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1.
Elife ; 82019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31644424

RESUMO

Recent longitudinal neuroimaging studies in patients with electroconvulsive therapy (ECT) suggest local effects of electric stimulation (lateralized) occur in tandem with global seizure activity (generalized). We used electric field (EF) modeling in 151 ECT treated patients with depression to determine the regional relationships between EF, unbiased longitudinal volume change, and antidepressant response across 85 brain regions. The majority of regional volumes increased significantly, and volumetric changes correlated with regional electric field (t = 3.77, df = 83, r = 0.38, p=0.0003). After controlling for nuisance variables (age, treatment number, and study site), we identified two regions (left amygdala and left hippocampus) with a strong relationship between EF and volume change (FDR corrected p<0.01). However, neither structural volume changes nor electric field was associated with antidepressant response. In summary, we showed that high electrical fields are strongly associated with robust volume changes in a dose-dependent fashion.


Assuntos
Depressão/terapia , Eletroconvulsoterapia/efeitos adversos , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/efeitos da radiação , Antidepressivos/uso terapêutico , Mapeamento Encefálico , Depressão/diagnóstico por imagem , Depressão/patologia , Radiação Eletromagnética , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/efeitos da radiação , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia , Lobo Temporal/efeitos da radiação
2.
Neurochem Int ; 128: 1-13, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30954502

RESUMO

Long term exposure of electromagnetic radiations (EMR) from cell phones and Wi-Fi hold greater propensity to cause anxiety disorders. However, the studies investigating the effects of repeated exposure of EMR are limited. Therefore, we investigated the effects of repeated exposure of discrete frequencies of EMR in experimental animals. Male rats were exposed to EMR (900, 1800 and 2450 MHz) for 28 (1 h/day) days. Long term exposure of EMR (2450 MHz) induced anxiety like behavior. It deregulated the hypothalamic pituitary adrenal (HPA) axis in rats as observed by increase in plasma corticosterone levels apart from decreased corticotrophin releasing hormone-2 (CRH-2) and Glucocorticoid receptor (GR) expression in amygdala. Further, it impaired mitochondrial function and integrity. The expression of Bcl2 showed significant decrease while Bax and ratio of Bax: Bcl2 were increased in the mitochondria and vice versa in cytoplasm indicating altered regulation of apoptosis. EMR exposure caused release of cytochrome-c and expression of caspase-9 ensuing activation of apoptotic cell death. Additional set of experiments performed to estimate the pattern of cell death showed necrotic and apoptotic amygdalar cell death after EMR exposure. Histopathological studies also revealed a significant decrease in neuronal cells in amygdala. The above findings indicate that long-term exposure of EMR radiation (2450 MHz) acts as a stressor and induces anxiety-like behaviors with concomitant pathophysiological changes in EMR subjected rats.


Assuntos
Ansiedade/metabolismo , Ansiedade/patologia , Radiação Eletromagnética , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/efeitos da radiação , Animais , Ansiedade/etiologia , Morte Celular/fisiologia , Morte Celular/efeitos da radiação , Corticosterona/sangue , Masculino , Aprendizagem em Labirinto/fisiologia , Aprendizagem em Labirinto/efeitos da radiação , Ratos , Estresse Psicológico/etiologia , Fatores de Tempo
3.
Radiother Oncol ; 136: 44-49, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31015128

RESUMO

BACKGROUND AND PURPOSE: The amygdalae are deep brain nuclei critical to emotional processing and the creation and storage of memory. It is not known whether the amygdalae are affected by brain radiotherapy (RT). We sought to quantify dose-dependent amygdala change one year after brain RT. MATERIALS AND METHODS: 52 patients with primary brain tumors were retrospectively identified. Study patients underwent high-resolution, volumetric magnetic resonance imaging before RT and 1 year afterward. Images were processed using FDA-cleared software for automated segmentation of amygdala volume. Tumor, surgical changes, and segmentation errors were manually censored. Mean amygdala RT dose was tested for correlation with amygdala volume change 1 year after RT via the Pearson correlation coefficient. A linear mixed-effects model was constructed to evaluate potential predictors of amygdala volume change, including age, tumor hemisphere, sex, seizure history, and bevacizumab treatment during the study period. As 51 of 52 patients received chemotherapy, possible chemotherapy effects could not be studied. A two-tailed p-value <0.05 was considered statistically significant. RESULTS: Mean amygdala RT dose (r = -0.28, p = 0.01) was significantly correlated with volume loss. On multivariable analysis, the only significant predictor of amygdala atrophy was radiation dose. The final linear mixed-effects model estimated amygdala volume loss of 0.17% for every 1 Gy increase in mean amygdala RT dose (p = 0.008). CONCLUSIONS: The amygdala demonstrates dose-dependent atrophy one year after radiotherapy for brain tumors. Amygdala atrophy may mediate neuropsychological effects seen after brain RT.


