Prenatal Stress and Sexual Differentiation of Monoaminergic Brain Systems

This review considers published data and results of the authors' studies of prenatal (maternal) stress-induced disturbances in the sexual differentiation of monoaminergic systems in sexually dimorphic brain regions. The significant role of glucocorticoid hormones as crucial humoral factors mediating the above effects of prenatal stress is emphasized. The involvement of enzymes, providing synthesis and metabolic transformations of biogenic monoamines in the brain, in modifications of the prenatal stress-related hormonal/transmitter imprinting of the developing brain is discussed in particular.     

The effects of sex and neonatal androgenization on neuron dendroarchitectonics in amygdala posterior cortical nucleus

Sex differences in neuron dendroarchitectonics of the amygdala posterior cortical nucleus of adult rats were described for the first time using the Golgi method. Long-axon sparse-branched neurons in male rats possessed a larger number of primary dendrites, while female rats had long-axon dense-branched neurons with longer dendrites. Injection of testosterone propionate at 1250 µg to females on day 5 after birth resulted in a greater number of primary dendrites of long-axon sparse branched neurons in adults, as compared to that in the control. Dendrites of long-axon sparse-branched neurons became much longer, thus enlarging the dendrite area.Translated from Ontogenez, Vol. 36, No. 1, 2005, pp. 64–67.Original Russian Text Copyright © 2005 by Akhmadeev, Kalimullina.     

Serotonin promotes feminization of the sexually dimorphic nucleus of the preoptic area,but not the calbindin cell group

Testosterone and its metabolites masculinize the brain during a critical perinatal window, including the relative volume of sexually dimorphic brain areas such as the sexually dimorphic nucleus of the preoptic area (SDN), which is larger in males than females. Serotonin (5HT) may mediate this hormone action, since 5HT given during the second week of life decreases (i.e., feminizes) SDN volume in males and testosterone‐treated females. Although previous work indicates that the 5HT_2A/2C receptor is sufficient to induce feminization, it is unclear whether other serotonin receptors are required and which subpopulation(s) of SDN cells are specifically organized by 5HT. Therefore, we injected male and female Sprague‐Dawley rat pups with saline, a nonselective 5HTR agonist, a 5HT_2A/2C agonist, or a 5HT_2A/2C antagonist over several timecourses in early life, and measured the Nissl‐SDN as well as a calbindin+ subdivision of the SDN, the CALB‐SDN. When examined on postnatal day 18 or early adulthood, the size of the Nissl‐SDN was feminized in males treated with any of the serotonergic drugs, eliminating the typical sex difference. In contrast, the sex difference in CALB‐SDN size was maintained regardless of serotoninergic drug treatment. This pattern suggests that although gonadal hormones shape the whole SDN, individual cellular phenotypes respond to different intermediary signals to become sexually dimorphic. Specifically, 5HT mediates sexual differentiation of non‐calbindin population(s) within the SDN. The results also caution against using measurement of the CALB‐SDN in isolation, as the absence of an effect on the CALB‐SDN does not preclude an effect on the overall nucleus. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1241–1253, 2016     

Morphogenetic effects of neonatal androgenization on neuron dendroarchitectonics in amygdala dorsomedial nucleus

Specific features of neuron dendroarchitectonics in the amygdale dorsomedial nucleus were described using the Golgi method after the injection of testosterone propionate at 1250 g to females on the fifth day after birth.     

