RESUMO
The epidemiological association between bacterial or viral maternal infections during pregnancy and increased risk for developing psychiatric disorders in offspring is well documented. Numerous rodent and non-human primate studies of viral- or, to a lesser extent, bacterial-induced maternal immune activation (MIA) have documented a series of neurological alterations that may contribute to understanding the pathophysiology of schizophrenia and autism spectrum disorders. Long-term neuronal and behavioral alterations are now ascribed to the effect of maternal proinflammatory cytokines rather than the infection itself. However, detailed electrophysiological alterations in brain areas relevant to psychiatric disorders, such as the dorsal hippocampus, are lacking in response to bacterial-induced MIA. This study determined if electrophysiological and morphological alterations converge in CA1 pyramidal cells (CA1 PC) from the dorsal hippocampus in bacterial-induced MIA offspring. A series of changes in the functional expression of K+ and Na+ ion channels altered the passive and active membrane properties and triggered hyperexcitability of CA1 PC. Contributing to the hyperexcitability, the somatic A-type potassium current (IA) was decreased in MIA CA1 PC. Likewise, the spontaneous glutamatergic and GABAergic inputs were dysregulated and biased toward increased excitation, thereby reshaping the excitation-inhibition balance. Consistent with these findings, the dendritic branching complexity of MIA CA1 PC was reduced. Together, these morphophysiological alterations modify CA1 PC computational capabilities and contribute to explaining cellular alterations that may underlie the cognitive symptoms of MIA-associated psychiatric disorders.
Assuntos
Imunidade , Neurônios , Canais de Potássio , Animais , Transtorno do Espectro Autista/imunologia , Região CA1 Hipocampal/citologia , Regulação para Baixo , Feminino , Neurônios/metabolismo , Canais de Potássio/metabolismo , Gravidez , Células Piramidais/imunologia , Esquizofrenia/imunologiaRESUMO
Experiences influence the development of the central nervous system. Cognitive training promotes changes in the structure of the brain, such as in its weight and number of cells, as well as ability to perform dendritic remodeling. The present study was designed to detect possible differences in the neuronal morphology of the dorsal hippocampus between female and male Long-Evans rats after cognitive training (CT). CT was promoted through three learning and memory tests: the Morris water maze, the Barnes circular maze, and Novel object recognition tests. Our data revealed no differences in learning or memory capacities between female and male rats; rats of the two sexes solved the behavioral test with equal efficiency. CT caused an increase in the basilar and apical dendritic arborization of CA1 neurons in male rats, whereas female rats that underwent CT presented only remodeling in the apical arbors of CA1 neurons. The basilar arbors of CA3 neurons of female rats showed an increase in arborization, but their apical arbors were not modified; the arbors of CA3 neurons of male rats submitted to CT were not modified. Total dendritic length was modified by CT in the apical arbors of CA1 neurons of female and male rats and in the basilar CA1 arbors of male rats. There was a significant increase in dendritic spine density in all arbors of CA1 and CA3 neurons of females and males subjected to CT. These results suggest that dendritic remodeling after CT is similar between female and male rats.
Assuntos
Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Cognição , Espinhas Dendríticas/fisiologia , Aprendizagem , Animais , Região CA1 Hipocampal/citologia , Região CA3 Hipocampal/citologia , Feminino , Masculino , Ratos , Ratos Long-Evans , Fatores SexuaisRESUMO
Ovarian steroids modulate the neuronal structure and function during the estrous cycle, contrasting peak effects during the proestrus cycle and low effects during the metestrus cycle. An ovariectomy (OVX) decreases gonadal hormones and tests the effects of substitutive therapies. We studied female rats with a normal estrous cycle and we also studied the effects of systemic progesterone (P4, 4.0 mg/kg) or its reduced metabolite allopregnanolone (ALLO, 4.0 mg/kg, both for 10 days) in females who had had an OVX 16.5 weeks prior to the study (long-term OVX) with the novel object recognition test (NORT) for associative memory. The dendritic shape and spine density in Golgi-impregnated basal dendrites (stratum oriens) of hippocampal pyramidal neurons was also studied. Proestrus females had a better performance than metestrus or OVX females in short-term memory (tested 1 h after the acquisition phase). Proestrus and metestrus females showed better results than OVX females for long-term memory (24 h after the initial phase). Both P4 and ALLO recovered the cognitive impairment induced by long-term OVX. Also, proestrus females had a higher density of dendritic spines than metestrus females, OVX reduced the density of spines when compared to intact females, whereas both P4 and ALLO treatments increased the dendritic spine density, number of dendritic branches along the dendritic length, and branching order compared to vehicle. These data add the dendrites of the stratum oriens as an additional site for naturally occurring changes in spine density during the estrous cycle and evidence the actions of progestins in both behavioral recovery and the structural dendritic rearrangement of hippocampal pyramidal neurons in long-term OVX female rats.
