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1.
Neuroscience ; 459: 85-103, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524494

RESUMO

The synaptogenic hypothesis of major depressive disorder implies that preventing the onset of depressive-like behavior also prevents the loss of hippocampal spine synapses. By applying the psychoactive drugs, diazepam and fluoxetine, we investigated whether blocking the development of helpless behavior by promoting stress resilience in the rat learned helplessness paradigm is associated with a synaptoprotective action in the hippocampus. Adult ovariectomized and intact female Sprague-Dawley rats (n = 297) were treated with either diazepam, fluoxetine, or vehicle, exposed to inescapable footshocks or sham stress, and tested in an active escape task to assess helpless behavior. Escape-evoked corticosterone secretion, as well as remodeling of hippocampal spine synapses at a timepoint representing the onset of escape testing were also analyzed. In ovariectomized females, treatment with diazepam prior to stress exposure prevented helpless behavior, blocked the loss of hippocampal spine synapses, and muted the corticosterone surge evoked by escape testing. Although fluoxetine stimulated escape performance and hippocampal synaptogenesis under non-stressed conditions, almost all responses to fluoxetine were abolished following exposure to inescapable stress. Only a much higher dose of fluoxetine was capable of partly reproducing the strong protective actions of diazepam. Importantly, these protective actions were retained in the presence of ovarian hormones. Our findings indicate that stress resilience is associated with the preservation of spine synapses in the hippocampus, raising the possibility that, besides synaptogenesis, hippocampal synaptoprotection is also implicated in antidepressant therapy.


Assuntos
Transtorno Depressivo Maior , Desamparo Aprendido , Animais , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Hipocampo , Ratos , Ratos Sprague-Dawley
2.
Vitam Horm ; 114: 257-279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723547

RESUMO

By nature's original design, stress is a protective mechanism, signaling danger to homeostasis and, as a result, stimulating the brain to initiate coping and adaptive responses, which ultimately increases the chances of survival. On the other hand, stress may become a danger to homeostasis itself, when it is so severe or so prolonged that it overpowers cellular reserves. One of the consequences of traumatic stress is loss of hippocampal spine synapses, which is the main topic of this chapter summarizing research findings from the last 10+ years. Loss of spine synapses is thought to be a neuronal defense mechanism against excitotoxic damage, so the subcellular mechanisms of synapse loss are reviewed in the context of glutamatergic insults. One of the main conceptual derivates of stress-induced synaptic alterations is the "synaptogenic" hypothesis of major depressive disorder. The synaptogenic hypothesis postulates an inverse correlation between the number of limbic, mainly prefrontal cortical and hippocampal, spine synapses and the severity of depressive behavior/symptoms. The synaptogenic hypothesis implies that synaptoprotective interventions, that are capable of countering the stress-induced loss of limbic spine synapses, are probably also capable of promoting stress resilience, which may provide the conceptual basis for a preventive approach in antidepressant therapy. Finally, we discuss why electron microscopic stereology is a reliable and highly accurate technique for the quantitative assessment of ultrastructural particulate objects, such as spines and synapses.


Assuntos
Hipocampo/citologia , Plasticidade Neuronal , Neurônios/fisiologia , Estresse Psicológico/fisiopatologia , Sinapses/fisiologia , Animais , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos
3.
Neuroscience ; 343: 384-397, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28012870

RESUMO

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness.


Assuntos
Depressão Pós-Parto/patologia , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Plasticidade Neuronal , Sinapses/patologia , Animais , Corticosterona/sangue , Depressão Pós-Parto/metabolismo , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estradiol/metabolismo , Feminino , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Ovariectomia , Período Pós-Parto , Proestro/fisiologia , Progesterona/administração & dosagem , Progesterona/metabolismo , Ratos Sprague-Dawley , Sinapses/metabolismo
4.
Nat Med ; 18(9): 1413-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885997

RESUMO

Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD). These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function­related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.


