889 research outputs found
A Novel Role for DNA Hydroxymethylation in Sexual Differentiation of the Mouse Brain
No full textFil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.Fil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.Many sex differences in the brain are differences in neuronal phenotype (i.e., number of cells expressing a specific neurochemical marker). Epigenetic modifications, such as DNA methylation, control the development of cell phenotype throughout the body during embryogenesis, and sex differences in neurochemical cell phenotype could be due to differences in the control of DNA methylation. To test this, we first inhibited DNA methylation in the brains of newborn mice during the critical period of sexual differentiation. We found sex-specific effects (the inhibition of DNA methylation increased the number of calbindin-expressing cells only in females, and the number of estrogen receptor alpha cells only in males). As a result, sex differences were reduced or eliminated in the treated groups. We next hypothesized that DNA methylation during development depends on a balance between the addition of methyl groups (by DNA methyltransferases, DNMTs), and their removal (by ten-eleven translocases, Tets). Tet enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine. This is a first step to removal of the methyl mark, but hydroxymethylation is also emerging as a stable epigenetic mark in its own right, especially in the brain where it is found at much higher levels than in other tissues. We find that both DNMTs and Tets are expressed at even higher levels in the neonatal brain than at later ages, and that sex differences in expression are found only during the first postnatal week. Males have greater expression of Tet2 and Tet3 and lower expression of Dnmt1 in the preoptic area of the hypothalamus and this is associated with less 5mC in the same region. We are currently examining the effects of a transient downregulation in Tet enzymes to test for a causal relationship between Tet enzyme expression and sex differences in neuronal phenotype. Overall, our results suggest the novel idea that DNA de-methylation may primarily drive sex differences early in brain developmentFunding: This study was funded by a seed grant from the Brains & Behavior Program at Georgia State University.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.Fil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.Bioquímica y Biología Molecular (ídem 3.1.10
Birth triggers an inflammatory response in the neonatal periphery and brain
No full textBirth is preceded by inflammation at the fetal/maternal interface. Additionally, the newborn experiences stimuli that under any other circumstance could elicit an immune response. It is unknown, however, whether birth elicits an inflammatory response in the newborn that extends to the brain. Moreover, it is unknown whether birth mode may alter such a response. To study these questions, we first measured corticosterone and pro- and anti-inflammatory cytokines in plasma of mouse offspring at several timepoints spaced closely before and after a vaginal or Cesarean birth. We found highest levels of IL-6 one day before birth and surges in corticosterone and IL-10 just after birth, regardless of birth mode. We next examined the neuroimmune response by measuring cytokine mRNA expression and microglial number and morphology in the paraventricular nucleus of the hypothalamus and hippocampus around the time of birth. We found a marked increase in TNF-α expression in both brain regions a day after birth, and rapid increases in microglial cell number in the first three days postnatal, with subtle differences by birth mode. To test whether the association between birth and cytokine production or expansion of microglia is causal, we manipulated birth timing. Remarkably, advancing birth by a day advanced the increases in all of the markers tested. Thus, birth triggers an immune response in the body and brain of offspring. Our results may provide a mechanism for effects of birth (e.g., acute changes in cell death and neural activation) previously reported in the newborn brain.Fil: Castillo Ruiz, Alexandra. Georgia State University; Estados UnidosFil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Sturgeon, Hannah. Georgia State University; Estados UnidosFil: Forger, Nancy G.. Georgia State University; Estados Unido
Developmental changes and sex differences in DNA methylation and demethylation in hypothalamic regions of the mouse brain
No full textDNA methylation is dynamically modulated during postnatal brain development, and plays a key role in neuronal lineage commitment. This epigenetic mark has also recently been implicated in the development of neural sex differences, many of which are found in the hypothalamus. The level of DNA methylation depends on a balance between the placement of methyl marks by DNA methyltransferases (Dnmts) and their removal, which is catalyzed by ten-eleven translocation (Tet) methylcytosine dioxygenases. Here, we examined developmental changes and sex differences in the expression of Tet and Dnmt enzymes from birth to adulthood in two hypothalamic regions (the preoptic area and ventromedial nucleus) and the hippocampus of mice. We found highest expression of all Tet enzymes (Tet1, Tet2, Tet3) and Dnmts (Dnmt1, Dnmt3a, Dnmt3b) in newborns, despite the fact that global methylation and hydroxymethylation were at their lowest levels at birth. Expression of the Dnmt co-activator, Dnmt3l, followed a pattern opposite to that of the canonical Dnmts (i.e., was very low in newborns and increased with age). Tet enzyme activity was much higher at birth than at weaning in both the hypothalamus and hippocampus, mirroring developmental changes in gene expression. Sex differences in Tet enzyme expression were seen in all brain regions examined during the first week of life, whereas Dnmt expression was more balanced between the sexes. Neonatal testosterone treatment of females only partially masculinized enzyme expression. Thus, Tet expression and activity are elevated during neonatal brain development, and may play important roles in sexual differentiation of the brain.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Georgia State University; Estados UnidosFil: Cortes, Laura R.. Georgia State University; Estados UnidosFil: Bruggeman, Emily C.. Emory University School Of Medicine; Estados UnidosFil: Yao, Bing. Emory University School Of Medicine; Estados UnidosFil: Forger, Nancy G.. Georgia State University; Estados Unido