Developing Brain as a Giant Multipotent Endocrine Gland

The brain of adult mammals is composed of neuronal ensembles, which are intergrated in the course of synaptic transmission by chemical signals (CSs). Among them, there are classical neurotransmitters, neuropeptides, etc. In addition, neurosecretory neurons secrete the same CSs to the blood vessels in the brain areas lacking the blood-brain barrier (BBB), though their spectrum is greatly limited. According to the conventional conception, the brain lacks the neuroendocrine function over the ontogenetic period lasting from the genesis of neuronal units to the development of neuron-to-neuron synaptic connections (synaptogenesis) and BBB. Nevertheless, some recent data contradict this concept making reasonable its that CSs and receptors are expressed in the neurons just after their origin and long before the establishment of BBB. During this period, CSs are considered diffusive inductors of the brain development, which provide the paracrine regulation of the neuronal differentiation. Although this regulation is beyond doubt, some data do not agree with the concept. For example, the receptors of CSs are transiently expressed in many areas of the developing brain, though there are no neuronal sources of the respective CSs in close vicinity. This might be explained by the CS transfer from the synthesizing neurons toward the target neurons via the circulation, i.e., due to the neuroendocrine autoregulation. According to our hypothesis, the neurons serve as endocrine cells, and the brain can be considered a giant multipotent endocrine gland providing the neuroendocrine regulation of the development of the brain itself and peripheral target organs over the period preceding synaptogenesis and the establishment of BBB. The term “giant multipotent” means that the spectrum of the brain-derived circulating CSs and their occupancy at the periphery in the developing organism should greatly exceed those in adulthood. Gonadotropin-releasing hormone (GnRH)-producing and dopaminergic neurons, the most representative populations of peptidergic and monoaminergic neurons were used for testing our hypothesis. According to the age dynamics of GnRH and dopamine (DA) in general circulation in rats, the concentrations of these agents were sufficiently great for the regulation of the target cells before the establishment of BBB, but they dropped to an undetectable level after the BBB appearance. Furthermore, the microsurgical lesion of most GnRH and DA-ergic neurons in the developing brain resulted in a dramatic drop of both CSs in the blood, confirming that the brain is the principal but not the only source of circulating CSs. Potential targets for the brain-derived circulating CSs, including GnRH and DA, should be neurons and peripheral cells. For example, the gonads begin to express the GnRH receptors simultaneously with the onset of GnRH synthesis in the brain in fetal rats. The DA-sensitive cells in the developing organism are, e.g., represented by neurons of the suprachiasmatic nucleus in the brain and epithelial cells of the kidney. Both cell types transiently express D₂ receptors before the establishment of BBB and the related fall of circulating DA. Thus, differentiating neurons and the developing brain play roles of secretory cells and of the endocrine gland, respectively, before the development of interneuronal synaptic connections and maturation of BBB. Neirofiziologiya/Neurophysiology, Vol. 37, No. 3, pp. 257–270, May–June, 2005.     

中国林蛙性腺的发育及温度对其性别分化的影响

为探讨幼蛙性别分化与温度的关系,在恒温和变温条件下培养中国林蛙（Rana chensinensis)受精卵至变态完成,结果表明：（1）胚胎发育到24期时生殖嵴开始出现,25期个别原始生殖细胞（PGCs)已迁移到生殖嵴中,生殖细胞与生殖嵴共同发育成生殖腺;（2）胚胎发育到31期生殖腺出现性别分化,卵巢分化初期较易识别,而精巢分化不明显;…（3）卵巢分化完成于37期,精巢分化完成于变态之后,两侧生殖腺等大;（4）胚胎发育从30期开始,性别分化对温度较为敏感,低温利于雌性化,高温利于雄性化;（5）15－25℃为变温培养时性比发生变化的敏感温度区,缓慢升温雄性比较显著增加,缓慢降温雌性比例显著增加。     

Estrogen‐regulated developmental neuronal apoptosis is determined by estrogen receptor subtype and the Fas/Fas ligand system

Adult sexual dimorphism in neuronal cell number is controlled by estrogen exposure during a tightly defined period of rat brain development. The mechanisms of estrogen's effect are unknown; one possibility is regulation of programmed cell death (apoptosis). In this study we have shown that estradiol can function as a neuroprotective agent or an inducer of apoptosis, depending on the estrogen receptor‐subtype present in the cell. Thus, ERα has a neuroprotective effect, while ERβ mediates the induction of apoptosis in neuronal cells. Moreover, we show that estrogen‐induced apoptosis through ER‐β requires the expression of Fas‐ and Fas ligand (FasL) proteins, since the absence of FasL in neurons prevents this effect. Furthermore, we demonstrate that microglia‐secreted products induce the expression of FasL necessary to mediate estradiol–ERβ apoptotic effect. These findings may explain the dichotomous effect of fetal estradiol on the adult neuronal number. © 2000 John Wiley & Sons, Inc. J Neurobiol 43: 64–78, 2000     

Organizing effect of androgenization on neurons in posterior medial nucleus of amygdala in rats

The changes in neuron dendroarchitectonics in the posteromedial nucleus of the amygdala induced by administration of 1250 μg testosterone propionate on neonatal day 5 have been revealed in adult female Wistar rats for the first time.     

Dynamic,Non-binary Specification of Sexual State in the C. elegans Nervous System

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用模式生物青鳉概观硬骨鱼性别决定及性分化研究进展

鱼类性别决定和性分化呈多元性,既有雌雄同体也有雌雄异体。性腺的雌雄性分化过程受遗传和环境因素(如温度、光照、激素和pH值等)影响,具有可逆可塑性。随着生物技术和基因组学的迅速发展,近年来脊椎动物性别决定和性分化的研究有了重大进展和显著突破。本文通过聚焦青鳉及其他硬骨鱼纲保守存在的dmrt1、gsdf、amh等雄性因子,探讨硬骨鱼普遍存在的雌雄性别可塑可逆信号通路,并介绍了新的基因组编辑和性控育种技术,为单性选育等水产养殖技术的研发提供参考。     