Assuntos
Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/efeitos da radiação , Neoplasias Encefálicas/radioterapia , Lesões por Radiação/patologia , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Atrofia/etiologia , Neoplasias Encefálicas/diagnóstico por imagem , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Memória/efeitos da radiação , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Neuron ; 101(6): 1109-1116.e5, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30765166

RESUMO

The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds.


Assuntos
Tonsila do Cerebelo/efeitos da radiação , Giro do Cíngulo/efeitos da radiação , Ondas Ultrassônicas , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Encéfalo/efeitos da radiação , Mapeamento Encefálico , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiologia , Macaca , Imageamento por Ressonância Magnética , Vias Neurais/fisiologia , Vias Neurais/efeitos da radiação
5.
Pharm Biol ; 55(1): 1833-1842, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28552029

RESUMO

CONTEXT: Effects of a radioprotective, standardized leaf extract (code SBL-1) from traditional medicinal plant, sea buckthorn [Hippophae rhamnoides L. (Elaeagnaceae)], on neurotransmitters and brain injuries in rats showing radiation-induced conditioned taste aversion (CTA), are not known. Understanding CTA in rats is important because its process is considered parallel to nausea and vomiting in humans. OBJECTIVE: This study investigated the levels of neurotransmitters, antioxidant defences and histological changes in rats showing radiation CTA, and their modification by SBL-1. MATERIALS AND METHODS: The inbred male Sprague-Dawley rats (age 65 days, weighing 190 ± 10 g) were used. Saccharin-preferring rats were selected using standard procedure and divided into groups. Group I (untreated control) was administered sterile water, group II was 60Co-γ-irradiated (2 Gy), and group III was administered SBL-1 before irradiation. Observations were recorded up to day 5. RESULTS: Irradiation (2 Gy) caused (i) non-recoverable CTA (≥ 64.7 ± 5.0%); (ii) degenerative changes in cerebral cortex, amygdala and hippocampus; (iii) increases in brain dopamine (DA, 63.4%), norepinephrine (NE, 157%), epinephrine (E, 233%), plasma NE (103%) and E (160%); and (iv) decreases in brain superoxide dismutase (67%), catalase (60%) and glutathione (51%). SBL-1 treatment (12 mg/kg body weight) 30 min before irradiation (i) countered brain injuries, (ii) reduced CTA (38.7 ± 3.0%, day 1) and (iii) normalized brain DA, NE, E, superoxide dismutase, catalase and CTA from day 3 onwards. DISCUSSION AND CONCLUSION: Radiation CTA was coupled with brain injuries, disturbances in neurotransmitters and antioxidant defences. SBL-1 pretreatment countered these disturbances, indicating neuroprotective action.


Assuntos
Suplementos Nutricionais , Hippophae/química , Neurônios/metabolismo , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/efeitos da radiação , Animais , Antioxidantes/química , Antioxidantes/normas , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos da radiação , Química Encefálica/efeitos da radiação , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/efeitos da radiação , Radioisótopos de Cobalto , Condicionamento Clássico , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/efeitos da radiação , Masculino , Neurônios/patologia , Neurônios/efeitos da radiação , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/normas , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos da radiação , Extratos Vegetais/química , Extratos Vegetais/normas , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Protetores contra Radiação/química , Protetores contra Radiação/normas , Distribuição Aleatória , Ratos Sprague-Dawley , Distúrbios do Paladar/etiologia , Distúrbios do Paladar/prevenção & controle
6.
Neurosci Lett ; 616: 5-10, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26806862