Assuntos
Transtorno Depressivo Maior/patologia , Regulação da Expressão Gênica/fisiologia , Córtex Pré-Frontal/patologia , Sinapses/patologia , Análise de Variância , Animais , Calmodulina/metabolismo , Linhagem Celular , Transtorno Depressivo Maior/metabolismo , Fator de Transcrição GATA1/metabolismo , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries , Microscopia Eletrônica , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses/metabolismo , Sinapsinas/metabolismo , Tubulina (Proteína)/metabolismo , Proteína rab3A de Ligação ao GTP/metabolismo , Proteínas rab4 de Ligação ao GTP/metabolismo
5.
J Neurosci Methods ; 205(1): 130-8, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22230770

RESUMO

We have recently reported that in the learned helplessness model of depression, the less hippocampal spine synapses rats have, the more helpless they become. It remains unclear, however, whether the observed synaptic changes are associated with the loss of CA1 pyramidal cells. Cell bodies in the CA1 pyramidal layer are very densely packed, making cell counting difficult in this hippocampal subregion. To address this issue, we developed a new approach that (1) yields excellent preservation of the three-dimensional tissue structure; (2) utilizes osmium tetroxide to unambiguously label nucleoli; and (3) facilitates and accelerates unbiased, reliable counting of densely packed cell bodies. Our method provides an improved tool for studies aiming to evaluate hippocampal atrophy and cell loss, the most characteristic features in many neurodegenerative diseases, such as Alzheimer's disease, temporal lobe epilepsy and ischemia, as well as in several psychiatric disorders. Using this new method, we demonstrated no significant changes in the number of CA1 pyramidal cells in the rat learned helplessness paradigm. In addition, volumes of the CA1 pyramidal cell layer and the entire CA1 subfield remained unchanged among treatment groups. We conclude that previously observed synaptic alterations in helpless rats are not associated with CA1 pyramidal cell loss. This finding suggests that behavioral outcome in the learned helplessness paradigm is related to plastic events at the synaptic level, rather than at the level of principal cells.


Assuntos
Região CA1 Hipocampal/citologia , Contagem de Células/métodos , Desamparo Aprendido , Células Piramidais/fisiologia , Algoritmos , Animais , Calbindinas , Eletrochoque , Resinas Epóxi , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Tetróxido de Ósmio , Ratos , Ratos Sprague-Dawley , Proteína G de Ligação ao Cálcio S100/metabolismo , Inclusão do Tecido , Fixação de Tecidos
6.
Int J Neuropsychopharmacol ; 14(10): 1411-5, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21733230

RESUMO

Schizophrenia patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. In this study we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodelling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than layer V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the non-human primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia.


Assuntos
Transtornos Cognitivos/patologia , Cognição , Espinhas Dendríticas/patologia , Fenciclidina , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Sinapses/patologia , Animais , Chlorocebus aethiops , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Masculino , Microscopia Eletrônica de Transmissão , Córtex Pré-Frontal/ultraestrutura , Esquizofrenia/induzido quimicamente , Psicologia do Esquizofrênico , Sinapses/ultraestrutura
7.
Neuropsychopharmacology ; 36(10): 2054-61, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21677652

RESUMO

Enduring cognitive deficits exist in schizophrenic patients, long-term abusers of phencyclidine (PCP), as well as in animal PCP models of schizophrenia. It has been suggested that cognitive performance and memory processes are coupled with remodeling of pyramidal dendritic spine synapses in prefrontal cortex (PFC), and that reduced spine density and number of spine synapses in the medial PFC of PCP-treated rats may potentially underlie, at least partially, the cognitive dysfunction previously observed in this animal model. The present data show that the decrease in number of asymmetric (excitatory) spine synapses in layer II/III of PFC, previously noted at 1-week post PCP treatment also occurs, to a lesser degree, in layer V. The decrease in the number of spine synapses in layer II/III was sustained and persisted for at least 4 weeks, paralleling the observed cognitive deficits. Both acute and chronic treatment with the atypical antipsychotic drug, olanzapine, starting at 1 week after PCP treatment at doses that restore cognitive function, reversed the asymmetric spine synapse loss in PFC of PCP-treated rats. Olanzapine had no significant effect on spine synapse number in saline-treated controls. These studies demonstrate that the effect of PCP on asymmetric spine synapse number in PFC lasts at least 4 weeks in this model. This spine synapse loss in PFC is reversed by acute treatment with olanzapine, and this reversal is maintained by chronic oral treatment, paralleling the time course of the restoration of the dopamine deficit, and normalization of cognitive function produced by olanzapine.


