2,298 research outputs found
Estrogen synthesis in the hippocampus
No full textEstradiol plays essential roles in the modulation of synaptic plasticity and neuroprotection in males as well as in females, as has been shown particularly in the hippocampus. Although it has long been known that aromatase, the final enzyme in estrogen synthesis, is expressed in the hippocampus, a new paradigm emerged when it was shown that estradiol is actually synthesized de novo in this part of the brain. Increasing evidence indicates that hippocampus-derived estradiol plays a role in synaptic plasticity and neuroptrotection, rather than estradiol originating from the gonads. In recent years, a number of in vivo and in vitro studies have shown that hippocampus-derived estradiol substantially contributes to hippocampal function, in particular to structural synaptic plasticity.Deutsche Forschungsgemeinschaft [Ru 436/4-1
Reptricket. Förord till Lars Gustafsson: Mot noll
No full textIntroduction to a collection of philosophical essays by Swedish author Lars Gustafsson (b. 1936)
Author Functions in Lars Kepler\u27s The Hypnotist: An Analysis
No full textThis paper examines Foucault\u27s notion of the author function as it pertains to Lars Kepler\u27s bestselling 2011 crime thriller, The Hypnotist. Lars Kepler is the pseudonym of a Swedish husband-wife writing duo, making him the perfect subject for analysis centering on illusory notion of the author. This paper will answer these questions: Who is the true author of The Hypnotist? What factors influence the author function of this bestelling novel? And what can The Hypnotist phenomenon tell us about the relationships between authors and their readers? This paper will demonstrate that no literary works may be ascribed to an individual person, and that authors hold no privileged knowledge of the works they produce, because authors cease to be authors the moment pen is lifted from page
Estrus cyclicity of spinogenesis: underlying mechanisms
No full textHippocampal spine density varies with the estrus cycle. The cyclic change in estradiol levels in serum was hypothesized to underlie this phenomenon, since treatment of ovariectomized animals with estradiol induced an increase in spine density in hippocampal dendrites of rats, as compared to ovariectomized controls. In contrast, application of estradiol to hippocampal slice cultures did not promote spinogenesis. In addressing this discrepancy, we found that hippocampal neurons themselves are capable of synthesizing estradiol de novo. Estradiol synthesis can be suppressed by aromatase inhibitors and by knock-down of Steroid Acute Regulatory Protein (StAR) and enhanced by substrates of steroidogenesis. Expression of estrogen receptors (ERs) and synaptic proteins, synaptogenesis, and long-term potentiation (LTP) correlated positively with aromatase activity in hippocampal cultures without any difference between genders. All effects due to inhibition of aromatase activity were rescued by application of estradiol to the cultures. Most importantly, gonadotropin-releasing hormone (GnRH) increased estradiol synthesis dose-dependently via an aromatase-mediated mechanism and consistently increased spine synapse density and spinophilin expression. As a consequence, our data suggest that cyclic fluctuations in spine synapse density result from pulsative release of GnRH from the hypothalamus and its effect on hippocampal estradiol synthesis, rather than from varying levels of serum estradiol. This hypothesis is further supported by higher GnRH receptor (GnRH-R) density in the hippocampus than in the cortex and hypothalamus and the specificity of estrus cyclicity of spinogenesis in the hippocampus, as compared to the cortex
Estrogen-regulated synaptogenesis in the hippocampus: Sexual dimorphism in vivo but not in vitro
No full textHippocampal neurons are capable of synthesizing estradiol de novo. Estradiol synthesis can be suppressed by aromatase inhibitors and by knock-down of steroid acute regulatory protein (StAR), whereas elevated levels of substrates of steroidogenesis enhance estradiol synthesis. In rat hippocampal cultures, the expression of estrogen receptors (ERs) and synaptic proteins, as well as synapse density, correlated positively with aromatase activity, regardless of whether the cultures originated from males or females. All effects induced by the inhibition of aromatase activity were rescued by application of estradiol to the cultures. In vivo, however, systemic application of letrozole, an aromatase inhibitor, induced synapse loss in female rats, but not in males. Furthermore, in the female hippocampus, density of spines and spine synapses varied with the estrus cycle. In addressing this in vivo-in vitro discrepancy, we found that gonadotropin-releasing hormone (GnRH) regulated estradiol synthesis via an aromatase-mediated mechanism and consistently regulated spine synapse density and the expression of synaptic proteins. Along these lines, GnRH receptor density was higher in the hippocampus than in the cortex and hypothalamus, and estrus cyclicity of spinogenesis was found in the hippocampus, but not in the cortex. Since GnRH receptor expression also varies with the estrus cycle, the sexual dimorphism in estrogen-regulated spine synapse density in the hippocampus very likely results from differences in the GnRH responsiveness of the male and the female hippocampus. This article is part of a Special Issue entitled 'Neurosteroids'. (C) 2011 Elsevier Ltd. All rights reserved.Deutsche Forschungsgemeinschaf
