RESUMEN
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.
Asunto(s)
Inmunidad , Neuronas , Canales de Potasio , Animales , Trastorno del Espectro Autista/inmunología , Región CA1 Hipocampal/citología , Regulación hacia Abajo , Femenino , Neuronas/metabolismo , Canales de Potasio/metabolismo , Embarazo , Células Piramidales/inmunología , Esquizofrenia/inmunologíaRESUMEN
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.
Asunto(s)
Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Cognición , Espinas Dendríticas/fisiología , Aprendizaje , Animales , Región CA1 Hipocampal/citología , Región CA3 Hipocampal/citología , Femenino , Masculino , Ratas , Ratas Long-Evans , Factores SexualesRESUMEN
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.
Asunto(s)
Región CA1 Hipocampal , Región CA2 Hipocampal , Disfunción Cognitiva , Espinas Dendríticas , Ciclo Estral/metabolismo , Aprendizaje , Ovariectomía/efectos adversos , Pregnanolona/metabolismo , Pregnanolona/farmacología , Progesterona/metabolismo , Progesterona/farmacología , Células Piramidales , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Conducta Animal/fisiología , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA2 Hipocampal/citología , Región CA2 Hipocampal/efectos de los fármacos , Región CA2 Hipocampal/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Espinas Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Pregnanolona/administración & dosificación , Progesterona/administración & dosificación , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Ratas Wistar , Reconocimiento en Psicología/fisiologíaRESUMEN
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.
Asunto(s)
Potenciales de Acción , Región CA1 Hipocampal/fisiología , Células Piramidales/fisiología , Animales , Región CA1 Hipocampal/citología , Hipocampo/citología , Hipocampo/fisiología , Canal de Potasio KCNQ2/metabolismo , Canal de Potasio KCNQ3/metabolismo , Masculino , Transición de Fase , Células Piramidales/citología , Ratas WistarRESUMEN
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.
Asunto(s)
Hipocampo/citología , Potenciales de Acción/fisiología , Animales , Región CA1 Hipocampal/citología , Interneuronas/citología , Masculino , Células Piramidales/citología , Ratas Long-Evans , Ritmo Teta/fisiología , Factores de TiempoRESUMEN
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.
Asunto(s)
Astrocitos/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Estreptozocina/farmacología , Animales , Astrocitos/citología , Región CA1 Hipocampal/citología , Región CA3 Hipocampal/citología , Forma de la Célula/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Región CA1 Hipocampal/citología , Región CA3 Hipocampal/citología , Espinas Dendríticas/fisiología , Metestro/fisiología , Neuronas/citología , Análisis de Varianza , Animales , Espinas Dendríticas/ultraestructura , Femenino , Neuronas/ultraestructura , Ratas , Ratas Wistar , Tinción con Nitrato de PlataRESUMEN
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.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Proteínas de Artrópodos/farmacología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Venenos de Araña/farmacología , Péptidos beta-Amiloides/toxicidad , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Muerte Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Embrión de Mamíferos/citología , Embrión de Mamíferos/patología , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Técnicas In Vitro , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Técnicas de Placa-Clamp , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
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.
Asunto(s)
Región CA1 Hipocampal/metabolismo , Interneuronas/metabolismo , Quinuclidinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Región CA1 Hipocampal/citología , Colina/farmacología , Técnicas In Vitro , Ratas Sprague-Dawley , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Isquemia Encefálica/enzimología , Estrés del Retículo Endoplásmico/fisiología , Hipocampo/irrigación sanguínea , Hipertensión/enzimología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas , Animales , Antracenos , Isquemia Encefálica/fisiopatología , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Modelos Animales de Enfermedad , Activación Enzimática , Proteínas de Choque Térmico/efectos de los fármacos , Hipocampo/enzimología , Hipocampo/fisiopatología , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Daño por Reperfusión/enzimología , Daño por Reperfusión/fisiopatología , Factor de Transcripción CHOP/metabolismoRESUMEN
