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1.
PLoS One ; 12(12): e0189075, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29211795

RESUMO

Relaxation and excitation are components of the effects of music listening. The tempo of music is often considered a critical factor when determining these effects: listening to slow-tempo and fast-tempo music elicits relaxation and excitation, respectively. However, the chemical bases that underlie these relaxation and excitation effects remain unclear. Since parasympathetic and sympathetic nerve activities are facilitated by oxytocin and glucocorticoid, respectively, we hypothesized that listening to relaxing slow-tempo and exciting fast-tempo music is accompanied by increases in the oxytocin and cortisol levels, respectively. We evaluated the change in the salivary oxytocin and cortisol levels of participants listening to slow-tempo and fast-tempo music sequences. We measured the heart rate (HR) and calculated the heart rate variability (HRV) to evaluate the strength of autonomic nerve activity. After listening to a music sequence, the participants rated their arousal and valence levels. We found that both the salivary oxytocin concentration and the high frequency component of the HRV (HF) increased and the HR decreased when a slow-tempo music sequence was presented. The salivary cortisol level decreased and the low frequency of the HRV (LF) to HF ratio (LF/HF) increased when a fast-tempo music sequence was presented. The ratio of the change in the oxytocin level was correlated with the change in HF, LF/HF and HR, whereas that in the cortisol level did not show any correlation with indices of autonomic nerve activity. There was no correlation between the change in oxytocin level and self-reported emotions, while the change in cortisol level correlated with the arousal level. These findings suggest that listening to slow-tempo and fast-tempo music is accompanied by an increase in the oxytocin level and a decrease in the cortisol level, respectively, and imply that such music listening-related changes in oxytocin and cortisol are involved in physiological relaxation and emotional excitation, respectively.


Assuntos
Hidrocortisona/análise , Música , Ocitocina/análise , Saliva/química , Adulto , Cromatografia Líquida , Humanos , Masculino , Espectrometria de Massas em Tandem , Adulto Jovem
2.
Horm Behav ; 74: 149-56, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26122288

RESUMO

This article is part of a Special Issue "Estradiol and cognition". Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2h. Spine head diameter analysis showed that the density of middle-head spines (0.4-0.5 µm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3ß antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER.


Assuntos
Espinhas Dendríticas/fisiologia , Giro Denteado/citologia , Estradiol/fisiologia , Proteínas Quinases/fisiologia , Animais , Contagem de Células , Espinhas Dendríticas/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Fulvestranto , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar
3.
Brain Res ; 1621: 121-32, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25511993

RESUMO

Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks. This article is part of a Special Issue entitled SI: Brain and Memory.


Assuntos
Androgênios/fisiologia , Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/fisiologia , Di-Hidrotestosterona/farmacologia , Sinapses/fisiologia , Testosterona/fisiologia , Androgênios/farmacologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Ratos , Ratos Wistar , Receptores Androgênicos/fisiologia , Sinapses/efeitos dos fármacos , Testosterona/farmacologia
4.
Brain Res ; 1621: 133-46, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25498865

RESUMO

Rapid modulation of hippocampal synaptic plasticity through synaptic estrogen receptors is an essential topic. We analyzed estradiol-induced modulation of CA1 dendritic spines using adult male ERαKO and ERßKO mice. A 2h treatment of estradiol particularly increased the density of middle-head spines (diameter 0.3-0.4 µm) in wild type mouse hippocampal slices. The enhancement of spinogenesis was completely suppressed by MAP kinase inhibitor. Estradiol-induced increase in middle-head spines was observed in ERßKO mice (which express ERα), but not in ERαKO, indicating that ERα is necessary for the spinogenesis. Direct observation of the dynamic estradiol-induced enhancing effect on rapid spinogenesis was performed using time-lapse imaging of spines in hippocampal live slices from yellow fluorescent protein expressed mice. Both appearance and disappearance of spines occurred, and the number of newly appeared spines was significantly greater than that of disappeared spines, resulting in the net increase of the spine density within 2h. As another type of synaptic modulation, we observed that estradiol rapidly enhanced N-methyl-D-aspartate (NMDA)-induced long-term depression (LTD) in CA1 of the wild type mouse hippocampus. In contrast, estradiol did not enhance NMDA-LTD in ERαKO mice, indicating the involvement of ERα in the estrogen signaling. This article is part of a Special Issue entitled SI: Brain and Memory.