Assuntos
Benzodiazepinas/administração & dosagem , Espinhas Dendríticas/efeitos dos fármacos , Fenciclidina/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Contagem de Células/métodos , Espinhas Dendríticas/fisiologia , Esquema de Medicação , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Olanzapina , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia , Resultado do Tratamento
8.
Front Neuroendocrinol ; 31(4): 519-30, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20609373

RESUMO

The potential adverse effects of Bisphenol A (BPA), a synthetic xenoestrogen, have long been debated. Although standard toxicology tests have revealed no harmful effects, recent research highlighted what was missed so far: BPA-induced alterations in the nervous system. Since 2004, our laboratory has been investigating one of the central effects of BPA, which is interference with gonadal steroid-induced synaptogenesis and the resulting loss of spine synapses. We have shown in both rats and nonhuman primates that BPA completely negates the ∼ 70-100% increase in the number of hippocampal and prefrontal spine synapses induced by both estrogens and androgens. Synaptic loss of this magnitude may have significant consequences, potentially causing cognitive decline, depression, and schizophrenia, to mention those that our laboratory has shown to be associated with synaptic loss. Finally, we discuss why children may particularly be vulnerable to BPA, which represents future direction of research in our laboratory.


Assuntos
Estrogênios não Esteroides/toxicidade , Neurogênese/efeitos dos fármacos , Fenóis/toxicidade , Sinapses/efeitos dos fármacos , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Compostos Benzidrílicos , Depressão/induzido quimicamente , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Fenóis/sangue , Fenóis/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Primatas , Ratos
9.
Biol Psychiatry ; 67(2): 168-74, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19811775

RESUMO

BACKGROUND: Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression. METHODS: With electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n = 70), under different conditions of estradiol exposure. RESULTS: Stress induced an acute and persistent loss of hippocampal spine synapses, whereas subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either before stress or before escape testing of nonstressed animals increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. CONCLUSIONS: These findings suggest that hippocampal spine synapse remodeling might be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.


Assuntos
Região CA1 Hipocampal/citologia , Espinhas Dendríticas/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Desamparo Aprendido , Neurônios/citologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Eletrochoque/efeitos adversos , Reação de Fuga/efeitos dos fármacos , Feminino , Microscopia Eletrônica de Transmissão/métodos , Neurônios/efeitos dos fármacos , Ovariectomia/métodos , Ratos , Ratos Sprague-Dawley , Análise de Regressão , Técnicas Estereotáxicas , Estresse Psicológico/complicações , Estresse Psicológico/etiologia , Estresse Psicológico/patologia , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Fatores de Tempo
10.
Biol Psychiatry ; 65(5): 392-400, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19006787

RESUMO

BACKGROUND: Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. METHODS: We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. RESULTS: Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects. CONCLUSIONS: These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.


Assuntos
Depressão/patologia , Reação de Fuga/efeitos dos fármacos , Desamparo Aprendido , Hipocampo/ultraestrutura , Sinapses/ultraestrutura , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos Tricíclicos/administração & dosagem , Biomarcadores Farmacológicos/análise , Corticosterona/sangue , Corticosterona/farmacologia , Depressão/sangue , Depressão/tratamento farmacológico , Desipramina/administração & dosagem , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Córtex Motor/efeitos dos fármacos , Córtex Motor/ultraestrutura , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico , Sinapses/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 105(37): 14187-91, 2008 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-18768812

RESUMO

Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.