Sexual differentiation of the zebra finch song system: Positive evidence,negative evidence,null hypotheses,and a paradigm shift

Permanent sex differences in the brain are found in many vertebrates, and are thought to be induced by sex differences in secretion of gonadal steroid hormones during critical periods of early development. This theory has received support primarily from many experiments conducted on mammals, but also from studies on other vertebrate classes, including birds. The only avian neural dimorphism that has allowed extensive tests of this hypothesis is the neural circuit for song in passerine birds, which is much larger in males than in females. Experiments in zebra finches have yielded contradictory results. Although it is relatively easy to induce masculine patterns of development in genetic females with estrogen, it has not been possible to induce feminine patterns of development in males with any treatments, including antiestrogens and inhibitors of estrogen synthesis. Moreover, genetic females that develop with large amounts of functional testicular tissue but with virtually no ovarian tissue nevertheless have a feminine song circuit. The latter studies fail to support the idea of steroid induction of sexual differentiation. An alternative to the steroidal control hypothesis is that nonhormonal gene products expressed in the brain early in development trigger sexually dimorphic patterns of development. Although current evidence in several neural and nonneural systems indicates that sexual differentiation of some somatic phenotypes cannot be explained by the actions of gonadal steroids, the idea of direct genetic (nonhormonal) induction of sexual differentiation has yet to be proved. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 572–584, 1997     

Investigating the Impact of Chronic Atrazine Exposure on Sexual Development in Zebrafish

Atrazine (ATZ) is a selective triazine herbicide used primarily for preemergent weed control in corn, sorghum, and sugar cane production. It is one of the most widely used herbicides in North America. Some research published over the last decade suggests that chronic exposure to environmentally relevant ATZ concentrations can adversely impact gonadal development and/or sexual differentiation in amphibians and fish, while other studies report no effect, or moderate effects. As a result, contrasting conclusions have been published regarding the potential effects of the herbicide ATZ on aquatic species. Two near‐identical 4‐month studies in 2009 (Study I) and 2010 (Study II) were performed investigating the potential for chronic ATZ exposure to affect zebrafish (Danio rerio) sexual development and differentiation. Zebrafish were chronically exposed to 0, 0.1, 1, 10 μM ATZ or 1 nM 17ß‐estradiol (E2). Fish were histologically examined to assign gender and to evaluate potential impacts of E2 or ATZ on gonadal development. Exposure to E2 consistently resulted in a significantly higher proportion of female fish to normal male fish when compared to unexposed fish (both studies). In both studies, ATZ exposure did not significantly influence the percentage of female or male fish when compared to unexposed fish. A greater percentage of abnormally developed male fish and fish lacking differentiated gonadal tissue was observed in Study II E2 exposures but not in ATZ exposures. Together, these studies indicate that long‐term exposure to ATZ at or above environmentally relevant concentrations does not significantly impact zebrafish gonadal development or sexual differentiation.     

Two sexes,one genome: the evolutionary dynamics of intralocus sexual conflict

As the evolutionary interests of males and females are frequently divergent, a trait value that is optimal for the fitness of one sex is often not optimal for the other. A shared genome also means that the same genes may underlie the same trait in both sexes. This can give rise to a form of sexual antagonism, known as intralocus sexual conflict (IASC). Here, a tug‐of‐war over allelic expression can occur, preventing the sexes from reaching optimal trait values, thereby causing sex‐specific reductions in fitness. For some traits, it appears that IASC can be resolved via sex‐specific regulation of genes that subsequently permits sexual dimorphism; however, it seems that whole‐genome resolution may be impossible, due to the genetic architecture of certain traits, and possibly due to the changing dynamics of selection. In this review, we explore the evolutionary mechanisms of, and barriers to, IASC resolution. We also address the broader consequences of this evolutionary feud, the possible interactions between intra‐ and interlocus sexual conflict (IRSC: a form of sexual antagonism involving different loci in each sex), and draw attention to issues that arise from using proxies as measurements of conflict. In particular, it is clear that the sex‐specific fitness consequences of sexual dimorphism require characterization before making assumptions concerning how this relates to IASC. Although empirical data have shown consistent evidence of the fitness effects of IASC, it is essential that we identify the alleles mediating these effects in order to show IASC in its true sense, which is a “conflict over shared genes.”     

