Do Sex Differences in the Brain Explain Sex Differences in the Hormonal Induction of Reproductive Behavior? What 25 Years of Research on the Japanese Quail Tells Us

Early workers interested in the mechanisms mediating sex differences in morphology and behavior assumed that differences in behavior that are commonly observed between males and females result from the sex specificity of androgens and estrogens. Androgens were thought to facilitate male-typical traits, and estrogens were thought to facilitate female-typical traits. By the mid-20th century, however, it was apparent that administering androgens to females or estrogens to males was not always effective in sex-reversing behavior and that in some cases a “female” hormone such as an estrogen could produce male-typical behavior and an androgen could induce female-typical behavior. These conceptual difficulties were resolved to a large extent by the seminal paper of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in (1959,Endocrinology65, 369–382) that illustrated that several aspects of sexual behavior are different between males and females because the sexes have been exposed during their perinatal life to a different endocrine milieu that has irreversibly modified their response to steroids in adulthood. Phoenixet al.(1959) therefore formalized a clear dichotomy between the organizational and activational effects of sex steroid hormones. Since this paper, a substantial amount of research has been carried out in an attempt to identify the aspects of brain morphology or neurochemistry that differentiate under the embryonic/neonatal effects of steroids and are responsible for the different behavioral response of males and females to the activation by steroids in adulthood. During the past 25 years, research in behavioral neuroendocrinology has identified many sex differences in brain morphology or neurochemistry; however many of these sex differences disappear when male and female subjects are placed in similar endocrine conditions (e.g., are gonadectomized and treated with the same amount of steroids) so that these differences appear to be of an activational nature and cannot therefore explain sex differences in behavior that are still present in gonadectomized steroid-treated adults. This research has also revealed many aspects of brain morphology and chemistry that are markedly affected by steroids in adulthood and are thought to mediate the activation of behavior at the central level. It has been explicitly, or in some cases, implicitly assumed that the sexual differentiation of brain and behavior driven by early exposure to steroids concerns primarily those neuroanatomical/neurochemical characteristics that are altered by steroids in adulthood and presumably mediate the activation of behavior. Extensive efforts to identify these sexually differentiated brain characteristics over the past 20 years has only met with limited success, however. As regards reproductive behavior, in all model species that have been studied it is still impossible to identify satisfactorily brain characteristics that differentiate under early steroid action and explain the sex differences in behavioral activating effects of steroids. This problem is illustrated by research conducted on Japanese quail (Coturnix japonica), an avian model system that displays prominent sex differences in the sexual behavioral response to testosterone, and in which the endocrine mechanisms that control sexual differentiation of behavior have been clearly identified so that subjects with a fully sex-reversed behavioral phenotype can be easily produced. In this species, studies of sex differences in the neural substrate mediating the action of steroids in the brain, including the activity of the enzymes that metabolize steroids such as aromatase and the distribution of steroid hormone receptors as well as related neurotransmitter systems, did not result in a satisfactory explanation of sex differences in the behavioral effectiveness of testosterone. Possible explanations for the relative failure to identify the organized brain characteristics responsible for behavioral sex differences in the responsiveness to steroids are presented. It is argued that novel research strategies may have to be employed to successfully attack the fundamental question of the hormonal mechanisms regulating sex differences in behavior.     

The Sex Specific Genetic Variation of Energetics in Bank Voles,Consequences of Introgression?

Interaction between mitochondrial and nuclear genomes is expected to affect energetic phenotypes of traits linked to mitochondrial physiology, further influencing the fitness. A rodent, the bank vole (Myodes glareolus), has a population structure completely or partially introgressed with mitochondria from its relative, the red vole (M. r utilus). Females that carried either bank vole mitochondria or mitochondria from the introgressed species were repeatedly mated with males of both mtDNA types. We found that in males, but not in females, morpho-physiological phenotypes are affected by sire type, causing decreases in body mass (BM) and basal metabolic rate (BMR; including BM corrected, rBMR) in individuals sired by fathers carrying introgressed mitochondria. Higher effect sizes for the proportion of additive genetic variation (and 5.6, 1.9 and 3.6 times higher narrow sense heritability for BM, BMR and rBMR, respectively), and lower for proportion of environmental variation were detected in progeny of non-introgressed males. Our data indicate that co-adapted and possibly co-introgressed nuclear genes related to energetic physiology have an important role in adaptation to the northern conditions in bank voles, and that sex linked nuclear genes are a potential source for variation in basal metabolic rate.     