RESUMO

Blue wavelength light has been used as an effective treatment for some types of mood disorders and circadian rhythm related sleep problems. We hypothesized that acute exposure to blue wavelength light would directly affect the functioning of neurocircuity implicated in emotion regulation (i.e., ventromedial prefrontal cortex, amygdala, insula, and anterior cingulate cortex [ACC]) during 'certain' and 'uncertain' anticipation of negative and positive stimuli. Thirty-five healthy adults were randomized to receive a thirty-minute exposure to either blue (active) or amber (placebo) light, immediately followed by an emotional anticipation task during functional magnetic resonance imaging (fMRI). In contrast to placebo, participants in the blue light group showed significantly reduced activation within the rostral ACC during 'uncertain' anticipation (i.e., uncertainty regarding whether a positive or negative stimulus would be shown) in comparison to 'certain' anticipation of a positive stimulus. These findings may be explicable in terms of interactions between blue light exposure and the influence of specific neuromodulators on ACC-mediated decision-making mechanisms.


Assuntos
Antecipação Psicológica , Giro do Cíngulo/efeitos da radiação , Luz , Incerteza , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/efeitos da radiação , Mapeamento Encefálico , Córtex Cerebral/fisiologia , Córtex Cerebral/efeitos da radiação , Emoções , Feminino , Giro do Cíngulo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Distribuição Aleatória , Recompensa , Adulto Jovem
7.
J Biol Rhythms ; 27(5): 339-52, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23010657

RESUMO

Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.


Assuntos
Transtorno Bipolar/fisiopatologia , Relógios Circadianos/genética , Transtorno Depressivo Maior/fisiopatologia , Núcleo Supraquiasmático/fisiopatologia , Tonsila do Cerebelo/efeitos da radiação , Animais , Antidepressivos/farmacologia , Transtorno Bipolar/genética , Proteínas CLOCK/genética , Relógios Circadianos/efeitos dos fármacos , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Giro do Cíngulo/efeitos da radiação , Habenula/efeitos da radiação , Hipocampo/efeitos da radiação , Humanos , Luz , Compostos de Lítio/farmacologia , Camundongos , Modelos Animais , Substância Cinzenta Periaquedutal/efeitos da radiação
8.
Nature ; 471(7338): 358-62, 2011 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-21389985

RESUMO

Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.


Assuntos
Tonsila do Cerebelo/fisiologia , Ansiedade/fisiopatologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos da radiação , Animais , Transtornos de Ansiedade/fisiopatologia , Halorrodopsinas/metabolismo , Luz , Camundongos , Modelos Neurológicos , Vias Neurais/fisiologia , Vias Neurais/efeitos da radiação , Neurônios/fisiologia , Neurônios/efeitos da radiação , Estresse Fisiológico/fisiologia , Sinapses/fisiologia , Sinapses/efeitos da radiação
9.
Neurosci Lett ; 441(2): 193-6, 2008 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-18577418

RESUMO

The antiepileptic activity of hydrophilic extract of Vitex agnus castus fruit (Vitex) was evaluated by the kindling model of epilepsy. Intact male rats (250-300 g) were stereotaxically implanted with a tripolar and two monopolar electrodes in amygdala and dura, respectively. The afterdischarge (AD) threshold was determined in each animal and stimulated daily until fully kindled. The animals were administered different doses (60, 120 or 180 mg/kg) of Vitex or 0.1 ml of hydro alcoholic solvent intra-peritoneally (i.p.) and kindling parameters including AD threshold, seizure stages (SS), afterdischarge duration (ADD), stage 4 latency (S4L) and stage 5 duration (S5D) were recorded 30 min post-injection. The obtained data showed that even low dose (60 mg/kg) of Vitex could significantly increase the AD threshold and decrease the ADD and S5D (P<0.05). These changes were more significant with higher doses (120 or 180 mg/kg) for ADD (P<0.01) and S5D (P<0.001). Vitex at the dose of 120 mg/kg, induced significant increment in S4L (P<0.05). This effect was more prominent at the dose of 180 mg/kg (P<0.001). The latter dose could significantly reduce seizure stage (P<0.01) and most of the animals did not show S5. These results indicate that Vitex can reduce or prevent epileptic activity as demonstrated by reduction of ADD and S5D (length of convulsion) in a dose dependent manner. In conclusion, Vitex at appropriate dose can probably reduce or control epileptic activities.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Fitoterapia/métodos , Preparações de Plantas/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/patologia , Vitex/química , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Excitação Neurológica , Masculino , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Convulsões/etiologia
10.
Epilepsia ; 49(10): 1749-58, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18513349