Nitric oxide (NO) is involved in synaptic plasticity in the hippocampus through different presynaptic and postsynaptic mechanisms that include the modulation of the GABAergic neurotransmission. Inhibitory synapses on hippocampal pyramidal neurons are known to possess the molecular machinery for retrograde NO-signaling, but the modulation of GABAARs function by NO in these neurons and the mechanisms of action involved have not been fully characterized. Here we show that suppression of the endogenous NO generation by the nitric oxide synthase (NOS) inhibitor L-NAME produces significant and reversible increases in the magnitude of both tonic and phasic GABAergic currents in CA1 hippocampal pyramidal neurons. GABA-evoked chloride currents were measured in the presence or absence of L-NAME using whole-cell patch-clamp recordings in acute hippocampal slices from young adult mice. Enhancement of the tonic GABA responses induced by L-NAME was insensitive to TTX and decreased by co-incubation with the NO donor DEA/NO. Applications of DEA/NO alone did not produce significant effects on tonic GABA responses. L-NAME treatment also increased the amplitude of phasic GABAergic currents evoked by GABA-puffs. Our results indicate that the extent of tonic and phasic inhibition mediated by GABAA receptors in CA1 hippocampal pyramidal neurons is affected by endogenous NO production.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Células Piramidales/efectos de los fármacos , Ácido gamma-Aminobutírico/fisiología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Ratones Endogámicos BALB C , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/biosíntesis , Células Piramidales/fisiología , Receptores de GABA-A/fisiología , Transmisión SinápticaRESUMEN
We investigated whether the morphology of microglia in the molecular layer of the dentate gyrus (DG-Mol) or in the lacunosum molecular layer of CA1 (CA1-LMol) was correlated with spatial learning and memory in the capuchin monkey (Cebus apella). Learning and memory was tested in 4 monkeys with visuo-spatial, paired associated learning (PAL) tasks from the Cambridge battery of neuropsychological tests. After testing, monkeys were sacrificed, and hippocampi were sectioned. We specifically immunolabeled microglia with an antibody against the adapter binding, ionized calcium protein. Microglia were selected from the middle and outer thirds of the DG-Mol (n=268) and the CA1-LMol (n=185) for three-dimensional reconstructions created with Neurolucida and Neuroexplorer software. Cluster and discriminant analyses, based on microglial morphometric parameters, identified two major morphological microglia phenotypes (types I and II) found in both the CA1-LMol and DG-Mol of all individuals. Compared to type II, type I microglia were significantly smaller, thinner, more tortuous and ramified, and less complex (lower fractal dimensions). PAL performance was both linearly and non-linearly correlated with type I microglial morphological features from the rostral and caudal DG-Mol, but not with microglia from the CA1-LMol. These differences in microglial morphology and correlations with PAL performance were consistent with previous proposals of hippocampal regional contributions for spatial learning and memory. Our results suggested that at least two morphological microglial phenotypes provided distinct physiological roles to learning-associated activity in the rostral and caudal DG-Mol of the monkey brain.
Asunto(s)
Región CA1 Hipocampal/citología , Giro Dentado/citología , Memoria/fisiología , Microglía/citología , Aprendizaje Espacial/fisiología , Animales , Región CA1 Hipocampal/fisiología , Cebus , Análisis por Conglomerados , Giro Dentado/fisiología , Femenino , Imagenología Tridimensional , Inmunohistoquímica , MasculinoRESUMEN
The Wnt signaling pathway plays an important role in developmental processes, including embryonic patterning, cell specification, and cell polarity. Wnt components participate in the development of the central nervous system, and growing evidence indicates that this pathway also regulates the function of the adult nervous system. In this study, we report that Wnt-5a, a noncanonical Wnt ligand, is a potent activator of mitochondrial dynamics and induces acute fission and fusion events in the mitochondria of rat hippocampal neurons. The effect of Wnt-5a was inhibited in the presence of sFRP, a Wnt scavenger. Similarly, the canonical Wnt-3a ligand had no effect on mitochondrial fission-fusion events, suggesting that this effect is specific for Wnt-5a alone. We also show that the Wnt-5a effects on mitochondrial dynamics occur with an increase in both intracellular and mitochondrial calcium (Ca(2+)), which was correlated with an increased phosphorylation of Drp1(Ser-616) and a decrease of Ser-637 phosphorylation, both indicators of mitochondrial dynamics. Electron microscope analysis of hippocampal tissues in the CA1 region showed an increase in the number of mitochondria present in the postsynaptic region, and this finding correlated with a change in mitochondrial morphology. We conclude that Wnt-5a/Ca(2+) signaling regulates the mitochondrial fission-fusion process in hippocampal neurons, a feature that might help to further understand the role of Wnt-related pathologies, including neurodegenerative diseases associated with mitochondrial dysfunction, and represents a potentially important link between impaired metabolic function and degenerative disorders.