Assuntos
Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/fisiologia , Estradiol/fisiologia , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Depressão Sináptica de Longo Prazo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Estradiol/administração & dosagem , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
5.
Artigo em Inglês | MEDLINE | ID: mdl-24917791

RESUMO

Activin A is known as a neuroprotective factor produced upon acute excitotoxic injury of the hippocampus (in pathological states). We attempt to reveal the role of activin as a neuromodulator in the adult male hippocampus under physiological conditions (in healthy states), which remains largely unknown. We showed endogenous/basal expression of activin in the hippocampal neurons. Localization of activin receptors in dendritic spines (=postsynapses) was demonstrated by immunoelectron microscopy. The incubation of hippocampal acute slices with activin A (10 ng/mL, 0.4 nM) for 2 h altered the density and morphology of spines in CA1 pyramidal neurons. The total spine density increased by 1.2-fold upon activin treatments. Activin selectively increased the density of large-head spines, without affecting middle-head and small-head spines. Blocking Erk/MAPK, PKA, or PKC prevented the activin-induced spinogenesis by reducing the density of large-head spines, independent of Smad-induced gene transcription which usually takes more than several hours. Incubation of acute slices with activin for 2 h induced the moderate early long-term potentiation (moderate LTP) upon weak theta burst stimuli. This moderate LTP induction was blocked by follistatin, MAPK inhibitor (PD98059) and inhibitor of NR2B subunit of NMDA receptors (Ro25-6981). It should be noted that the weak theta burst stimuli alone cannot induce moderate LTP. These results suggest that MAPK-induced phosphorylation of NMDA receptors (including NR2B) may play an important role for activin-induced moderate LTP. Taken together, the current results reveal interesting physiological roles of endogenous activin as a rapid synaptic modulator in the adult hippocampus.


Assuntos
Receptores de Ativinas/metabolismo , Ativinas/metabolismo , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Células Piramidais/metabolismo , Receptores de Ativinas/genética , Ativinas/genética , Ativinas/farmacologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Front Neural Circuits ; 7: 191, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348341

RESUMO

Modulation of synapses under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. We tried to test whether rapid CORT effects involve activation of essential kinases as non-genomic processes. We demonstrated rapid effects (~1 h) of CORT on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. The application of CORT at 100, 500, and 1000 nM induced a rapid increase in the density of thorns in the stratum lucidum of CA3 pyramidal neurons. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, including MAPK, PKA, or PKC, suppressed CORT-induced enhancement of thorn-genesis. On the other hand, GSK-3ß was not involved in the signaling of thorn-genesis. Blocking AMPA receptors suppressed the CORT effect. Expression of CA3 synaptic/extranuclear GR was demonstrated by immunogold electron microscopic analysis. From these results, stress levels of CORT (100-1000 nM) might drive the rapid thorn-genesis via synaptic/extranuclear GR and multiple kinase pathways, although a role of nuclear GRs cannot be completely excluded.


Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Corticosterona/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Sinapses/efeitos dos fármacos , Animais , Região CA3 Hipocampal/metabolismo , Espinhas Dendríticas/metabolismo , Antagonistas de Hormônios/farmacologia , Masculino , Mifepristona/farmacologia , Neurônios/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/antagonistas & inibidores , Sinapses/metabolismo
7.
PLoS One ; 7(4): e34124, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22509272

RESUMO

BACKGROUND: Modulation of dendritic spines under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrated the mechanisms of rapid effect (∼1 h) of CORT on the density and morphology of spines by imaging neurons in adult male rat hippocampal slices. The application of CORT at 100-1000 nM induced a rapid increase in the density of spines of CA1 pyramidal neurons. The density of small-head spines (0.2-0.4 µm) was increased even at low CORT levels (100-200 nM). The density of middle-head spines (0.4-0.5 µm) was increased at high CORT levels between 400-1000 nM. The density of large-head spines (0.5-1.0 µm) was increased only at 1000 nM CORT. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, such as MAPK, PKA, PKC or PI3K, suppressed CORT-induced enhancement of spinogenesis. Blocking NMDA receptors suppressed the CORT effect. CONCLUSIONS/SIGNIFICANCE: These results imply that stress levels of CORT (100-1000 nM) drive the spinogenesis via synaptic GR and multiple kinase pathways.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Corticosterona/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Proteínas Quinases/metabolismo , Receptores de Glucocorticoides/metabolismo , Sinapses/metabolismo , Adrenalectomia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Masculino , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Glutamato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Fatores de Tempo
8.
Cereb Cortex ; 22(4): 926-36, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21725036