Sex Differences in Hypertension: Contribution of the Renin–Angiotensin System

Numerous studies have shown that female human beings exhibit lower blood pressure levels over much of their life span compared with their age-matched counterparts. This sexual dimorphism is apparent in human beings as well as most, if not all, mammals. However, after the onset of menopause blood pressure levels in women increase and become similar to those in men, suggesting an important role of sex hormones in the regulation of blood pressure. The lower blood pressure levels in premenopausal women are associated with a lower risk of development and progression of cardiovascular disease and hypertension compared with age-matched men. This clear female advantage with respect to lower incidence of cardiovascular disease no longer exists after menopause, again highlighting the importance of sex hormones in the pathophysiology of cardiovascular disease in both men and women. In fact, both estrogens and androgens have been implicated in the development of cardiovascular disease and hypertension, with estrogens, in general, being protective and androgens being detrimental. Although the exact mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated, there is increasing evidence that modulating the activity of locally active hormonal systems is one of the major mechanisms of sex hormone actions in target organs, including the vasculature and kidneys. Indeed, several studies have demonstrated the importance of the interaction between sex hormones and the renin–angiotensin system in regulating cardiovascular function and blood pressure. Furthermore, the differential effects of estrogens and androgens on the expression and activity of the components of the renin–angiotensin system could possibly explain the sex differences in blood pressure levels and the development and progression of cardiovascular disease and hypertension.     

Differences in Mouse Maternal Care Behavior – Is There a Genetic Impact of the Glucocorticoid Receptor?

Depressive episodes are frequently preceded by stressful life events. Evidence from genetic association studies suggests a role for the glucocorticoid receptor (GR), an essential element in the regulation of stress responses, in the pathophysiology of the disorder. Since the stress response system is affected by pregnancy and postpartum-associated changes, it has also been implicated in the pathophysiology of postpartum depression. Using a 2 × 2 factorial design, we investigated whether a heterozygous deletion of GR would influence maternal care behavior in C57BL/6 and Balb/c mice, two inbred strains known to display qualitative differences in this behavior. Behavioral observation was carried out between postnatal days 1 and 7, followed by a pup retrieval test on postnatal days 7 or 8. While previously noted inter-strain differences were confirmed for different manifestations of caring behavior, self-maintenance and neglecting behaviors as well as the pup retrieval test, no strain-independent effect of the GR mutation was noted. However, an interaction between GR genotype and licking/grooming behavior was observed: it was down-regulated in heterozygous C57BL/6 mice to the level recorded for Balb/c mice. Home cage observation poses minimal disturbance of the dam and her litter as compared to more invasive assessments of dams' emotional behavior. This might be a reason for the absence of any overall effects of the GR mutation, particularly since GR heterozygous animals display a depressive-like phenotype under stressful conditions only. Still, the subtle effect we observed may point towards a role of GR in postpartum affective disorders.     

Sex Differences in β-Adrenergic Responsiveness of Action Potentials and Intracellular Calcium Handling in Isolated Rabbit Hearts

Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by β-adrenergic signaling. However, further studies examining sex differences in β-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during β-adrenergic stimulation. The non-selective β-agonist isoproterenol (Iso) decreased AP duration (APD₉₀), CaT duration (CaD₈₀), and the decay constant of the CaT (τ) in a dose-dependent manner (1–316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD₉₀ and τ (but not CaD₈₀) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to β-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and “maximal” levels of Iso effects), however this reduced β-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity.     

Sex Differences in the Biomechanics and Contractility of Intramural Coronary Arteries in Angiotensin II–Induced Hypertension