RESUMO

PURPOSE: Understanding the molecular mechanisms underlying epilepsy is crucial to designing novel therapeutic regimens. This report focuses on alterations in the secretory machinery responsible for neurotransmitter (NT) release. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) complexes mediate the fusion of synaptic vesicle and active zone membranes, thus mediating NT secretion. SNARE regulators control where and when SNARE complexes are formed. Previous studies showed an asymmetric accumulation of 7S SNARE complexes (7SC) in the ipsilateral hippocampus of kindled animals. The present studies probe the persistence of 7SC accumulation and the effect of the anticonvulsant, levetiracetam (LEV), on 7SC and SNARE regulators. METHOD: Quantitative Western blotting was used to monitor levels of 7SC and SNARE regulators in hippocampal synaptosomes from kindled animals both before and after LEV treatment. RESULTS: The asymmetric accumulation of 7SC is present 1-year postamygdalar kindling. The synaptic vesicle protein, synaptic vesicle protein 2 (SV2), a primary LEV-binding protein, and the SNARE regulator Tomosyn increase, whereas NSF decreases in association with this accumulation. Treatment with LEV prevented kindling-induced accumulation of SV2, but did not affect the transient increase of Tomosyn or the long-term decrease NSF. LEV treatment retarded the electrical and behavioral concomitants of amygdalar kindling coincident with a decrease in accumulation of 7SC. CONCLUSIONS: The ipsilateral hippocampal accumulation of SNARE complexes is an altered molecular process associated with kindling that appears permanent. Kindling epileptogenesis alters synaptosomal levels of the SNARE regulators: NSF, SV2, and Tomosyn. Concomitant treatment with LEV reverses the kindling-induced 7SC accumulation and increase of SV2.


Assuntos
Anticonvulsivantes/farmacologia , Hipocampo/efeitos dos fármacos , Excitação Neurológica , Piracetam/análogos & derivados , Proteínas SNARE/metabolismo , Convulsões/metabolismo , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Levetiracetam , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas Sensíveis a N-Etilmaleimida/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Piracetam/farmacologia , Proteínas R-SNARE/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Epilepsia ; 49(10): 1759-76, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18494789

RESUMO

PURPOSE: Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. METHODS: For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. RESULTS: Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated-plus maze test), behavioral hyperexcitability (approach-response, touch-response, pick-up tests), and learning and memory (Morris water maze). DISCUSSION: Our hypothesis that AED-resistant rats will show more severe behavioral and cognitive changes than AED-responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Resistência a Medicamentos , Epilepsia/complicações , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Estimulação Elétrica/efeitos adversos , Eletroencefalografia/métodos , Epilepsia/etiologia , Epilepsia/patologia , Epilepsia/prevenção & controle , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Fenobarbital/uso terapêutico , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley , Prevenção Secundária , Estatísticas não Paramétricas , Natação/fisiologia , Fatores de Tempo
12.
Epilepsia ; 49(10): 1686-95, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18397293

RESUMO

PURPOSE: Studies in animal models and patients have implicated changes in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the pathogenesis of temporal lobe epilepsy (TLE). However, the nature of HCN changes during the epileptogenic process and their commonality across different TLE models is unknown. Here HCN1 and HCN2 mRNA expression was quantitatively measured at different time points during epileptogenesis in two distinct animal models of TLE; the kainic acid (KA)-induced status epilepticus (SE) and amygdala kindling models. METHODS: Hippocampal subregions (CA1, CA3, and dentate gyrus [DG]) and entorhinal cortex were dissected at different time-points. For KA-induced SE animals this was 24 h, 7 days (preepileptic), and 6 weeks (epileptic) post status. For amygdala kindling animals this was 2 weeks after reaching either "partially kindled" (one class II/III seizure) or "fully kindled" (five class V seizures) states. Quantification of regional hippocampal neuronal loss in the KA-treated animals was done using NeuN immunofluorescence and confocal microscopy. RESULTS: HCN mRNA levels decreased in an isoform and region specific manner at all time points after KA-induced SE. The decrease in neuronal number could not account for all reductions in HCN mRNA levels post-KA insult, implicating transcriptional changes. A reduction in HCN2 mRNA levels was also observed in fully kindled animals in the CA3 region. CONCLUSIONS: A reduction in HCN mRNA levels is present in two different models of TLE. This supports the case that a reduction in HCN channel expression is an accompaniment of epileptogenesis in different adult models of TLE.


Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Regulação para Baixo/fisiologia , Hipocampo/metabolismo , Canais Iônicos/genética , Excitação Neurológica/metabolismo , Canais de Potássio/genética , RNA Mensageiro/metabolismo , Estado Epiléptico/patologia , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Morte Celular/efeitos dos fármacos , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/efeitos da radiação , Eletroencefalografia/métodos , Eletrochoque/efeitos adversos , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/metabolismo , Feminino , Hipocampo/anatomia & histologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/metabolismo , Ácido Caínico , Fosfopiruvato Hidratase/metabolismo , Canais de Potássio/metabolismo , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Fatores de Tempo
13.
Neurobiol Dis ; 30(1): 84-93, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18313316

RESUMO

Protease-activated receptor-2 (PAR(2)), primarily involved in inflammation, is highly expressed in limbic regions of the brain such as the hippocampus. Although extracellular proteolysis is involved in normal and stress-related neuronal plasticity associated with learning, memory and inflammatory disease states, little is known about the role of PAR(2) and its physiological agonist, trypsin, in the brain. We show immunohistochemically that trypsin co-localises with tissue plasminogen activator within granular-like structures in PAR(2)-positive pyramidal neurons of the rat hippocampus. Central administration of the PAR(2) peptide agonist, SLIGRL, inhibited electrical amygdala kindling-induced epileptogenesis and abolished kindling-induced over-expression of trypsin in the hippocampus. SLIGRL similarly attenuated kindling when administered subcutaneously. Non-enzymatic activation of neuronal PAR(2) using SLIGRL may thus activate feedback mechanisms to inhibit the over-production of trypsin and possibly other proteases during brain insults and thereby attenuate pathogenesis. Prophylactic systemic administration of non-proteolytic PAR(2) agonists may therefore represent a novel approach to protect against epileptogenic brain insults.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Receptor PAR-2/fisiologia , Convulsões/patologia , Tripsina/metabolismo , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Encéfalo/patologia , Relação Dose-Resposta à Radiação , Estimulação Elétrica/efeitos adversos , Eletrodos Implantados , Eletroencefalografia/métodos , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/efeitos da radiação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oligopeptídeos/farmacologia , Ratos , Ratos Wistar , Convulsões/etiologia
14.
Horm Behav ; 53(2): 358-65, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18078937

RESUMO

Testosterone or its metabolite, estrogen, regulates aggression in males of many mammalian species. Because plasma testosterone levels are typically positively correlated with both aggression and reproduction, aggression is expected to be higher when males are in reproductive condition. However, in some photoperiodic species such as Siberian hamsters (Phodopus sungorus), males are significantly more aggressive in short day lengths when the testes are regressed and circulating testosterone concentrations are reduced. These results led to the formation of the hypothesis that aggression is modulated independently of circulating steroids in Siberian hamsters. Thus, recent studies have been designed to characterize the role of other neuroendocrine factors in modulating aggression. However, aggression may be mediated by testosterone or estrogen despite basal concentrations of these steroids by increasing sensitivity to steroids in specific brain regions. Consistent with this hypothesis, we found that males housed under short days have increased expression of estrogen receptor alpha in the bed nucleus of the stria terminalis, medial amygdala, and central amygdala. Neural activation in response to an aggressive encounter was also examined across photoperiod.