Asunto(s)
Dinámicas Mitocondriales , Proteínas Wnt/fisiología , Animales , Región CA1 Hipocampal/citología , Señalización del Calcio , Células Cultivadas , Dinaminas/metabolismo , Potencial de la Membrana Mitocondrial , Ratones Endogámicos C57BL , Mitocondrias/fisiología , Mitocondrias/ultraestructura , Neuronas/metabolismo , Neuronas/ultraestructura , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Ratas Sprague-Dawley , Proteína Wnt-5aRESUMEN
Current knowledge concerning the molecular mechanisms of the cellular response to excitotoxic insults in neurodegenerative diseases is insufficient. Although glutamate (Glu) has been widely studied as the main excitatory neurotransmitter and principal excitotoxic agent, the neuroprotective response enacted by neurons is not yet completely understood. Some of the molecular participants have been revealed, but the signaling pathways involved in this protective response are just beginning to be identified. Here, we demonstrate in vivo that, in response to the cell damage and death induced by Glu excitotoxicity, neurons orchestrate a survival response through the extracellular signal-regulated kinase (ERK) signaling pathway by increasing ERK expression in the rat hippocampal (CA1) region, allowing increased neuronal survival. In addition, this protective response is specifically reversed by U0126, an ERK inhibitor, which promotes cell death only when it is administered together with Glu. Our findings demonstrate that the ERK signaling pathway has a neuroprotective role in the response to Glu-induced excitotoxicity in hippocampal neurons. Therefore, the ERK signaling pathway may be activated as a cellular response to excitotoxic injury to prevent damage and neural loss, representing a novel therapeutic target in the treatment of neurodegenerative diseases.
Asunto(s)
Región CA1 Hipocampal/metabolismo , Ácido Glutámico/toxicidad , Sistema de Señalización de MAP Quinasas , Neuronas/metabolismo , Potenciales de Acción , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Supervivencia Celular , Células Cultivadas , Neuronas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus.
Asunto(s)
Región CA1 Hipocampal/citología , Endocannabinoides/metabolismo , Neuronas/fisiología , Receptores Muscarínicos/metabolismo , Transmisión Sináptica/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Colinérgicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Masculino , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
Phenylketonuria (PKU) is the most frequent aminoacidopathy that damage the central nervous system and is characterized by neural injury, mental retardation and accumulation of phenylalanine and its metabolites in plasma and tissues. So far, the only effective protection against brain injury is the administration of special phenylalanine-free diets. Animals with lesions in the hippocampus and amygdala had behavioral impairments indicating the importance of the integrity of these brain structures in learning and memory tasks which are disability characteristics of patients affected by PKU. In the present study we aimed to test the effect of the combination of two energetic and antioxidant compounds-pyruvate and creatine (intraperitoneal injections of 0.2 mg/g of body weight and 0.4 mg/g of body weight, respectively, treatment from the 7th to the 28th postnatal day)-in animals subjected to a chronic model of PKU. To assess likely effects, the density of dendritic spines in the hippocampal CA1 region and in the posterodorsal medial amygdala of 60-day-old male rats were analyzed under confocal microscopy. Present results showed that the co-treatment with pyruvate and creatine prevented the reduction in dendritic spine density in the stratum radiatum of the CA1 hippocampal field and in the posterodorsal medial amygdala of PKU animals. If this can also occur in PKU patients, it is possible that creatine and pyruvate may help to prevent brain damage in patients under specific diet.
Asunto(s)
Amígdala del Cerebelo/citología , Creatina/farmacología , Espinas Dendríticas/efectos de los fármacos , Hipocampo/citología , Fenilcetonurias/patología , Ácido Pirúvico/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/patología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/patología , Recuento de Células , Colorantes , Hipocampo/efectos de los fármacos , Hipocampo/patología , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Cognitive impairment or its recovery has been associated with the absence or reestablishment of estrogenic actions in the central nervous system of female experimental animals or women. It has been proposed that these cognitive phenomena are related to estrogen-mediated modulatory activity of synaptic transmission in brain structures involved in cognitive functions. In the present work a morphological study was conducted in adult female ovariectomized rats to evaluate estradiol-dependent dendritic spine sprouting in hippocampal pyramidal neurons, and changes in the presynaptic marker synaptophysin. Three or ten days after estradiol treatment (10 µg/day, twice) in the ovariectomized rats, a significant increase of synaptophysin was observed, which was coincident with a significant higher numerical density of thin (22%), stubby (36%), mushroom (47%) and double spines (125%), at day 3, without significant changes of spine density at day 10, after treatment. These results may be interpreted as evidence of pre- and postsynaptic plastic events that may be involved in the modulation of cognitive-related behavioral performance after estrogen replacement therapy.