East Timor's transition to independence: Building up an economy from scratch
No full textAfter the extensive destruction caused by the violence that followed the vote for independence on August 30th, 1999, the reconstruction of East Timor's infrastructure inevitably was the top priority. Supported by massive aid inflows, achievements in this area have been quite remarkable. As a result, East Timor's production capacity is likely to return to pre-crisis levels within a few years. The much more difficult task is to initiate and then sustain a long-run development process. This requires a whole bundle of measures of which only a part has been introduced up to now. At the macroeconomic level, three policy areas figure most prominently. First, to ensure a certain degree of macroeconomic stability as a prerequisite for growth, it is recommended to implement a combination of a Currency Board regime for the exchange rate and a sound fiscal policy based on a broad domestic revenue base. Second, permanent growth can only be achieved via the accumulation of physical and human capital. Secure property rights and a transparent investment code are among the essential conditions for physical capital formation. Human capital formation can be fostered by reallocating public resources towards basic services, which were seriously neglected under Indonesian rule. Third, a country like East Timor with its very small domestic market and its limited technical knowledge can reap large benefits from adopting an open trade and foreign investment regime. From a sectoral perspective, agriculture will remain the backbone of the economy in the foreseeable future. Incentives that lead to a more dynamic development of this sector are thus of particular importance, not only for growth but also for poverty alleviation as the vast majority of poor people live in rural areas. Such incentives include a market-oriented pricing policy, a stable and competitive exchange rate, access to credit, a basic rural infrastructure, and the provision of adequate research and extension facilities. A development strategy based on agriculture alone would, however, leave the economy vulnerable to shocks. Only a diversification of production will open the way to more robust growth. One significant step in this direction could be the exploitation of existing oil fields. If future oil revenues live up to expectations, the main policy challenge will be to avoid an overvaluation of the domestic currency (Dutch Disease). In the medium run, the establishment of labor-intensive industries could be another step towards a more diversified economy. Whether this option can be realized will depend to a large extent on East Timor's ability to import capital and know-how via foreign direct investment. Overall, if political stability prevails, the outlook for sustained progress seems better than in many other low-income countries, where the international community is less consistently engaged and where much stronger vested interests block reform efforts. At the moment, the most significant danger for long-term development in East Timor arises from the uncertainty of land and property rights, which is likely to hamper investment and agricultural development. Moreover, it has to be kept in mind that various important measures, such as investments in education, will take considerable time to materialize fully. --
Synaptopodin is regulated by aromatase activity
No full textLocally synthesized estradiol plays an important role in synaptic plasticity in the hippocampus. We have previously shown that in hippocampal neurons, activity of the enzyme aromatase, which converts testosterone into estradiol, is reduced via Ca2+-dependent phosphorylation. Synaptopodin is a highly estrogen responsive protein, and it has been shown that it is an important regulator of synaptic plasticity, mediated by its close association with internal calcium stores. In this study, we show that the expression of synaptopodin is stronger in the hippocampus of female animals than in that of male animals. Phosphorylation of aromatase, using letrozole, however, down-regulates synaptopodin immunohistochemistry in the hippocampus of both male and females. Similarly, in aromatase knock-out mice synaptopodin expression in the hippocampus is reduced sex independently. Using primary-dissociated hippocampal neurons, we found that evoked release of Ca2+ from internal stores down regulates aromatase activity, which is paralleled by reduced expression of synaptopodin. Opposite effects were achieved after inhibition of the release. Calcium-dependent regulation of synaptopodin expression was abolished when the control of aromatase activity by the Ca2+ transients was disrupted. Our data suggest that the regulation of aromatase activity by Ca2+ transients in neurons contributes to synaptic plasticity in the hippocampus of male and female animals as an on- site regulatory mechanism.Deutsche Forschungsgemeinschaf
Der Einfluss der endogenen 17β-Estradiolsynthese auf die Motilität von Podozyten der Ratte in vitro