RESUMO

We investigated rapid protection effect by estradiol on corticosterone (CORT)-induced suppression of synaptic transmission. Rapid suppression by 1 µM CORT of long-term potentiation (LTP) at CA3-CA1 synapses was abolished via coperfusion of 1 nM estradiol. N-methyl-D-aspartate (NMDA) receptor-derived field excitatory postsynaptic potential (NMDA-R-fEPSP) was used to analyze the mechanisms of these events. Estradiol abolished CORT-induced suppression of NMDA-R-fEPSP slope. This CORT-induced suppression was abolished by calcineurin inhibitor, and the rescue effect by estradiol on the CORT-induced suppression was inhibited by mitogen-activated protein (MAP) kinase inhibitor. The CORT-induced suppressions of LTP and NMDA-R-fEPSP slope were abolished by glucocorticoid receptor (GR) antagonist, and the restorative effects by estradiol on these processes were mimicked by estrogen receptor α (ERα) and ERß agonists. Taken together, estradiol rapidly rescued LTP and NMDA-R-fEPSP slope from CORT-induced suppressions. A GR→calcineurin pathway is involved in these suppressive effects. The rescue effects by estradiol are driven via ERα or ERß→MAP kinase pathway. Synaptic/extranuclear GR, ERα, and ERß probably participate in these rapid events. Mass-spectrometric analysis determined that acute hippocampal slices used for electrophysiological measurements contained 0.48 nM estradiol less than exogenously applied 1 nM. In vivo physiological level of 8 nM estradiol could protect the intact hippocampus against acute stress-induced neural suppression.


Assuntos
Estradiol/farmacologia , Estrogênios/farmacologia , Hipocampo/efeitos dos fármacos , Receptores de Estradiol/metabolismo , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Análise de Variância , Animais , Anti-Inflamatórios/farmacologia , Biofísica , Corticosterona/farmacologia , Estimulação Elétrica , Estradiol/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Espectrometria de Massas , Microscopia Imunoeletrônica , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Wistar , Esteroides/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura
9.
J Steroid Biochem Mol Biol ; 131(1-2): 37-51, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22075082

RESUMO

The hippocampus synthesizes estrogen and androgen in addition to the circulating sex steroids. Synaptic modulation by hippocampus-derived estrogen or androgen is essential to maintain healthy memory processes. Rapid actions (1-2h) of 17ß-estradiol (17ß-E2) occur via synapse-localized receptors (ERα or ERß), while slow genomic E2 actions (6-48h) occur via classical nuclear receptors (ERα or ERß). The long-term potentiation (LTP), induced by strong tetanus or theta-burst stimulation, is not further enhanced by E2 perfusion in adult rats. Interestingly, E2 perfusion can rescue corticosterone (stress hormone)-induced suppression of LTP. The long-term depression is modulated rapidly by E2 perfusion. Elevation of the E2 concentration changes rapidly the density and head structure of spines in neurons. ERα, but not ERß, drives this enhancement of spinogenesis. Kinase networks are involved downstream of ERα. Testosterone (T) or dihydrotestosterone (DHT) also rapidly modulates spinogenesis. Newly developed Spiso-3D mathematical analysis is used to distinguish these complex effects by sex steroids and kinases. It has been doubted that the level of hippocampus-derived estrogen and androgen may not be high enough to modulate synaptic plasticity. Determination of the accurate concentration of E2, T or DHT in the hippocampus is enabled by mass-spectrometric analysis in combination with new steroid-derivatization methods. The E2 level in the hippocampus is approximately 8nM for the male and 0.5-2nM for the female, which is much higher than that in circulation. The level of T and DHT is also higher than that in circulation. Taken together, hippocampus-derived E2, T, and DHT play a major role in modulation of synaptic plasticity.


Assuntos
Estradiol/fisiologia , Hipocampo/metabolismo , Plasticidade Neuronal , Testosterona/fisiologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/fisiologia , Di-Hidrotestosterona/metabolismo , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos
10.
PLoS One ; 6(7): e21631, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21829438

RESUMO

BACKGROUND: Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21). METHODOLOGY/PRINCIPAL FINDINGS: The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of (3)H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11ß1) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h. CONCLUSIONS/SIGNIFICANCE: These results imply the complete pathway of corticosteroid synthesis of 'pregnenolone →PROG→DOC→CORT' in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands.