Assuntos
Agressão/fisiologia , Receptor alfa de Estrogênio/metabolismo , Fotoperíodo , Núcleos Septais/metabolismo , Agressão/efeitos da radiação , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos da radiação , Animais , Cricetinae , Imuno-Histoquímica , Luz , Masculino , Phodopus , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/efeitos da radiação
15.
Brain Res Bull ; 75(1): 15-7, 2008 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-18158090

RESUMO

Corticotropin-releasing factor (CRF) is the major neuromodulator of the hypothalamic-pituitary-adrenal axis, regulating the behavioural, endocrine, autonomic and immune responses to stress. Together with the recently discovered members of the CRF peptide family, urocortin 1, urocortin 2 and urocortin 3, it also has neurotransmitter actions. Previous publication has demonstrated that stress induces CRF release in the paraventricular nucleus of the hypothalamus and the release of both CRF and GABA in the amygdala. Accordingly, the aim of the present study was to determine the effects of the members of the CRF peptide family on GABA release from the amygdala by using an in vitro superfusion system. In order to study the participation of different CRF receptors (CRF1 and CRF2) in this process, rat amygdalar slices were pretreated with selective CRF1 and CRF2 antagonists. CRF and urocortin 1 significantly increased the release of [(3)H]GABA from the slices following electrical stimulation, whereas urocortin 2 and urocortin 3 were ineffective. The actions of CRF and urocortin 1 were blocked by the selective CRF1 receptor antagonist antalarmin, but were not inhibited by the selective CRF2 receptor antagonist astressin 2B, both administered in equimolar doses. Our results demonstrate that the release of GABA from the amygdala is mediated by CRF and urocortin 1 through the activation of CRF1 receptors.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Urocortinas/farmacologia , Ácido gama-Aminobutírico/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Estimulação Elétrica/métodos , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Análise Espectral , Trítio/metabolismo
16.
Horm Behav ; 53(1): 192-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17976598

RESUMO

In three genuses and four species of rodents, housing in winter-like short days (8L:16D) increases male aggressive behavior. In all of these species, males undergo short-day induced regression of the reproductive system. Some studies, however, suggest that the effect of photoperiod on aggression may be independent of reproductive responses. We examined the effects of photoperiod on aggressive behavior in California mice (Peromyscus californicus), which do not display reproductive responsiveness to short days. As expected, short days had no effect on plasma testosterone. Estrogen receptor alpha and estrogen receptor beta immunostaining did not differ in the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, or medial amygdala. However, males housed in short days were significantly more aggressive than males housed in long days. Similar to previous work in beach mice (Peromyscus polionotus), estradiol rapidly increased aggression when male California mice were housed in short days but not when housed in long days. These data suggest that the effects of photoperiod on aggression and estrogen signaling are independent of reproductive responses. The rapid action of estradiol on aggression in short-day mice also suggests that nongenomic mechanisms mediate the effects of estrogens in short days.


Assuntos
Agressão/fisiologia , Estradiol/fisiologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Peromyscus/fisiologia , Fotoperíodo , Agressão/efeitos da radiação , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos da radiação , Animais , Estradiol/administração & dosagem , Receptor alfa de Estrogênio/efeitos da radiação , Receptor beta de Estrogênio/efeitos da radiação , Luz , Masculino , Área Pré-Óptica/metabolismo , Área Pré-Óptica/efeitos da radiação , Distribuição Aleatória , Núcleos Septais/metabolismo , Núcleos Septais/efeitos da radiação , Septo do Cérebro/metabolismo , Septo do Cérebro/efeitos da radiação , Testículo/anatomia & histologia , Testículo/fisiologia , Testículo/efeitos da radiação , Testosterona/sangue
17.
Neuroreport ; 18(14): 1449-53, 2007 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-17712272

RESUMO

We employed magnetoencephalography (MEG) to examine amygdala activity during a linguistic affective priming task. The experimental design included positive and negative word pairs. Using synthetic aperture magnetometry in the analysis of MEG data, we identified a left amygdala power increase in the theta frequency range during priming involving negative words. We found that the amygdala displayed a time-dependent intensification in responsiveness to negative stimuli, specifically between 150 and 400 ms after target presentation. This study provides evidence for theta power changes in the amygdala and demonstrates that the analysis of brain oscillations provides a powerful tool to explore mechanisms implicated in emotional processing.