Assuntos
Estradiol/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fenóis/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Sinapses/metabolismo , Animais , Compostos Benzidrílicos , Chlorocebus aethiops , Feminino , Ovariectomia , Coluna Vertebral/efeitos dos fármacos , Sinapses/efeitos dos fármacos
12.
Horm Behav ; 53(5): 638-46, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18262185

RESUMO

Accumulating evidence indicate that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. We have learned from studies investigating neuronal remodeling that estrogens have an exceptional synaptogenic potential that seems to be specific to limbic areas of the adult female brain. On the other hand, structural synaptic plasticity in the adult male brain and the synaptogenic effect of androgens received relatively little attention. During the last five years, the Leranth laboratory provided conclusive evidence that the hippocampus and prefrontal cortex of adult male rodents and non-human primates retain considerable structural synaptic plasticity similar to the female, and that androgens are capable of inducing spine synapse growth in both the hippocampus and prefrontal cortex similar to estrogens. Our recent work also demonstrates that androgen-induced remodeling of spine synapses in the prefrontal cortex of adult male rats is dependent, at least to some extent, on functional androgen receptors, while being entirely independent of the androgen receptor in the hippocampus. Based on these findings and on their many beneficial effects, we believe that androgens hold a great and undeservingly neglected therapeutic potential that could be employed to reverse synaptic pathology in various neurocognitive and neuropsychiatric disorders.


Assuntos
Androgênios/fisiologia , Encéfalo/fisiologia , Sistema Límbico/fisiologia , Receptores Androgênicos/fisiologia , Medula Espinal/fisiologia , Sinapses/fisiologia , Animais , Feminino , Hipocampo/embriologia , Hipocampo/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/embriologia , Córtex Pré-Frontal/fisiologia , Primatas , Ratos , Receptores Androgênicos/genética
13.
Endocrinology ; 149(3): 988-94, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18048497

RESUMO

Exposure measurement data from several developed countries indicate that human beings are widely exposed to low levels of the synthetic xenoestrogen, bisphenol A. We reported previously that bisphenol A, even at doses below the reference safe daily limit for human exposure, recommended by the U.S. Environmental Protection Agency, impairs the synaptogenic response to 17beta-estradiol in the hippocampus of ovariectomized rats. Recent experiments revealed that bisphenol A also interferes with androgen receptor-mediated transcriptional activities. Thus, to investigate whether bisphenol A impairs synaptogenesis in the medial prefrontal cortex (mPFC) and hippocampus of adult male rats, castrated and sham-operated animals were treated with different combinations of bisphenol A (300 microg/kg), testosterone propionate (1.5 mg/kg), and sesame oil vehicle. The brains were processed for electron microscopic stereology, and the number of asymmetric spine synapses in the mPFC and CA1 hippocampal area was estimated. In both regions analyzed, bisphenol A reduced the number of spine synapses in sham-operated, gonadally intact animals, which was accompanied by a compensatory increase in astroglia process density. In addition, bisphenol A prevented both the prefrontal and hippocampal synaptogenic response to testosterone supplementation in castrated males. These results demonstrate that bisphenol A interferes with the synaptogenic response to testosterone in the mPFC and hippocampus of adult male rats. Because the hippocampal synaptogenic action of androgens seems to be independent of androgen and estrogen receptors in males, the potential mechanisms that underlie these negative effects of bisphenol A remain the subject of further investigation.