Assuntos
Corticosterona/metabolismo , Desoxicorticosterona/metabolismo , Hipocampo/metabolismo , Progesterona/metabolismo , Animais , Southern Blotting , Cromatografia Líquida , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Hipocampo/citologia , Hibridização In Situ , Masculino , Microscopia Imunoeletrônica , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Cereb Cortex ; 21(12): 2704-11, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21527787

RESUMO

Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our "Spiso-3D" software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex.


Assuntos
Automação Laboratorial/métodos , Espinhas Dendríticas , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Software , Algoritmos , Androgênios/farmacologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Estrogênios/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Microscopia Confocal , Ratos , Ratos Wistar
12.
Horm Mol Biol Clin Investig ; 7(2): 361-75, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25961274

RESUMO

Estradiol is synthesized from cholesterol in hippocampal neurons of adult rats by cytochrome P450 and hydroxysteroid dehydrogenase enzymes. These enzymes are expressed in the glutamatergic neurons of the hippocampus. Surprisingly, the concentration of estradiol and androgen in the hippocampus is significantly higher than that in circulation. Locally synthesized estradiol rapidly and potently modulates synaptic plasticity within the hippocampus. E2 rapidly potentiates long-term depression and induces spinogenesis through synaptic estrogen receptors and kinases. The rapid effects of estradiol are followed by slow genomic effects mediated by both estrogen receptors located at the synapse and nucleus, modulating long-term potentiation and promoting the formation of new functional synaptic contacts. Age-related changes in hippocampally derived estradiol synthesis and distribution of estrogen receptors may alter synaptic plasticity, and could potentially contribute to age-related cognitive decline. Understanding factors which regulate hippocampal estradiol synthesis could lead to the identification of alternatives to conventional hormone therapy to protect against age-related cognitive decline.

13.
Artigo em Inglês | MEDLINE | ID: mdl-22701110

RESUMO

Sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. Accumulating evidence shows that hippocampal neurons synthesize both estrogen and androgen. Recently, we also revealed the hippocampal synthesis of corticosteroids. The accurate concentrations of these hippocampus-synthesized steroids are determined by liquid chromatography-tandem mass-spectrometry in combination with novel derivatization. The hippocampal levels of 17ß-estradiol (E2), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CORT), are 5-15 nM, and these levels are sufficient to modulate synaptic plasticity. Hippocampal E2 modulates memory-related synaptic plasticity not only slowly/genomically but also rapidly/non-genomically. Slow actions of E2 occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized or extranuclear ERα or ERß. Nanomolar concentrations of E2 change rapidly the density and morphology of spines in hippocampal neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis in adult animals. Nanomolar concentrations of androgens (T and DHT) and CORT also increase the spine density. Kinase networks are involved downstream of ERα and androgen receptor. Newly developed Spiso-3D mathematical analysis is useful to distinguish these complex effects by sex steroids and kinases. Significant advance has been achieved in investigations of rapid modulation by E2 of the long-term depression or the long-term potentiation.

14.
Ophthalmology ; 117(9): 1800-9, 1809.e1-2, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20673590

RESUMO

OBJECTIVE: To compare pathologic changes in photoreceptors in eyes with resolved central serous chorioretinopathy (CSC) seen on high-resolution images obtained by adaptive optics scanning laser ophthalmoscopy (AO SLO) with visual acuity (VA) and findings on spectral-domain optical coherence tomography (SD OCT). DESIGN: Observational case series. PARTICIPANTS: Forty-five eyes of 38 patients with resolved CSC and 20 normal eyes of 20 volunteer subjects. METHODS: All patients underwent a full ophthalmologic examination, SD OCT, and imaging with an original prototype AO SLO system fabricated using liquid crystal-on-silicon technology. MAIN OUTCOME MEASURES: Cone mosaic patterns and cone density on AO SLO images and VA in eyes with CSC. RESULTS: In normal eyes, AO SLO images showed a regular photoreceptor mosaic pattern and average cone densities 0.2, 0.5, and 1.0 mm from the central fovea of 67,900, 33,320, and 14,450 cones/mm(2). In eyes with CSC, cone densities were significantly lower at each distance from the central fovea (P = 0.009 at 0.2 mm, P = 0.007 at 0.5 mm, and P = 0.004 at 1.0 mm), and 2 distinct cone mosaic patterns were seen. Group 1 CSC eyes had regular cone mosaic patterns with small dark regions. Group 2 CSC eyes had irregular mosaic patterns with large dark regions. Compared with group 1, group 2 had significantly lower average cone density and worse average logarithm of the minimum angle of resolution (logMAR) VA (P<0.001). Mean cone density in eyes with disruptions in the photoreceptor inner and outer segment (IS/OS) junction or in the intermediate line on SD OCT images was significantly lower than that in eyes with an intact IS/OS junction or intermediate line (P<0.001 for both). Cone density 0.2 mm from the central fovea correlated with logMAR VA and mean foveal thickness (1-mm diameter area) measured on SD OCT images (P<0.001 for both). CONCLUSIONS: Adaptive optics SLO images showed abnormal cone mosaic patterns and reduced cone densities in eyes with resolved CSC, and these abnormalities were associated with VA loss, suggesting that AO SLO is a useful means to detect and measure cone abnormalities associated with VA loss in these eyes.