BackgroundIt is well known that sex differences occur in both the pathogenesis and therapy of hypertension. A deeper understanding of the underlying processes may be helpful when planning a personalized therapeutic strategy.ObjectiveIn laboratory animal experiments, we studied the early mechanisms of vascular adaptation of the intramural small coronary arteries that play a fundamental role in the blood supply of the heart.MethodsIn our study, an osmotic minipump was implanted into 10 male and 10 female Sprague-Dawley rats. The pump remained in situ for 4 weeks, infusing a dose of 100 ng/kg/min angiotensin II acetate. Four weeks later, the animals were killed, and the intramural coronary arteries from the left coronary branch, which are fundamentally responsible for the blood supply of the heart, were prepared. The pharmacologic reactivity and biomechanical properties of the prepared segments were studied in a tissue bath.ResultsThe relative heart mass and vessel wall thickness were greater in females than males (0.387 [0.009] g/100 g vs 0.306 [0.006] g/100 g body weight; 41.9 [4.09] μm vs 33.45 [3.37] μm on 50 mm Hg). The vessel tone and vasoconstriction in response to thromboxane agonists were, however, significantly more pronounced in males. The extent of relaxation in response to bradykinin was also greater in females. Although we observed inward eutrophic remodeling in females, an increase in wall stress and elastic modulus dominated in males.ConclusionThe early steps of angiotensin II–dependent hypertension evoked very different adaptation mechanisms in males and females.     

Genetic Analysis of the Bacteriophage λ Attl Nucleoprotein Complex

Site-specific recombination in bacteriophage λ involves interactions among proteins required for integration and excision of DNA molecules. We have analyzed the elements required to form an in vivo nucleoprotein complex of integrase (Int) and integration host factor (IHF). Interaction of Int with the core (the site of strand exchange) is stabilized by the flanking arm region of attL. IHF, in addition to Int, is required for efficient Int-core binding. We used the in vivo attL binding assay to characterize several Int variants for their abilities to form stable attL complexes. Substitution of Int active site tyrosine 342 by phenylalanine had no effect on the ability of the protein to form attL complexes. Three other amino acids that are completely conserved in the integrase family of recombinases (arginine 212, histidine 308, and arginine 311) were separately substituted by glutamine, leucine, and histidine, respectively. In each case, the mutant protein was altered in its ability to form attL complexes while retaining its ability to bind to the λ arm-type sites. We propose that, in addition to their role in catalysis, this triad of amino acids helps the Int protein to interact with the λ core sites.     

eCOMPAGT – efficient Combination and Management of Phenotypes and Genotypes for Genetic Epidemiology

Background  

High-throughput genotyping and phenotyping projects of large epidemiological study populations require sophisticated laboratory information management systems. Most epidemiological studies include subject-related personal information, which needs to be handled with care by following data privacy protection guidelines. In addition, genotyping core facilities handling cooperative projects require a straightforward solution to monitor the status and financial resources of the different projects.     

Variance‐Sensitive Green Woodhoopoes: A New Explanation for Sex Differences in Foraging?

Studies of cooperatively breeding birds rarely benefit from the extensive research on adaptive foraging behaviour, despite the potential for concepts such as state‐dependent foraging to explain many aspects of behaviour in social groups. For example, sex differences in preferred foraging techniques used by green woodhoopoes, Phoeniculus purpureus, have previously been explained by sexual dimorphism in bill length and the benefits afforded by foraging specialization and niche differentiation within cooperative groups. Contrary to this argument, there were no sex differences in mean foraging success and/or prey size captured when males and females used the same foraging techniques. Subordinates of both sexes did experience lower and more varied foraging success compared with dominants, but probably only as a consequence of competition or inexperience. However, dominant males experienced greater variance in individual foraging success compared with dominant females, and dominant males also experienced greater variances in prey size when using their preferred foraging techniques. Dominant males therefore appeared to specialize in foraging techniques that provided more variable rewards, whilst dominant females consistently chose to minimize variation in reward. Dominant females also experienced less variance in foraging returns when using the same techniques as males, suggesting a possible link with sexual dimorphism in bill length. Partitioning of foraging niches in dominant green woodhoopoes therefore appears to be better explained by sex differences in variance (risk) sensitivity to foraging rewards. We suggest that this kind of detailed analysis of state‐dependent foraging has the potential to explain many of the crucial age and sex differences in behaviour within cooperative groups.     