Assuntos
Tonsila do Cerebelo/fisiologia , Mapeamento Encefálico , Emoções/fisiologia , Magnetoencefalografia , Adulto , Tonsila do Cerebelo/efeitos da radiação , Feminino , Humanos , Idioma , Masculino , Estimulação Luminosa , Tempo de Reação/fisiologia , Fatores de Tempo
18.
Horm Behav ; 52(3): 283-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17604030

RESUMO

We investigated whether puberty influences the morphology of the medial nucleus of the amygdala (MeA) by comparing Siberian hamsters (Phodopus sungorus) that had been raised from birth in either long day (LD; 16:8 h light:dark) or short day (SD; 8:16) photoperiods. Hamsters were sacrificed at 42-49 days of age, at which point all LD hamsters were reproductively mature, as evidenced by adult-like testes weights (mean: 657 mg). In contrast, the testes weights of the SD hamsters were low (mean: 31 mg), indicating that the SD photoperiod had delayed puberty. The regional volume and mean soma size of the four MeA subnuclei was estimated bilaterally by stereological procedures. In the posterior dorsal and ventral MeA subnuclei, regional volume was 22-25% larger, and mean soma size 18% larger, in LD males than SD males. Unbiased cell counts in the posterior dorsal MeA showed that LD and SD hamsters have equivalent neuron numbers. In the anterior MeA subnuclei, regional volumes and soma sizes from LD and SD hamsters were equivalent. Additionally, the regional volume of the posteroventral subnucleus was larger in the right hemisphere than the left, but this laterality did not respond to photoperiod manipulation. These results suggest that the extant neurons within the posterior MeA, a steroid-sensitive nucleus implicated in socio-sexual behavior, grow in response to the elevated levels of circulating androgen accompanying puberty, and that photoperiodic regulation of puberty affects morphological maturation of this nucleus.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Fotoperíodo , Maturidade Sexual/fisiologia , Testículo/crescimento & desenvolvimento , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos da radiação , Androgênios/sangue , Animais , Cricetinae , Feminino , Lateralidade Funcional , Luz , Masculino , Neurônios/fisiologia , Neurônios/efeitos da radiação , Tamanho do Órgão , Phodopus , Maturidade Sexual/efeitos da radiação , Testículo/efeitos da radiação
19.
Neuropharmacology ; 53(2): 207-21, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17585956

RESUMO

Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.


Assuntos
Anticonvulsivantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Dano Encefálico Crônico/prevenção & controle , Piracetam/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/efeitos da radiação , Análise de Variância , Animais , Dano Encefálico Crônico/patologia , Diazepam/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Estimulação Elétrica/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipercinese/tratamento farmacológico , Hipercinese/etiologia , Levetiracetam , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Piracetam/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/complicações , Estado Epiléptico/etiologia , Estado Epiléptico/patologia , Natação/psicologia , Fatores de Tempo
20.
Brain Res ; 1142: 46-53, 2007 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-17303088

RESUMO

Presentation of a tonal cue that previously had been associated with a fearful experience (footshock) produces alterations in arousal and sleep that occur after the fearful cue is no longer presented. To begin investigating neurochemical mechanisms that may underlie the effects of fearful cue presentation, we measured release of [(3)H]-norepinephrine ([(3)H]-NE]) and [(14)C]-gamma-amino-butyric acid ([(14)C]-GABA) from brain regions known to regulate arousal states and REM sleep. Depolarization-evoked release of [(3)H]-NE from amygdalar slices of mice, which were trained to recognize a tone as a fearful cue, was suppressed at 2-3 h after exposure of animals to the fearful cue, but recovered after 4-5 h. Interestingly, depolarization-evoked release of [(14)C]-GABA was significantly increased in the amygdala, and also showed a tendency for enhancement in the hippocampus, NPO, and DRN at 2-3 h after cue presentation. The changes in [(14)C]-GABA release were also transient; 4-5 h after cue presentation no significant differences were detected between samples derived from experimental groups which experienced fearful or neutral cues. The similar time course of fearful cue-induced changes in neurotransmitter release and changes in arousal and REM sleep suggests that alterations in amygdalar neurotransmission may be involved in the changes in arousal and sleep that occur after fear.


Assuntos
Tonsila do Cerebelo/metabolismo , Medo , Norepinefrina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Estimulação Acústica/métodos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/efeitos da radiação , Animais , Cálcio/farmacologia , Condicionamento Clássico , Relação Dose-Resposta a Droga , Eletrochoque/efeitos adversos , Técnicas In Vitro , Isótopos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Potássio/farmacologia , Fatores de Tempo
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