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Región CA1 Hipocampal/citología , Espinas Dendríticas/efectos de los fármacos , Estradiol/farmacología , Estrógenos/farmacología , Células Piramidales/ultraestructura , Análisis de Varianza , Animales , Región CA1 Hipocampal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ovariectomía , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tinción con Nitrato de Plata , Sinaptofisina/metabolismoRESUMEN
BACKGROUND: Chewing imbalances are associated with neurodegeneration and are risk factors for senile dementia in humans and memory deficits in experimental animals. We investigated the impact of long-term reduced mastication on spatial memory in young, mature and aged female albino Swiss mice by stereological analysis of the laminar distribution of CA1 astrocytes. A soft diet (SD) was used to reduce mastication in the experimental group, whereas the control group was fed a hard diet (HD). Assays were performed in 3-, 6- and 18-month-old SD and HD mice. RESULTS: Eating a SD variably affected the number of astrocytes in the CA1 hippocampal field, and SD mice performed worse on water maze memory tests than HD mice. Three-month-old mice in both groups could remember/find a hidden platform in the water maze. However, 6-month-old SD mice, but not HD mice, exhibited significant spatial memory dysfunction. Both SD and HD 18-month-old mice showed spatial memory decline. Older SD mice had astrocyte hyperplasia in the strata pyramidale and oriens compared to 6-month-old mice. Aging induced astrocyte hypoplasia at 18 months in the lacunosum-moleculare layer of HD mice. CONCLUSIONS: Taken together, these results suggest that the impaired spatial learning and memory induced by masticatory deprivation and aging may be associated with altered astrocyte laminar distribution and number in the CA1 hippocampal field. The underlying molecular mechanisms are unknown and merit further investigation.
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Envejecimiento/fisiología , Astrocitos/fisiología , Región CA1 Hipocampal/fisiología , Masticación/fisiología , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/fisiopatología , Animales , Astrocitos/citología , Región CA1 Hipocampal/citología , RatonesRESUMEN
Chronic caffeine consumption has been inversely associated with the risk of developing dementia and Alzheimer's disease. Here we assessed whether chronic caffeine treatment prevents the behavioral and cognitive decline that male Wistar rats experience from young (≈3 months) to middle age (≈10 months). When animals were young they were evaluated at weekly intervals in three tests: motor activity habituation in the open field (30-min sessions at the same time on consecutive days), continuous spontaneous alternation in the Y-maze (8 min), and elevated plus-maze (5 min). Afterward, rats from the same litter were randomly assigned either to a caffeine-treated group (n=13) or a control group (n=11), which received only tap water. Caffeine treatment (5 mg/kg/day) began when animals were ≈4 months old, and lasted for 6 months. Behavioral tests were repeated from day 14 to day 28 after caffeine withdrawal, a time period that is far in excess for the full excretion of a caffeine dose in this species. Thirty days after caffeine discontinuation brains were processed for Golgi-Cox staining. Compared with controls, we found that middle-aged rats that had chronically consumed low doses of caffeine (1) maintained their locomotor habituation during the second consecutive day exposure to the open field (an index of non-associative learning), (2) maintained their exploratory drive to complete the conventional minimum of nine arm visits required to calculate the alternation performance in the Y-maze in a greater proportion, (3) maintained their alternation percentage above chance level (an index of working memory), and (4) did not increase the anxiety indexes assessed by measuring the time spent in the open arms of the elevated plus maze. In addition, morphometric analysis of hippocampal neurons revealed that dendritic branching (90-140 µm from the soma), length of 4th and 5th order branches, total dendritic length, and spine density in distal dendritic branches were greater in the basal but not the apical dendrites of CA1 pyramidal neurons from rats chronically treated with caffeine, in comparison with their age- and littermate-matched controls. Altogether, the present findings strengthen the epidemiological observations suggesting that prolonged caffeine intake prevents the cognitive decline associated with aging, and open the possibility that this process could be mediated by promoting the growth of dendrites and spines in neurons of the adult mammalian brain.
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Región CA1 Hipocampal/citología , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Trastornos del Conocimiento/prevención & control , Dendritas/efectos de los fármacos , Dendritas/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Envejecimiento/fisiología , Animales , Ansiedad/inducido químicamente , Ansiedad/psicología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/ultraestructura , Trastornos del Conocimiento/psicología , Interpretación Estadística de Datos , Fenómenos Electrofisiológicos/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Movimiento/fisiología , Ratas , Ratas WistarRESUMEN
Bariatric surgery has been the most effective therapeutic intervention for morbidly obese patients. However, recent evidence has shown that this procedure may cause serious neurological complications such as Wernicke encephalopathy, depression, and memory impairment. With this in mind, we conducted an experimental study to investigate whether weight-reduction surgery would promote morphological changes in the hippocampal formation, a brain region linked to cognitive and emotional processes. To do so, the present study evaluated the hippocampal expression of parvalbumin interneurons in rats submitted to a gastric restrictive procedure (experimental phytobezoar). Our results demonstrated that rats with gastric-reduced capacity presented a significant increase in the expression of the parvalbumin interneurons in the hippocampal CA1 and CA3 subfields. These data are the first experimental evidence that restrictive bariatric surgery may alter hippocampal cytoarchitecture.