Assuntos
Androgênios/farmacologia , Estrogênios não Esteroides/toxicidade , Hipotálamo/efeitos dos fármacos , Fenóis/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Testosterona/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Compostos Benzidrílicos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Relação Dose-Resposta a Droga , Hipotálamo/citologia , Hipotálamo/fisiologia , Masculino , Orquiectomia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Propionato de Testosterona/farmacologia
14.
Prog Brain Res ; 163: 63-84, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17765712

RESUMO

The dentate gyrus is the first stage of the intrahippocampal, excitatory, trisynaptic loop, and a primary target of the majority of entorhinal afferents that terminate in a laminar fashion on granule cell dendrites and carry sensory information of multiple modalities about the external world. The electric activity of the trisynaptic pathway is controlled mainly by different types of local, GABAergic interneurons, and subcortical and commissural afferents. In this chapter we will outline the origin and postsynaptic targets in the dentate gyrus of chemically identified subcortical inputs. These systems are afferents originating from the medial septum/diagonal band of Broca GABAergic and cholinergic neurons, neurochemically distinct types of neurons located in the supramammillary area, serotonergic fibers from the median raphe, noradrenergic afferents from the pontine nucleus, locus ceruleus, dopamine axons originating in the ventral tegmental area, and the commissural projection system. Because of the physiological implications, these afferents are discussed in the context of the glutamatergic innervation of the dentate gyrus. One common feature of the extrinsic dentate afferent systems is that they originate from a relatively small number of neurons. However, the majority of these afferents are able to exert a powerful control over the electrical activity of the hippocampus. This strong influence is due to the fact that the majority of the extrinsic afferents terminate on a relatively small, but specific, populations of neurons that are able to control large areas of the hippocampal formation.


Assuntos
Vias Aferentes/anatomia & histologia , Giro Denteado/anatomia & histologia , Vias Aferentes/metabolismo , Vias Aferentes/ultraestrutura , Dopamina/metabolismo , Norepinefrina/metabolismo , Ácido gama-Aminobutírico/metabolismo
15.
Prog Brain Res ; 163: 399-415, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17765731

RESUMO

In the late 1980s, the finding that the dentate gyrus contains more granule cells in the male than in the female of certain mouse strains provided the first indication that the dentate gyrus is a significant target for the effects of sex steroids during development. Gonadal hormones also play a crucial role in shaping the function and morphology of the adult brain. Besides reproduction-related processes, sex steroids participate in higher brain operations such as cognition and mood, in which the hippocampus is a critical mediator. Being part of the hippocampal formation, the dentate gyrus is naturally involved in these mechanisms and as such, this structure is also a critical target for the activational effects of sex steroids. These activational effects are the results of three major types of steroid-mediated actions. Sex steroids modulate the function of dentate neurons under normal conditions. In addition, recent research suggests that hormone-induced cellular plasticity may play a larger role than previously thought, particularly in the dentate gyrus. Specifically, the regulation of dentate gyrus neurogenesis and synaptic remodeling by sex steroids received increasing attention lately. Finally, the dentate gyrus is influenced by gonadal hormones in the context of cellular injury, and the work in this area demonstrates that gonadal hormones have neuroprotective potential. The expression of estrogen, progestin, and androgen receptors in the dentate gyrus suggests that sex steroids, which could be of gonadal origin and/or synthesized locally in the dentate gyrus, may act directly on dentate cells. In addition, gonadal hormones could also influence the dentate gyrus indirectly, by subcortical hormone-sensitive structures such as the cholinergic septohippocampal system. Importantly, these three sex steroid-related themes, functional effects in the normal dentate gyrus, mechanisms involving neurogenesis and synaptic remodeling, as well as neuroprotection, have substantial implications for understanding normal cognitive function, with clinical importance for epilepsy, Alzheimer's disease and mental disorders.


Assuntos
Giro Denteado/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Animais , Humanos , Caracteres Sexuais
16.
Synapse ; 61(10): 862-5, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17630673

RESUMO

Prenatal exposure to cocaine has been associated with cognitive deficits in children and in animal models. An excess activation of pyramidal neurons in the prefrontal cortex has been proposed as a potential cause for these deficits based on previous studies. The goal of this study was to determine if prenatal exposure to cocaine was associated with an increase in the number of excitatory synapses on dendritic spines in layer II/III of the prelimbic cortex. Frontal cortex of young adult male and female rats, exposed to either saline or cocaine (3 mg/kg i.e., twice a day, embryonic day 10-20), were examined using electron microscopy and the number of asymmetric spines synapses were estimated using the physical disector method. Both male and female rats prenatally exposed to cocaine had about twice as many synapses on dendritic spines as the prenatal saline controls. The increase in number of excitatory synaptic inputs associated with prenatal cocaine exposure could contribute to the increased neuronal activation and cognitive deficits noted.


