Parental enriched environment: A look through key temporary windows.

Environmental enrichment is a widely used experimental manipulation that physically, cognitively and socially stimulates individuals. It has a great variety of long-term effects at neuroanatomical, neurochemical, and behavioral level; however, the influence of parental environmental enrichment during gestation and pregestation on the development of the offspring and on the mother's behavior has been poorly explored. This article presents a review of the literature from the year 2000 about the effects of maternal and paternal environmental enrichment on the behavioral, endocrine, and neural systems of offspring and parents. Relevant research terms were searched for on the biomedical databases, PubMed, Medline, ScienceDirect, and Google Scholar. The data suggest that paternal/maternal environmental enrichment can profoundly affect the developmental trajectories of offspring through putative epigenetic mechanisms. Environmental enrichment presents as a promising therapeutic tool for human health interventions, especially to counteract the deleterious effects of impoverished and adverse growing conditions.

Gonadal hormone-independent sex differences in GABAA receptor activation in rat embryonic hypothalamic neurons.

BACKGROUND AND PURPOSE: GABAA receptor functions are dependent on subunit composition, and, through their activation, GABA can exert trophic actions in immature neurons. Although several sex differences in GABA-mediated responses are known to be dependent on gonadal hormones, few studies have dealt with sex differences detected before the critical period of brain masculinisation. In this study, we assessed GABAA receptor functionality in sexually segregated neurons before brain hormonal masculinisation. EXPERIMENTAL APPROACH: Ventromedial hypothalamic neurons were obtained from embryonic day 16 rat brains and grown in vitro for 2 days. Calcium imaging and electrophysiology recordings were carried out to assess GABAA receptor functional parameters. KEY RESULTS: GABAA receptor activation elicited calcium entry in immature hypothalamic neurons mainly through L-type voltage-dependent calcium channels. Nifedipine blocked calcium entry more efficiently in male than in female neurons. There were more male than female neurons responding to GABA, and they needed more time to return to resting levels. Pharmacological characterisation revealed that propofol enhanced GABAA -mediated currents and blunted GABA-mediated calcium entry more efficiently in female neurons than in males. Testosterone treatment did not erase such sex differences. These data suggest sex differences in the expression of GABAA receptor subtypes. CONCLUSION AND IMPLICATIONS: GABA-mediated responses are sexually dimorphic even in the absence of gonadal hormone influence, suggesting genetically biased differences. These results highlight the importance of GABAA receptors in hypothalamic neurons even before hormonal masculinisation of the brain.

Sex differences in depolarizing actions of GABAA receptor activation in rat embryonic hypothalamic neurons.

GABAA receptor activation exerts trophic actions in immature neurons through depolarization of resting membrane potential. The switch to its classical hyperpolarizing role is developmentally regulated. Previous results suggest that a hormonally biased sex difference exists at the onset of the switch in hypothalamic neurons. The aim of this work was to evaluate sex differences in GABAA receptor function of hypothalamic neurons before brain masculinization by gonadal hormones. Hypothalamic cells were obtained from embryonic day 16 male and female rat foetuses, 2 days before the peak of testosterone production by the foetal testis, and grown in vitro for 9 days. Whole-cell and perforated patch-clamp recordings were carried out in order to measure several electrophysiological parameters. Our results show that there are more male than female neurons responding with depolarization to muscimol. Additionally, among cells with depolarizing responses, males have higher and longer lasting responses than females. These results highlight the relevance of differences in neural cell sex irrespective of exposure to sex hormones.

Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.

Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1(G93A)) increases persistent sodium inward currents (PC(Na)), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Na(v)) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1(G93A). These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1(G93A) on motoneurons is increased excitability, an observation with direct implications for therapy of ALS.

Sex chromosome complement contributes to sex differences in bradycardic baroreflex response.

To investigate whether sex chromosome complement modulates bradycardic baroreflex response and contributes to the angiotensin II-bradycardic baroreflex sex differences, we used the four core genotype mouse model in which the effect of gonadal sex and sex chromosome complement is dissociated, allowing comparisons of sexually dimorphic traits among XX and XY females, as well as in XX and XY males. In conscious gonadectomized (GDX) MF1 transgenic mice we evaluated baroreflex regulation of heart rate in response to changes in blood pressure evoked by phenylephrine (1 mg/mL), angiotensin II (100 µg/mL), and sodium nitroprusside (1 mg/mL). The administration of phenylephrine in GDX-XY females resulted in a significantly lower baroreflex response when compared with the other genotypes (in beats · min(-1) · mm Hg(-1) [slopes of regression lines for GDX-XY females -3.56±0.37 versus -6.06±0.38, -6.37±0.54 and -6.70±0.34 for GDX-XY male, GDX-XX female, and GDX-XX male mice, respectively]) {F(1,19)=9.63; P<0.01}. In addition, in both GDX-XY males and females, the angiotensin II-bradycardic baroreflex response was attenuated when compared with heart rate changes in GDX-XX male and female mice (in beats · min(-1) · mm Hg(-1) [slopes of regression lines: -2.83±0.28 versus -5.76±0.26 in GDX-XY and GDX-XX mice, respectively]) {F(1,19)=13.91; P<0.005}. In contrast, reflex tachycardic responses to sodium nitroprusside were comparable in all of the genotypes. These data support the hypothesis that sex chromosome complement modulates reflex inhibition of heart rate to phenylephrine and angiotensin II. Elucidating the foundational sources of sexually dimorphic traits in the regulation of baroreceptor reflex may enable the design of more appropriate sex-tailored therapeutic treatments in the future.