Assuntos
Coriorretinopatia Serosa Central/diagnóstico , Oftalmoscopia , Células Fotorreceptoras Retinianas Cones/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Coriorretinopatia Serosa Central/fisiopatologia , Coriorretinopatia Serosa Central/terapia , Corantes , Feminino , Angiofluoresceinografia , Humanos , Verde de Indocianina , Fotocoagulação a Laser , Masculino , Pessoa de Meia-Idade , Fotoquimioterapia , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia
15.
Biochim Biophys Acta ; 1800(10): 1030-44, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19909788

RESUMO

The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention. Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17ß-estradiol (17ß-E2) occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized ERα or ERß. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1-CA3 neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERα. The long-term depression but not the long-term potentiation is modulated rapidly by changes of E2 level. Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity. Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.


Assuntos
Estradiol/metabolismo , Estrogênios/metabolismo , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hipocampo/citologia , Humanos , Masculino , Neurônios/citologia
16.
Endocrinology ; 150(11): 5106-12, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19589866

RESUMO

Estradiol (E2) and other sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. To clarify the mechanisms for these events, it is important to determine the respective role of circulating vs. locally produced sex steroids in the male hippocampus. Liquid chromatography-tandem mass spectrometry in combination with novel derivatization was employed to determine the concentration of sex steroids in adult male rat hippocampus. The hippocampal levels of 17beta-E2, testosterone (T), and dihydrotestosterone (DHT) were 8.4, 16.9, and 6.6 nm, respectively, and these levels were significantly higher than circulating levels. The hippocampal estrone (E1) level was, in contrast, very low around 0.015 nm. After castration to deplete circulating high level T, hippocampal levels of T and DHT decreased considerably to 18 and 3%, respectively, whereas E2 level only slightly decreased to 83%. The strong reduction in hippocampal DHT resulting from castration implies that circulating T may be a main origin of DHT. In combination with results obtained from metabolism analysis of [(3)H]steroids, we suggest that male hippocampal E2 synthesis pathway may be androstenedione --> T --> E2 or dehydroepiandrosterone --> androstenediol --> T --> E2 but not androstenedione --> E1 --> E2.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Hipocampo/metabolismo , Animais , Feminino , Hormônios Esteroides Gonadais/análise , Hipocampo/química , Masculino , Ratos , Ratos Wistar
17.
Biochem Biophys Res Commun ; 381(4): 728-32, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19254689

RESUMO

Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10nM DHT or T induced rapid increase in the density of thorns within 2h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.


Assuntos
Androgênios/fisiologia , Dendritos/fisiologia , Hipocampo/fisiologia , Androgênios/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dendritos/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Testosterona/farmacologia , Testosterona/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Mol Cell Endocrinol ; 290(1-2): 31-43, 2008 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-18541362

RESUMO

Estrogen and androgen are synthesized from cholesterol locally in hippocampal neurons of adult animals. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases (HSDs) and 5alpha-reductase. The expression levels of enzymes are as low as 1/200-1/50,000 of those in endocrine organs, however these numbers are high enough for local synthesis. Localization of P450(17alpha), P450arom, 17beta-HSD and 5alpha-reductase is observed in principal glutamatergic neurons in CA1, CA3 and the dendate gyrus. Several nanomolar levels of estrogen and androgen are observed in the hippocampus. Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. Rapid action of 17beta-estradiol via membrane receptors is demonstrated for spinogenesis and long-term depression (LTD). The enhancement of LTD by 1-10nM estradiol occurs within 1 h. The density of spine is increased in CA1 pyramidal neurons within 2h after application of estradiol. The density of spine-like structure is, however, decreased by estradiol in CA3 pyramidal neurons. ERalpha, but not ERbeta, induces the same enhancement/suppression effects on both spinogenesis and LTD.