Assuntos
Córtex Cerebral/patologia , Cocaína , Espinhas Dendríticas/fisiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Sinapses/patologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/crescimento & desenvolvimento , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/ultraestrutura , Feminino , Masculino , Microscopia Eletrônica de Transmissão , Neurônios/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
17.
Endocrinology ; 148(5): 1963-7, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17317772

RESUMO

Recent studies suggest that, in female monkeys and rats, estrogens elicit dendritic spine synapse formation in the prefrontal cortex, an area that, similar to the hippocampus, plays a critical role in cognition. However, whether gonadal hormones induce synaptic remodeling in the male prefrontal cortex remains unknown. Here we report that gonadectomy reduced, whereas administration of 5alpha-dihydrotestosterone or estradiol-benzoate to castrated male rats increased, the number of medial prefrontal cortical (mPFC) spine synapses, with estradiol-benzoate being less effective than 5alpha-dihydrotestosterone. To investigate whether the androgen receptor contributes to the mediation of these changes, we compared the response of testicular feminization mutant (Tfm) male rats to that of wild-type animals. The number of mPFC spine synapses in gonadally intact Tfm rats and 5alpha-dihydrotestosterone-treated castrated Tfm males was considerably reduced compared to intact wild-type animals, whereas the synaptogenic effect of estradiol-benzoate was surprisingly enhanced in Tfm rats. These data are consistent with the hypothesis that remodeling of spine synapses in the prefrontal cortex may contribute to the cognitive effect of gonadal steroids. Our findings in Tfm animals indicate that androgen receptors may mediate a large part of the synaptogenic action of androgens in the mPFC of adult males. However, because this effect of 5alpha-dihydrotestosterone is not completely lost in Tfm rats, additional mechanisms may also be involved.


Assuntos
Androgênios/farmacologia , Anticoncepcionais/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Estradiol/análogos & derivados , Feminização/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Fatores Etários , Animais , Espinhas Dendríticas/ultraestrutura , Estradiol/farmacologia , Feminização/patologia , Masculino , Microscopia Eletrônica , Orquiectomia , Córtex Pré-Frontal/citologia , Ratos , Ratos Long-Evans , Ratos Mutantes , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura
18.
Biol Psychiatry ; 60(6): 639-44, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16814748

RESUMO

BACKGROUND: A growing body of evidence suggests the existence of synaptic pathology in schizophrenia. Here we used the phencyclidine schizophrenia model to directly investigate at the electron microscopic level whether structural synaptic alterations are present in these animals. METHODS: Adult male rats were treated according to our subchronic phencyclidine paradigm (5 mg/kg twice daily for 7 days, intraperitoneally). Following a one-week withdrawal period, the number of prefrontal cortical spine synapses was calculated using an unbiased electron microscopic stereological approach. The number of astroglia cells and the density of their processes was also analyzed following glial-fibrillary acidic protein immunohistochemistry. RESULTS: Subchronic phencyclidine treatment resulted in a 41.2% decrease in the number of prefrontal spine synapses when compared to controls. This was accompanied by a 58.8% increase in astroglia process density, without significant change in the number of astroglia cells. CONCLUSIONS: Our results demonstrate a severe reduction in the number of prefrontal spine synapses in an animal model of schizophrenia. This phenomenon may contribute to phencyclidine-induced cognitive dysfunction and decreased prefrontal cellular activity observed in this model.


Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Córtex Pré-Frontal/ultraestrutura , Sinapses/efeitos dos fármacos , Animais , Espinhas Dendríticas/ultraestrutura , Imuno-Histoquímica/métodos , Masculino , Microscopia Eletrônica de Transmissão/métodos , Ratos , Ratos Sprague-Dawley , Sinapses/ultraestrutura
19.
Neurology ; 66(6 Suppl 3): S13-22, 2006 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-16567737

RESUMO

Recent advances in our understanding of the actions of sex steroids on the brain and the pathophysiology of depression have provided a hypothetical framework that may functionally connect epilepsy, ovarian hormone levels, and depression. The hippocampus plays a critical role in both seizure activity and mood disorders, which suggests that pathology in this area of the brain might provide a link between epilepsy and depression. Recent findings support the view that neurogenesis is not the only factor that contributes to the pathomechanism of depression and antidepressant responses, which may involve other hippocampal cellular or molecular changes, or both. Specifically, remodeling of the hippocampal spine synapses may play a significant role in the neurobiology of depression and the effects of antidepressant therapy. Because the effects of estrogens on hippocampal synaptogenesis parallel those of antidepressants, loss of estrogen appears to be a critical contributor to the etiology of depressive disorders. The increased incidence of depression observed in women with epilepsy might therefore reflect a hormonal deficiency state because epilepsy is frequently associated with defects in reproductive function. In women with catamenial epilepsy, changes in gonadal steroid production are seen to link seizure frequency with reproductive state, emphasizing the importance of gonadal steroid levels not only in depression but also in seizure activity. Paradoxical features of epilepsy, i.e., seizure-induced increases in hippocampal neurotrophin expression and neurogenesis, suggest that the most important factor in the neurobiology of depression might be the extent to which the hippocampus can adapt appropriately to changes in the environment through alterations in hippocampal synaptic connectivity.


Assuntos
Depressão/patologia , Epilepsia/patologia , Hipocampo/patologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/complicações , Epilepsia/complicações , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Modelos Neurológicos , Fatores Sexuais
20.
Endocrinology ; 147(5): 2392-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16439462

RESUMO

The effects of estradiol benzoate (EB), dihydrotestosterone (DHT), or the antiandrogen hydroxyflutamide on CA1 pyramidal cell dendritic spine synapses were investigated in adult male rats. To elucidate the contribution of the androgen receptor to the hormone-induced increase in hippocampal CA1 synapses, wild-type males were compared with males expressing the Tfm mutation, which results in synthesis of defective androgen receptors. Orchidectomized rats were treated with EB (10 microg/rat.d), DHT (500 mug/rat.d), hydroxyflutamide (5 mg/rat.d), or the sesame oil vehicle sc daily for 2 d and examined using quantitative electron microscopic stereological techniques, 48 h after the second injection. In wild-type males, DHT and hydroxyflutamide both induced increases in the number of spine synapses in the CA1 stratum radiatum, whereas EB had no effect. DHT almost doubled the number of synaptic contacts observed, whereas hydroxyflutamide increased synapse density by approximately 50%, compared with the vehicle-injected controls. Surprisingly, in Tfm males, the effects of EB, DHT, and hydroxyflutamide were all indistinguishable from those observed in wild-type animals. These observations demonstrate that Tfm male rats resemble normal males in having no detectable hippocampal synaptic response to a dose of EB that is highly effective in females. Despite the reduction in androgen sensitivity as a result of the Tfm mutation, hippocampal synaptic responses to both DHT and a mixed androgen agonist/antagonist (hydroxyflutamide) remain intact in Tfm males. These data are consistent with previous results suggesting that androgen effects on hippocampal spine synapses may involve novel androgen response mechanisms.


Assuntos
Androgênios/metabolismo , Hipocampo/metabolismo , Mutação , Receptores Androgênicos/genética , Animais , Dendritos/metabolismo , Células Dendríticas/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Flutamida/análogos & derivados , Flutamida/farmacologia , Genótipo , Masculino , Microscopia Eletrônica , Modelos Estatísticos , Neurônios/metabolismo , Orquiectomia , Ratos , Receptores Androgênicos/fisiologia , Óleo de Gergelim/metabolismo , Sinapses/metabolismo , Fatores de Tempo
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