No full textZahlreiche Studien liefern Hinweise darauf, dass Geschlechtshormone einen Einfluss auf Nierenerkrankungen haben könnten. Kummer et al. (2012) konnten in ihrer Arbeit demonstrieren, dass die klinische Prognose chronisch renaler Erkrankungen bei Männern schlechter ist als bei Frauen. In der Niere spielen Podozyten eine zentrale Rolle bei Aufrechterhaltung der Blut-Harn-Schranke und von ihrem dynamischen Zytoskelett hängen die physiologische Form und Funktion ab. Pathologien an der Filtrationsbarriere manifestieren sich zellulär an den Podozyten durch eine nicht mehr intakte Filtrationsbarriere. Für die physiologische Funktion der Podozyten sind die Fußfortsätze maßgeblich. Sie organisieren sich durch das Aktin-Zytoskelett. An der Orchestrierung des Zytoskeletts sind Proteine wie Cofilin und Synaptopodin beteiligt. Diese Proteine bedingen Veränderungen an den Fußfortsätzen und sie sind responsiv für Sexualhormone wie Estrogen. Ein besseres Verständnis für den Einfluss von Sexual-Hormonen auf die Progression renaler Erkrankungen ist von großer Bedeutung, da die Behandlung nicht- renaler Erkrankungen auch die Nierenfunktion und die Struktur beeinflusst und Hormonrezeptormodulation ein Behandlungsansatz renaler Erkrankungen sein könnten. Die genaue Rolle der Geschlechtshormone in der Niere ist bisher unzureichend erforscht. In dieser Arbeit wurde die Rolle von Geschlechtshormonen innerhalb der Niere und auf ihre Funktionen untersucht. Dazu wurde im Tiermodell an Podozyten der Ratte die Bildung von 17β-Estradiol und die Ausbildung spezifischer Estrogenrezeptoren analysiert. Außerdem wurde die Anpassung des Zellgerüstes der Podozyten auf das Vorhandensein und die Reduktion von 17β-Estradiol in männlichen und weiblichen Zellkulturen untersucht. Die dafür verantwortlichen, spezifischen Proteine Synaptopodin und Cofilin wurden mittels Laser- Scanning-Mikroskopie und Western-Blot-Technik untersucht. In der vorliegenden Arbeit wurde im Tiermodell mit Podozyten der Ratte nachgewiesen, dass 17β-Estradiol im Podozyten de novo gebildet wird und spezifische Rezeptoren (ERalpha und ERbeta) in den Zellen für dieses Hormon vorhanden sind. 17β-Estradiol im Podozyten kontrolliert das Aktin- Zytoskelett: Inhibition der 17β-Estradiol-Synthese resultiert in Hochregulation von Synaptopodin und vermehrter Phosphorylierung von Cofilin in männlichen Podozyten der Ratte, aber in verminderter Expression von Synaptopodin und verringerter Phosphorylierung von Cofilin in weiblichen Ratten-Podozyten. Diese Arbeit liefert Hinweise darauf, dass die Motilität der männlichen, jedoch nicht der weiblichen Podozyten herabgesetzt wird. Meine Daten zeigen, dass das Aktin-Zytoskelett von Podozyten durch 17β-Estradiolspiegel geschlechtsspezifisch reguliert werden könnte. Die Ergebnisse dieser Arbeit tragen dazu bei, die Rolle der Sexualhormone in der Niere besser zu verstehen und neue, geschlechterspezifische Therapien bei Erkrankungen der Niere zu entwickeln
Cholesterol-Promoted Synaptogenesis Requires the Conversion of Cholesterol to Estradiol in the Hippocampus
No full textCholesterol of glial origin promotes synaptogenesis (Mauch et al., (2001) Science 294:1354-1357). Because in the hippocampus local estradiol synthesis is essential for synaptogenesis, we addressed the question of whether cholesterol-promoted synapse formation results from the function of cholesterol as a precursor of estradiol synthesis in this brain area. To this end, we treated hippocampal cultures with cholesterol, estradiol, or with letrozole, a potent aromatase inhibitor. Cholesterol increased neuronal estradiol release into the medium, the number of spine synapses in hippocampal slice cultures, and immunoreactivity of synaptic proteins in dispersed cultures. Simultaneous application of cholesterol and letrozole or blockade of estrogen receptors by ICI 182 780 abolished cholesterol-induced synapse formation. As a further approach, we inhibited the access of cholesterol to the first enzyme of steroidogenesis by knock-down of steroidogenic acute regulatory protein, the rate-limiting step in steroidogenesis. A rescue of reduced synaptic protein expression in transfected cells was achieved by estradiol but not by cholesterol. Our data indicate that in the hippocampus cholesterol-promoted synapse formation requires the conversion of cholesterol to estradiol. (C) 2009 Wiley-Liss, Inc.Deutsche Forschungsgemeinschaft [Ru 436/4-4
Oestrogen synthesis in the hippocampus: Role in axon outgrowth
No full textOvarian oestrogens have been postulated to be neuroprotective. It has also been shown that considerable amounts of oestrogens are synthesised in hippocampal neurones. In the present study, we focused on a potential role of hippocampus-derived oestradiol compared to gonad-derived oestradiol on axon outgrowth of hippocampal neurones. To address the role of hippocampus-derived oestradiol, we inhibited oestrogen synthesis by treatment of neonatal hippocampal cell cultures with letrozole, a specific aromatase inhibitor. As an alternative, we used siRNA against steroidogenic acute regulatory protein (StAR). Axon outgrowth and GAP-43 expression were significantly down-regulated in response to letrozole and in siRNA-StAR transfected cells. The effects after inhibition of oestrogen synthesis in response to letrozole and in siRNA-StAR transfected cells were reversed by oestrogen supplementation. No difference was found between ovariectomised animals, cycling animals at pro-oestrus and ovariectomised and subsequently oestradiol-treated animals. However, high pharmacological doses of oestradiol promoted axon outgrowth, which was possible to abolish by the oestrogen receptor antagonist ICI 182,780. Our results show that oestradiol-induced neurite outgrowth is very likely mediated by genomic oestrogen receptors and requires higher doses of oestradiol than physiological serum concentrations derived from the gonads
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