Effect of early life knock down of TETs on sex differences in cell type in the hypothalamus
No full textFil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.Fil: Golynker, Ilona. Georgia State University; Estados Unidos.Fil: Castillo-Ruiz, Alexandra. Georgia State University; Estados Unidos.Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.One type of sex difference in the brain involves differences in the number of cells expressing a particular marker. For example, females have more cells expressing estrogen receptor alpha (ERa) in the ventrolateral region of the ventromedial nucleus of the hypothalamus (VMHvl), while males have more cells expressing calbindin in the sexually dimorphic nucleus of the preoptic area (CALB-SDN). DNA methylation and hydroxymethylation are crucial for the differentiation of neuronal cell phenotype during development, and we hypothesize that they may also play a role in the sexual differentiation of cell phenotype. To test this, we first treated newborn mice with zebularine, a global inhibitor of DNA methyl transferases (DNMTs). Zebularine treatment had a lasting effects on the number of cells expressing ERa and calbindin and reduced or eliminated sex differences in these markers (Mosley et al. 2019). DNA methylation and de-methylation are carried out by DNMTs (DNMT1, DNMT3b, and DNMT3a) and TET enzymes (TET1, TET2, TET3), respectively. We find that expression of these enzymes is much higher early in life compared to adulthood, and there are sex differences in the expression of all TETs and of DNMT1. To test whether these sex differences in enzyme expression underlie sex differences in cell phenotype, we used small interfering RNAs (siRNA) down-regulate DNMT1/DNMT3a or TET2/TET3. We found that injecting 2 microliters of 400pmol siRNA into the ventricles of male and female pups on P5 leads to a robust (~40%) down-regulation of expression compared to animals given control siRNA. Animals will be sacrificed at weaning and we will determine whether neonatal DNMT or TET knocknown alters the number of cells expressing ERa in the VMHvl and medial POA and calbindin in the SDN-POA and bed nucleus of the stria terminalis.https://www.sfn.org/meetings/neuroscience-2019Fil: Cortes, Laura R. Georgia State University. Neuroscience Institute; USA.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Biología Celular; Argentina.Fil: Cisternas, Carla Daniela. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Fisiología Animal; Argentina.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina.Fil: Golynker, Ilona. Georgia State University; Estados Unidos.Fil: Castillo-Ruiz, Alexandra. Georgia State University; Estados Unidos.Fil: Forger, Nancy G. Georgia State University. Neuroscience Institute; USA.Bioquímica y Biología Molecular (ídem 3.1.10
Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
No full textMany neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Cortese, Maria Laura. Georgia State University; Estados UnidosFil: Golynker, Ilona. Georgia State University; Estados UnidosFil: Castillo-Ruiz, Alexandra. Georgia State University; Estados UnidosFil: Forger, Nancy G.. Georgia State University; Estados Unido
Role of DNA Methylation in Sexual Differentiation of Neurochemical Phenotype in the Brain
No full textSex differences in the brain underlie sex-specific behaviors and physiological processes, and may help to explain male- or female-biased neuropsychiatric disorders. Some of the best-studied neural sex differences depend on differential cell death in males and females, but other sex differences persist even if cell death is prevented. These include sex differences in stable patterns of gene expression, or what we refer to as the differentiation of neurochemical phenotype. The mechanisms contributing to sex differences in neurochemical phenotype are unknown, but epigenetic modifications, such as DNA methylation, control cell phenotype “decisions” throughout the body in developing animals. We recently discovered that expression of enzymes that place or remove DNA methylation marks peaks during the first week of life in the mouse brain and overlaps with the perinatal critical period of sexual differentiation. Thus, my over-arching hypothesis is that sex differences in DNA methylation early in life underlie sexual differentiation of cell phenotype. I tested this using a combination of techniques, including: pharmacological inhibition of DNA methyltransferases, siRNA knock-down of Ten-eleven-translocases, immunohistochemistry, pyrosequencing, and in situ hybridization. The results of this dissertation demonstrate that 1) neonatal inhibition of DNA methylation abolishes several sex differences in cell phenotype in the hypothalamus; 2) DNA methylation and demethylation both contribute to sex differences in the development of one cell type (estrogen receptor alpha, ERα) in the hypothalamic ventromedial nucleus (VMH) and arcuate nucleus, in a region-specific manner; and 3) sexual differentiation of cell phenotype in the VMH is not present at birth, but develops over the first few postnatal weeks and involves a developmental decrease in cell marker expression of Tac1, Rprm, and Pdyn, specifically in males. In summary, we demonstrate that neonatal DNA methylation and demethylation establish neurochemical cell phenotype in a sex- and brain region-specific manner, providing the first studies demonstrating a mechanism by which sexual differentiation of neuronal cell type occurs.Doctor of Philosophy (PhD)Neuroscience Institut
Les professeurs strasbourgeois de la galerie des portraits de la Faculté de pharmacie de Nancy
No full textDie Porträtgalerie der pharmazeutischen Fakultät von Nancy : die strassburger Professoren in Nancy.