Sex differences in structure and expression of the sex chromosome genes CHD1Z and CHD1W in zebra finches

Genes on the sex chromosomes are unique because of their sex-specific inheritance. One question is whether homologous gene pairs on the sex chromosomes, which have diverged in their sequence, have acquired different functions. We have analyzed the first homologous pair of genes (CHD1Z and CHD1W) discovered on the avian Z and W sex chromosomes of the zebra finch (Taeniopygia guttata) to examine whether functional differences may have evolved. Sequence analysis revealed that the two genes maintained a high degree of similarity especially within the C, H, and D domains, but outside of these regions larger differences were observed. Expression studies showed that CHD1W was unique to females and has the potential to produce a protein that CHD1Z does not. CHD1Z mRNA was expressed at a higher level in the male brain than in the female brain at various post-hatch ages. Reporter constructs containing the 5' flanking regions of each gene showed they had the ability to drive reporter expression in primary cell cultures. The 5' flanking region sequence of CHD1Z and CHD1W exhibited little homology, and differences in putative promoter elements were apparent. These differences between CHD1Z and CHD1W suggest that the two proteins may have diverged in their function.     

Evolution of sex comb from the primitive bristle pattern in drosophila is associated with modification in the developmental regulatory protein dachshund

Sex comb is a recently evolved male specific character confined to the Sophophoran group of Drosophila. Such innovations in phenotypes as Waddington proposed, are, outcome of “canalization” in developmental pathways that occur due to mutations creating “choice points” in genetic regulatory pathways. Our interest in the present study is to understand the shifts in genetic network, which has lead to the origin of sex comb from the basic bristle pattern that is seen in rest of the members of Drosophilidae. Here we have made a comparative analysis of expression of some of the key regulators of sex comb morphogenesis, between D. melanogaster and a group of selected species, which primitively lack sex comb. Sex combs reduced (Scr), dachshund (dac), and bric‐a‐brac (bab) gene expression were studied. We show that, primitive bristle pattern is marked by a strikingly down regulated expression of Sex combs reduced in the first tarsal segment of the prothoracic leg discs of male flies. Further a remarkable change with respect to Dachshund, an activator of sex combs reduced gene in the sex comb regulatory pathway, is seen. This is attributed to changes in DAC protein that might have taken place between the two groups of species. bric‐a‐brac does not reveal any significant expression modulation between the sex comb bearing and the primitive patterned species. Earlier works had shown that within the Sophophoran group, dynamic changes in SCR expression is responsible for the diversity seen in sex comb morphology, where as no such variation is witnessed with respect to DAC expression. Our findings have demonstrated that the scenario is different between the group primitively lacking sex comb and D. melanogaster wherein an obvious change in the protein has taken place. genesis 51:97–109, 2013, 2013. © 2012 Wiley Periodicals, Inc.     

Calcium Signalling in Rat Brain Neurons and Differentiation of PC-12 Cells Induced by Application of a Probiotic Product

The effects of a biotechnological probiotic product, PP, produced by food fermentation with Lactobacilli (US patent approved), on the growth of neurites in rat pheochromocytoma cells (PC-12) and on calcium responses of rat brain neurons were studied in culture. The PP increased the length of neurites in PC-12 cells, resulting in an irreversible differentiation of cancerous cells into neuron-like structures. Moreover, a change in the neurotransmitter phenotype of differentiated cells was found; some cells, such as excitatory neurons, began to respond to glutamate application by increasing [Ca²⁺] _i . The PP directly activated PC-12 cells and neurons by the release of Ca²⁺ from the intracellular stores in a steady manner. The PP also stimulated the entry of Ca²⁺ into the cells in a Ca²⁺ add-back protocol, which was considerable upon washing out of PP. Thus, the products of Lactobacillus metabolism, such as those in PP, can act as a neuronal growth factor and manifest clear pharmacological reactions at the cellular level. By comparison, commercial lyophilized probiotic bacteria also induced a Ca²⁺ rise in neurons, but not in PC-12 cells. Some neurons did not respond to probiotic bacteria, and some neurons responded with some delay. Upon wash out of probiotic bacteria, a huge entry of Ca²⁺ into the cells was observed. Neirofiziologiya/Neurophysiology, Vol. 37, No. 3, pp. 284–293, May–June, 2005.     

Sexual selection uncouples the evolution of brain and body size in pinnipeds

The size of the vertebrate brain is shaped by a variety of selective forces. Although larger brains (correcting for body size) are thought to confer fitness advantages, energetic limitations of this costly organ may lead to trade-offs, for example as recently suggested between sexual traits and neural tissue. Here, we examine the patterns of selection on male and female brain size in pinnipeds, a group where the strength of sexual selection differs markedly among species and between the sexes. Relative brain size was negatively associated with the intensity of sexual selection in males but not females. However, analyses of the rates of body and brain size evolution showed that this apparent trade-off between sexual selection and brain mass is driven by selection for increasing body mass rather than by an actual reduction in male brain size. Our results suggest that sexual selection has important effects on the allometric relationships of neural development.