Assuntos
Encéfalo/metabolismo , Estrogênios/biossíntese , Memória , Plasticidade Neuronal , Sinapses/metabolismo , Animais , Encéfalo/ultraestrutura , Humanos , Sinapses/ultraestrutura
19.
Brain Res Rev ; 57(2): 363-75, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17822775

RESUMO

Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. However, molecular mechanisms of the rapid action are yet largely unknown. We here describe rapid modulation of representative synaptic plasticity, i.e., long-term depression (LTD), long-term potentiation (LTP) and spinogenesis, by 17beta-estradiol, selective estrogen agonists as well as endocrine disrupters. The authors demonstrated that 1-10 nM estradiol induced rapid enhancement of LTD within 1 h in not only CA1 but also CA3 and dentate gyrus (DG). On the other hand, the modulation of LTP by estradiol was not statistically significant. The total density of spines was increased in CA1 pyramidal neurons, within 2 h after application of estradiol. The total density of thorns (postsynaptic spine-like structure) was, however, decreased by estradiol in CA3 pyramidal neurons. Both the increase of spines in CA1 and the decrease of thorns in CA3 were completely suppressed by Erk MAP kinase inhibitor. Only ERalpha agonist PPT induced the same enhancement/suppression effect as estradiol on both LTD and spinogenesis in CA1 and CA3. ERbeta agonist DPN induced completely different results. ERalpha localized in spines and presynapses of principal glutamatergic neurons in CA1, CA3 and DG. The same ERalpha was also located in nuclei and cytoplasm. Identification of ERalpha was successfully performed using purified RC-19 antibody. Non-purified ERalpha antisera, however, reacted significantly with unknown proteins, resulting in wrong immunostaining different from real ERalpha distribution. An issue of 'endocrine disrupters' (1-100 nM low dose of environmental chemicals), which are artificial xenoestrogenic or anti-xenoestrogenic substances, has emerged as a social and environmental problem. Endocrine disrupters were found to significantly modulate LTD and spinogenesis. Bisphenol A (BPA) and diethylstilbestrol (DES) enhanced LTD in CA1 and CA3. The total spine density was significantly increased by BPA and DES in CA1. Most probable receptors for BPA and DES may be Ralpha; however, other receptors might also be involved.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Compostos Benzidrílicos , Dietilestilbestrol/toxicidade , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Estrogênios não Esteroides/toxicidade , Hipocampo/fisiologia , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Fenóis/toxicidade , Ratos
20.
Neuroscientist ; 13(4): 323-34, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17644764

RESUMO

It is believed that sex hormones are synthesized in the gonads and reach the brain via the blood circulation. In contrast with this view, the authors have demonstrated that sex hormones are also synthesized locally in the hippocampus and that these steroids act rapidly to modulate neuronal synaptic plasticity. The authors demonstrated that estrogens are locally synthesized from cholesterol through dehydroepiandrosterone and testosterone in adult hippocampal neurons. Significant expression of mRNA for P450(17alpha), P450arom, and other steroidogenic enzymes was demonstrated. Localization of P450(17alpha) and P450arom was observed in synapses of principal neurons. In contrast to the slow action of gonadal estradiol, hippocampal neuron-derived estradiol may act locally and rapidly within the neurons. For example, 1 to 10 nM estradiol rapidly enhances long-term depression (LTD). The density of thin spines is selectively increased within two hours upon application of estradiol in pyramidal neurons. Estrogen receptor ERalpha agonist has the same enhancing effect as estradiol on both LTD and spinogenesis. Localization of ERalpha in spines in addition to nuclei of principal neurons implies that synaptic ERalpha is responsible for rapid modulation of synaptic plasticity by endogenous estradiol. Activin A, a peptide sex hormone, may also play a role as a local endogenous modulator of synaptic plasticity.


Assuntos
Hormônios Esteroides Gonadais/fisiologia , Hipocampo/citologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Hormônios Esteroides Gonadais/farmacologia , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sinapses/efeitos dos fármacos
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