In Würdigung der « École supérieure de Pharmacie » von Strasbourg, hat die « École de Pharmacie » von Nancy, deren Erbin sie war, ab 1914, eine Sammlung von Porträts der früheren Professoren beider Städte zusammengestellt. Porträts verschiedener früherer Strassburger sind immer noch in der Fakultät ausgestellt : die von I.-L. Oberlin, E.-T. Jacquemin, C.-F. Schlagdenhauffen, C.-E. Schmitt und G.-M. Bleicher. Der Verfasser schildert die Tätigkeit dieser Professoren in Nancy und reproduziert drei Karikaturen in denen sie erscheinen.The gallery of portraits in the Faculty of Pharmacy in Nancy : Strasburg professors in Nancy.
In homage to the Graduate School of Pharmacy in Strasburg, the School of Pharmacy of Nancy, who became its heir, instituted, beginning in 1914, a collection of portraits of former professors from these two cities. The portraits of several former Strasburgians are still exhibited in the Faculty at this time : those of I.-L. Oberlin, E.- T. Jacquemin, C.-F. Schlagdenhauffen, C.-E. Schmitt and G.-M. Bleicher. The author reviews the activities of these professors in Nancy and reproduces three caricatures in which they are shown.Labrude Pierre. Les professeurs strasbourgeois de la galerie des portraits de la Faculté de pharmacie de Nancy. In: Revue d'histoire de la pharmacie, 84e année, N. 308, 1996. pp. 39-52
Achieving Foundation Accountability and Transparency: Lessons From the Robert Wood Johnson Foundation’s \u3ci\u3eScorecard\u3c/i\u3e
No full text· The purpose of this article is to help foundations in their accountability and transparency efforts by sharing lessons from one foundation’s journey to develop a scorecard.
· A commitment to funding and sharing the results from rigorous evaluations set the tone for Robert Wood Johnson Foundation (RWJF) accountability.
· The Scorecard is a powerful tool for RWJF to set goals, track organizational effectiveness, and motivate responses to shortcomings.
· Foundations can tailor their scorecard to include what best serves their needs.
· With its Scorecard, RWJF found that comparative and quantitative measures are the most powerful forces to motivate change.
· Setting targets motivates staff to focus their efforts on certain areas and make improvements
Sex Differences in Stress-Responsive Neural Substrates and the Development of Mood Disorder-Like Behavior Following a Rodent Model of Early-Life Adversity
No full textStress-related mood disorders, such as anxiety and depression, are the most common psychiatric conditions, occurring with a lifetime risk of 15-20%. Women are twice as likely to develop anxiety and depression than men, and this sex difference emerges during puberty. Exposure to abuse or maltreatment during early life increases mood disorder susceptibility, suggesting that females may be especially sensitive to long-lasting, negative effects of early-life stress. While the female-bias in mood disorders is one of the most robust sex differences in psychiatry, the origin of this difference remains unknown. Sexually dimorphic processing of stressors by the adolescent brain, or the sex-specific expression of stress-related neural substrates, may be mechanisms by which stress-related mood disorders are more prominent in females. We developed a novel animal model of early-life adversity, Juvenile Social Subjugation (JSS), to test the effect of chronic adolescent social stress on mood disorder-like pathology in adulthood. This dissertation addressed the following research questions: (1) Does chronic JSS induce sex-specific anxiety and depression-like behaviors and HPA axis dysfunction in adulthood? (2) Is JSS differentially processed by the male and female adolescent brain? (3) Is the corticotropin-releasing factor receptor (CRF) system sex-specifically expressed across development? Together our data point to regional sex differences in neuronal activation and CRF receptor expression in the brain as potential mechanisms by which stressors such as JSS induce sex-specific mood disorder-like behavior in adulthood
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