Assuntos
Região CA1 Hipocampal , Região CA2 Hipocampal , Disfunção Cognitiva , Espinhas Dendríticas , Ciclo Estral/metabolismo , Aprendizagem , Ovariectomia/efeitos adversos , Pregnanolona/metabolismo , Pregnanolona/farmacologia , Progesterona/metabolismo , Progesterona/farmacologia , Células Piramidais , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Comportamento Animal/fisiologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região CA2 Hipocampal/citologia , Região CA2 Hipocampal/efeitos dos fármacos , Região CA2 Hipocampal/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Pregnanolona/administração & dosagem , Progesterona/administração & dosagem , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
There is increasing evidence that the brain resides in a state of criticality. The purpose of the present work is to characterize the dynamics of individual hippocampal CA1 pyramidal cells and to investigate how it is influenced by changes in Kv7.2/7.3 (M-channel) ion channel modulation, which is known to be key in determining the neuronal excitability. We show that the resting activity of CA1 neurons exhibit random dynamics with low information content, while changes in M-channel modulation move the neuronal activity near a phase transition to richer non-trivial dynamics. We interpret these results as the basis upon which the state of self-organized criticality is built.
Assuntos
Potenciais de Ação , Região CA1 Hipocampal/fisiologia , Células Piramidais/fisiologia , Animais , Região CA1 Hipocampal/citologia , Hipocampo/citologia , Hipocampo/fisiologia , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/metabolismo , Masculino , Transição de Fase , Células Piramidais/citologia , Ratos WistarRESUMO
Spatial navigation relies on visual landmarks as well as on self-motion information. In familiar environments, both place and grid cells maintain their firing fields in darkness, suggesting that they continuously receive information about locomotion speed required for path integration. Consistently, "speed cells" have been previously identified in the hippocampal formation and characterized in detail in the medial entorhinal cortex. Here we investigated speed-correlated firing in the hippocampus. We show that CA1 has speed cells that are stable across contexts, position in space, and time. Moreover, their speed-correlated firing occurs within theta cycles, independently of theta frequency. Interestingly, a physiological classification of cell types reveals that all CA1 speed cells are inhibitory. In fact, while speed modulates pyramidal cell activity, only the firing rate of interneurons can accurately predict locomotion speed on a sub-second timescale. These findings shed light on network models of navigation.
Assuntos
Hipocampo/citologia , Potenciais de Ação/fisiologia , Animais , Região CA1 Hipocampal/citologia , Interneurônios/citologia , Masculino , Células Piramidais/citologia , Ratos Long-Evans , Ritmo Teta/fisiologia , Fatores de TempoRESUMO
Sporadic Alzheimer's disease (SAD) is the most common form of dementia; therefore, there is an urgent need for a model that recapitulates the main pathologic hallmarks of this disease. The intracerebroventricular (icv) injection of streptozotocin (icv-STZ) in rats constitutes a promising model, and thus, icv-STZ rats develop insulin-resistant brain state and cognitive impairments. Even though a great piece of studies has hitherto described this system as a model for SAD, further behavioral and morphometric studies are still needed to fully characterize it. In this study, using Sprague Dawley rats, we evaluated short-term effects on behavior and hippocampus morphometry of the icv-STZ injection at two doses: 1 (STZ1) and 3 mg/kg (STZ3). We found that, following icv-STZ injection, STZ3 animals, but not STZ1, exhibited impairments in spatial reference learning and memory (Barnes maze test) and in recognition memory (object recognition test). Furthermore, the results from behavioral and morpho-histochemical data are compatible. STZ3 rats displayed Stratum Radiatum volume reduction and a decreased NeuN immunoreactivity (neuron loss) in hippocampal CA1 region, together with an increased immunoreactivity for microglial (Iba1) and astroglial (GFAP) markers (neuroinflammation). Sholl analysis revealed the vulnerability of hippocampal astrocytes to STZ in CA1 and CA3. Thus, both doses induced a reduction in process length and in the number of main processes, accompanied by a frank decrease in branching complexity. The present study provides important knowledge of this AD rat model. Overall, we found that the only high STZ dose induced severe and acute neurodegenerative lesions, associated with an inflammation process.
Assuntos
Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Estreptozocina/farmacologia , Animais , Astrócitos/citologia , Região CA1 Hipocampal/citologia , Região CA3 Hipocampal/citologia , Forma Celular/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Studies have shown that changes in ovarian hormone concentrations promote natural fluctuations in the density of dendritic spines of hippocampal neurons in female Sprague-Dawley rats, without changes in dendritic length, throughout the estrous cycle. However, it is still unknown whether these fluctuations are present in other rat strains. Due to our interest in Wistar rats, the objective of the present study was to determine if there is natural dendritic remodeling in the female Wistar rat throughout the estrous cycle. This study analyzed the dendritic arborization of pyramidal neurons CA1 and CA3 of the dorsal hippocampus in each phase of the estrous cycle. We used the Golgi-Cox staining method and Sholl analysis to evaluate the dendritic length and density of dendritic spines. Our results showed that the dendritic length of the basilar and apical trees of CA1 neurons was longer in the metestrus phase. In CA3 neurons, only the apical dendritic trees showed longer dendritic length during metestrus. There was no variation in the density of dendritic spines in relation to any of the phases of the estrous cycle. Taken together, these results indicated that pyramidal neurons of the CA1 and CA3 regions of the dorsal hippocampus in the Wistar rat exhibited changes in dendritic length in the metestrus phase of the estrous cycle. Together, these data are important when considering the use of these organisms in behavioral studies.
