-adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1–35 (early restriction; ER), or 36–70 (late restriction; LR). Female offspring (F₁) were mated and fed ad libitum to create second generation (F₂) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F₁ and F₂ offspring. ER_F1 males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ER_F2 offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.     

Direct and indirect effects of functionalised fluorescence-labelled nanoparticles on human osteoclast formation and activity

Recently, it was demonstrated that phosphonate-functionalised nanoparticles were successfully taken up by mesenchymal stem cells without influencing their viability and differentiation capacity, suggesting that they may provide a promising basis for the development of nanoparticles for drug delivery or cell labelling. The present study aimed to investigate the effects of these nanoparticles on osteoclast formation and activity as well as on the inflammatory response of osteoclasts and osteoblasts. The intracellular uptake of the particles by human osteoclasts and osteoblasts was demonstrated by confocal laser scanning microscopy, transmission electron microscopy and fluorescence microscopy. The expression of tartrate-resistant acid phosphatase, carboanhydrase II, cathepsin K, calcitonin receptor and osteoclast-specific vacuolar proton pump subunit TCIRG1 as well as actin ring formation were not significantly altered in osteoclasts by particle treatment, as demonstrated by cytochemical staining and immunostaining. Active calcium phosphate resorption by osteoclasts was also not significantly influenced by the particles. The expression and secretion of pro-inflammatory cytokines (IL-6, IL-1β) by osteoclasts and osteoblasts and the expression of osteoclast-regulating genes (M-CSF, OPG, RANKL) in osteoblasts were similarly not significantly affected. In conclusion, phosphonate-functionalised nanoparticles did not affect osteoclast formation and activity either directly or indirectly, suggesting that they could provide a promising tool for the development of particle-based treatments for anti-resorptive therapies.     

Acute effects of continuous and high‐intensity interval exercise on executive function

The purpose of this study was to examine the acute effects of 20‐min of cycling exercise at varying exercise intensities on executive function performance. Participants (N = 107) completed a baseline measure of executive function (Stroop task [ST]) and a graded cardiovascular exercise test during Visit 1. During Visit 2, participants were randomized to groups and completed 20 min of activity involving: high‐intensity interval exercise, high‐, moderate‐ or very‐light intensity continuous exercise, or no‐exercise (control). The ST was performed immediately following the exercise/control manipulation and at 10‐min post‐manipulation. Results showed exercise positively influenced executive function immediately after exercising in all groups with the exception of the very‐light intensity exercise group, while all groups showed significant improvements at 10‐min post‐exercise. Findings also revealed a significant difference between the moderate‐intensity exercise group in comparison to the very‐light intensity exercise group immediately post‐exercise. Among the exercise stimuli investigated, results suggest moderate‐intensity exercise provides the greatest beneficial effects on executive function immediately following exercise. Future research should focus on mechanisms that would account for enhanced executive function performance following acute exercise and dose–response effects.     

Direct and indirect effects of muscimol on medial vestibular nucleus neurones in guinea-pig brainstem slices

Inhibitory amino acids are considered as major transmitters in the vestibular system. Using intracellular recordings in slices, we applied gamma-aminobutyric acid (GABA) and muscimol (a specific agonist of the GABA_A receptor) to the two main types of medial vestibular nucleus neurones (A and B MVNn). In either a high Mg²⁺/low Ca²⁺ solution, or a solution containing tetrodotoxin, all MVNn were hyperpolarized by GABA and muscimol. This indicates that both types of MVNn are endowed with postsynaptic, hyperpolarising GABA_A receptors. In a normal medium, about half of A and B MVNn were, in contrast, depolarised by GABA and muscimol, whereas the remaining cells were hyperpolarised. These results could be due to a modulation by GABA and muscimol of a tonic GABA release in the slice. Such a release was, indeed, suggested by results showing the depolarising effect of either tetrodotoxin (TTX) or bicuculline, when applied alone. The cells that were depolarised by GABA or muscimol in control conditions were always hyperpolarised in the presence of TTX. Our data therefore suggest that GABA acting at GABA_A receptors in the medial vestibular nucleus can play a role either through a postsynaptic hyperpolarising action or indirectly by inhibiting a tonic GABA release, probably resulting from the spontaneous activity of local inhibitory interneurones. A GABAergic regulation of these interneurones could be important in processes of vestibular habituation and/or adaptation.     