Genetic Basis of a Violation of Dollo’s Law: Re-Evolution of Rotating Sex Combs in Drosophila bipectinata

Phylogenetic analyses suggest that violations of “Dollo’s law”—that is, re-evolution of lost complex structures—do occur, albeit infrequently. However, the genetic basis of such reversals has not been examined. Here, we address this question using the Drosophila sex comb, a recently evolved, male-specific morphological structure composed of modified bristles. In some species, sex comb development involves only the modification of individual bristles, while other species have more complex “rotated” sex combs that are shaped by coordinated migration of epithelial tissues. Rotated sex combs were lost in the ananassae species subgroup and subsequently re-evolved, ∼12 million years later, in Drosophila bipectinata and its sibling species. We examine the genetic basis of the differences in sex comb morphology between D. bipectinata and D. malerkotliana, a closely related species with a much simpler sex comb representing the ancestral condition. QTL mapping reveals that >50% of this difference is controlled by one chromosomal inversion that covers ∼5% of the genome. Several other, larger inversions do not contribute appreciably to the phenotype. This genetic architecture suggests that rotating sex combs may have re-evolved through changes in relatively few genes. We discuss potential developmental mechanisms that may allow lost complex structures to be regained.     

Plasma Lipid Peroxides in Murine Sepsis —Sex Differences and Effect of Antioxidative/Anti-Inflammatory Therapy

In order to investigate the influence of antioxidative anti-inflammatory combination therapy (AACT) with dimethyl sulfoxide (DMSO). chlorpromaittic (CPZ) and vitamin E upon the activity of the inflammation. plasma lipid peroxide was measured as thiobarbituric acid reactive substance (TBARS) 12hrs postoperatively in the moclitied cecal ligation sepsis model in the mouse.

Significantly higher TBARS levels were found in the male control group (13.7 ± 0.7nmol MDA/ml) than in the female control group (11.6 ± 0.6nmol MDA/ml).

The operated male group had significantly higher TBARS levels (16.2 ± 0.6 nmol MDA/ml) than the unoperdted male control group (13.7 ± 0.7nmol MDA/ml). No increase of TBARS levels was observed in the operated female group.

Both male and female operated group. when postoperatively treated with AACT had the same TBARS level as the not operated male or female control group.

Survival curves of operated male and female group did not demonstrate any significant difference. The survival was better in an operated male and an operated female group. when postoperatively treated with AACT.

It was concluded that the applied TBARS test IS too insensitive to follow the activity of the inflammation and has no predictive value for the outcome of sepsis in this model.     

Can Differences in Host Behavior Drive Patterns of Disease Prevalence in Tadpoles?

Differences in host behavior and resistance to disease can influence the outcome of host-pathogen interactions. We capitalized on the variation in aggregation behavior of Fowler''s toads (Anaxyrus [ = Bufo] fowleri) and grey treefrogs (Hyla versicolor) tadpoles and tested for differences in transmission of Batrachochytrium dendrobatidis (Bd) and host-specific fitness consequences (i.e., life history traits that imply fitness) of infection in single-species amphibian mesocosms. On average, A. fowleri mesocosms supported higher Bd prevalences and infection intensities relative to H. versicolor mesocosms. Higher Bd prevalence in A. fowleri mesocosms may result, in part, from higher intraspecific transmission due to the aggregation of tadpoles raised in Bd treatments. We also found that, independent of species, tadpoles raised in the presence of Bd were smaller and less developed than tadpoles raised in disease-free conditions. Our results indicate that aggregation behavior might increase Bd prevalence and that A. fowleri tadpoles carry heavier infections relative to H. versicolor tadpoles. However, our results demonstrate that Bd appears to negatively impact larval growth and developmental rates of A. fowleri and H. versicolor similarly, even in the absence of high Bd prevalence.     

Diurnal Variation of Plasma Brain‐Derived Neurotrophic Factor (BDNF) in Humans: An Analysis of Sex Differences

Scant information is available on the diurnal variation of peripheral neurotrophic factors, including brain‐derived neurotrophic factor (BDNF), in human beings. We explored plasma and serum BDNF levels at three different clock times in a study of 28 healthy subjects of both sexes. Statistically significant diurnal variation in plasma BDNF level was detected in men, with the peak at 08:00 h and nadir at 22:00 h. At this time, the plasma BDNF concentration of men was significantly lower than that of women (p=.02). However, no diurnal variation was found either in plasma BDNF of women, in either the follicular or luteal phases of the menstrual cycle, or in serum BDNF level in both men and women. These findings support the concept of rhythmic variation in plasma BDNF regulation that seems to be sex‐related. (Author correspondence: dmarazzi@psico.med.unipi.it)