Assuntos
Região CA1 Hipocampal/citologia , Região CA3 Hipocampal/citologia , Espinhas Dendríticas/fisiologia , Metestro/fisiologia , Neurônios/citologia , Análise de Variância , Animais , Espinhas Dendríticas/ultraestrutura , Feminino , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Coloração pela PrataRESUMO
Spider toxins are recognized as useful sources of bioactive substances, showing a wide range of pharmacological effects on neurotransmission. Several spider toxins have been identified biochemically and some of them are specific glutamate receptors antagonists. Previous data indicate that PnTx4-5-5, a toxin isolated from the spider Phoneutria nigriventer, inhibits the N-methyl-d-aspartate receptor (NMDAR), with little or no effect on AMPA, kainate or GABA receptors. In agreement with these results, our findings in this study show that PnTx4-5-5 reduces the amplitude of NMDAR-mediated EPSCs in hippocampal slices. It is well established that glutamate-mediated excitotoxic neuronal cell death occurs mainly via NMDAR activation. Thus, we decided to investigate whether PnTx4-5-5 would protect against various cell death insults. For that, we used primary-cultured corticostriatal neurons from wild type (WT) mice, as well as from a mouse model of Huntington's disease, BACHD. Our results showed that PnTx4-5-5 promotes neuroprotection of WT and BACHD neurons under the insult of high levels of glutamate. Moreover, the toxin is also able to protect WT neurons against amyloid ß (Aß) peptide toxicity. These results indicate that the toxin PnTx4-5-5 is a potential neuroprotective drug.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Proteínas de Artrópodes/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Venenos de Aranha/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/patologia , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Técnicas In Vitro , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Patch-Clamp , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Acute brain ischemia can induce the activation of c-Jun N-terminal kinases (JNKs). Hypertension is a critical etiology for brain ischemia. We identified the effects of hypertension on the activation of JNK as well as its impact on SP600125, a JNK inhibitor, during endoplasmic reticulum stress (ERS) in the hippocampus using a rat model. Transient whole-brain ischemia was induced by 4-vessel occlusion (bilateral vertebral and bilateral common carotid arteries) in normal and spontaneous hypertensive rats. SP600125 (0.05 mg/kg, iv) was administered 30 min before ischemia. Morphological changes in hippocampal nerve cells were observed by cresyl violet staining. Phosphorylation of JNK, and expression levels of CHOP and GPR78, markers for ERS, were detected by western blot at 1, 6, 24, and 48 h, and neurological outcomes were measured using an eight-arm radial maze 48 h after ischemia. Hypertension apparently aggravated impairment of memory function, decreased the density of surviving neurons, increased phosphorylation of JNK, and enhanced CHOP expression, but reduced GPR78 levels in hippocampal tissues following brain ischemia. SP600125 alleviated neurological dysfunction, improved neuron survival, decreased phosphorylation of JNK and levels of CHOP, but increased expression of GPR78 in rats with hypertension during cerebral ischemia by inhibition of ERS.
Assuntos
Isquemia Encefálica/enzimologia , Estresse do Retículo Endoplasmático/fisiologia , Hipocampo/irrigação sanguínea , Hipertensão/enzimologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Antracenos , Isquemia Encefálica/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática , Proteínas de Choque Térmico/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/fisiopatologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição CHOP/metabolismoRESUMO
Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the brain. Particularly α7-containing nAChRs, associated with several physiological roles and pathologies, are one of the most abundant. Here, we studied 2-(4-hexyloxybenzyl)-1-methylquinuclidin-1-ium iodide (designated as 8d), on ion currents elicited by choline, ICh, (Ch, a selective agonist for α7-containing nAChRs), recorded in interneurons from the stratum radiatum of the rat hippocampal CA1 region by using the whole-cell voltage-clamp technique. The 8d-concentration/Ch-response relationship exhibited high and low inhibitory affinities for α7-containing nAChRs, with IC50 values of 0.59 and 6.80 µM, respectively. Interestingly, 8d in a range of 3-10 µM exerted opposite effects: a short early potentiation and a long late inhibition of the ICh; and 8d alone elicited a non-decaying inward current. Furthermore, potentiation and inhibition of the ICh by 8d depended on the membrane potential, both being stronger at -20 than at -70 mV; indicating that 8d interacts with at least two sites into the ion channel/receptor complex: one for potentiating and another for inhibiting the α7-containing nAChRs. These results suggest that 8d may act as agonist, antagonist and positive modulator of α7-containing nAChRs in hippocampal interneurons.