Direct and indirect effects of breast milk on the neurobehavioral and cognitive development of premature infants

Eighty-six premature infants were tested to examine the effects of maternal breast milk on infant development. Infants were classified by breast-milk consumption during the hospitalization period (M = 57.4 days) into three groups: those receiving minimal (<25% of nutrition), intermediate (25-75%), and substantial (>75%) amounts of breast milk. Infants in the three groups were matched for birth weight, gestational age (GA), medical risk, and family demographics. At 37 weeks GA, mother-infant interaction was videotaped, maternal depression self-reported, and neurobehavioral maturation assessed by the Neonatal Behavior Assessment Seale (Brazelton, 1973). At 6 months corrected age, infants were tested with the Bayley II (Bayley, 1993). Infants receiving substantial amounts of breast milk showed better neurobehavioral profiles-in particular, motor maturity and range of state. These infants also were more alert during social interactions, and their mothers provided more affectionate touch. Higher maternal depression scores were associated with lower quantities of breast milk, longer latencies to the first breast-milk feeding, reduced maternal affectionate touch, and lower infant cognitive skills. Maternal affectionate touch moderated the relations between breast milk and cognitive development, with infants receiving a substantial amount of breast milk and frequent touch scoring the highest. In addition to its nutritional value, breast milk may be related to improved maternal mood and interactive behaviors, thereby indirectly contributing to development in premature infants.     

The effects of prenatal alcohol exposure on radial arm maze performance in adult rats

The hippocampal formation is sensitive to the in utero exposure to ethanol. It is one brain area thought to play an important role in spatial memory. We examined radial arm maze performance in rats exposed to ethanol prenatally. Pregnant rats were placed into the following treatment groups: LC, 17% EDC (ethanol-derived calories), 35% EDC, PF 35% or PF 17%. The LC group was fed lab chow and water ad lib, the 17% EDC and 35% EDC groups were fed a liquid diet containing either 3.3% or 6.7% v/v ethanol, respectively. Pair-fed controls were fed the same volume of an isocaloric diet as was consumed by their respective ethanol-treated groups. At birth, litters were culled to six and cross fostered to untreated surrogate mothers. Testing was initiated at 60 days of age and continued until the test criterion was satisfied. One-half of the rats in the 35% EDC group did not reach criterion. The remainder of the 35% EDC group and the 17% EDC rats attained criterion but required twice as many trials as their respective pair-fed controls. These results suggest that in utero administration of ethanol affects spatial memory capacity in rat, an observation consistent with other deficits seen in hippocampus of rats prenatally exposed to ethanol.     

Acute effects of exercise posture on executive function in transient ischemic attack patients

In patients with stroke or transient ischemic attacks (TIA), a decline in executive function may limit an individual's ability to process motor tasks and relearn motor skills. The purpose of this study was to assess the acute effect of exercise posture (seated vs. supine cycle ergometry) on executive function and prefrontal cortex perfusion in patients with TIA. Eleven TIA patients (65 ± 10 years) and 15 age‐matched, healthy controls (HC; 62 ± 7 years) completed two exercise tests to maximal capacity (one seated, one supine) and two 30‐min submaximal exercise tests (one seated, one supine). Executive function was assessed prior to and following (1.5 min post, 15 min post) the submaximal exercise tests using a Stroop task. Prefrontal cortex perfusion (total hemoglobin) was continuously recorded using near‐infrared spectroscopy. There was no Posture (seated, supine) × Group (TIA, HC) interaction for the Stroop task (p > .05). HC completed Stroop tasks significantly faster than TIA (51.9[SD = 10.3] vs. 64.2[8.5] s, respectively), while Stroop completion time significantly improved between baseline and 1.5 min post (61.3[10] vs. 58.1[9.4] s, respectively) and 1.5 min post and 15 min post (54.8[8.9] s). Posture and group had no significant influence on prefrontal cortex perfusion (p > .05). In summary, executive function improves to a similar extent in TIA and age‐matched, healthy controls following an acute bout of exercise, regardless of exercise posture. As acute improvements in executive function were maintained for 15 min, there could be an important window of opportunity for assigning executive tasks following exercise rehabilitation for patients with TIA.     

Age effects on executive ability

Heterogeneity of executive tasks has made it difficult to determine whether there are age-related declines in executive functioning. To address this issue, 112 individuals, 20-79 years old, took the California Trail Making Test (CTMT) and the California Stroop Test (CST), subtests of the Delis-Kaplan Executive Function Scale (D. C. Delis, E. Kaplan, & J. H. Kramer, in press) that include measurement of component skills embedded in the executive function tasks. Multiple regression analyses revealed that after controlling for component skills, age had a significant effect on the executive requirement of the CST, namely speed on the interference condition. Age did not affect switching performance on the letter-number condition of the CTMT. Additional analyses revealed that age was significantly associated with commission of certain types of errors. This study confirms the importance of partialing out components in the assessment of multidimensional cognitive tasks, particularly when making age comparisons. It also emphasizes specificity over generalizability when examining the impact of age on cognition.