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The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.
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To watch a person doing an activity has an impact on the viewer. In fact, the film industry hinges on viewers looking at characters doing all sorts of narrative activities. From previous works, we know that media and non-media professionals perceive differently audiovisuals with cuts. Media professionals present a lower eye-blink rate, a lower activity in frontal and central cortical areas, and a more organized functional brain connectivity when watching audiovisual cuts. Here, we aimed to determine how audiovisuals with no formal interruptions such as cuts were perceived by media and non-media professionals. Moreover, we wondered how motor actions of characters in films would have an impact on the brain activities of the two groups of observers. We presented a narrative with 24 motor actions in a one-shot movie in wide shot with no cuts to 40 participants. We recorded the electroencephalographic (EEG) activity of the participants and analyzed it for the periods corresponding to the 24 motor actions (24 actions × 40 participants = 960 potential trials). In accordance with collected results, we observed differences in the EEG activity of the left primary motor cortex. A spectral analysis of recorded EEG traces indicated the presence of significant differences in the beta band between the two groups after the onset of the motor activities, while no such differences were found in the alpha band. We concluded that media expertise is related with the beta band identified in the EEG activity of the left primary motor cortex and the observation of motor actions in videos.
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During embryonic development, heterozygous mutant kreisler mice undergo ectopic expression of the Hoxa3 gene in the rostral hindbrain, affecting the opioid and noradrenergic systems. In this model, we have investigated behavioral and cognitive processes in their adulthood. We confirmed that pontine and locus coeruleus neuronal projections are impaired, by using startle and pain tests and by analyzing immunohistochemical localization of tyrosine hydroxylase. Our results showed that, even if kreisler mice are able to generate eyelid reflex responses, there are differences with wild-types in the first component of the response (R1), modulated by the noradrenergic system. The acquisition of conditioned motor responses is impaired in kreisler mice when using the trace but not the delay paradigm, suggesting a functional impairment in the hippocampus, subsequently confirmed by reduced quantification of alpha2a receptor mRNA expression in this area but not in the cerebellum. Moreover, we demonstrate the involvement of adrenergic projection in eyelid classical conditioning, as clonidine prevents the appearance of eyelid conditioned responses in wild-type mice. In addition, hippocampal motor learning ability was restored in kreisler mice by administration of adrenergic antagonist drugs, and a synergistic effect was observed following simultaneous administration of idazoxan and naloxone.
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Condicionamiento Clásico , Condicionamiento Palpebral , Ratones , Animales , Condicionamiento Clásico/fisiología , Neuronas/fisiología , Condicionamiento Palpebral/fisiología , Párpados , Rombencéfalo/fisiología , Proteínas de HomeodominioRESUMEN
Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3-CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance.
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Hipocampo , Plasticidad Neuronal , Animales , Región CA1 Hipocampal/fisiología , Hipocampo/fisiología , Ratones , Plasticidad Neuronal/fisiología , Potasio , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-AminobutíricoRESUMEN
ß-hydroxy ß-methylbutyrate (HMB), a metabolite of the essential amino acid leucine, has been shown to preserve muscle mass and strength during aging. The signaling mechanism by which HMB elicits its favorable effects on protein metabolism in skeletal muscle is also preserved in the brain. However, there are only a few studies, all at relatively high doses, addressing the effect of HMB supplementation on cognition. This study evaluated the effects of different doses of HMB on the potentiation of hippocampal synapses following the experimental induction of long-term potentiation (LTP) in the hippocampus of behaving rats, as well as on working memory test (delayed matching-to-position, DMTP) in mice. HMB doses in rats were 225 (low), 450 (medium), and 900 (high) mg/kg body weight/day and were double in mice. Rats who received medium or high HMB doses improved LTP, suggesting that HMB administration enhances mechanisms related to neuronal plasticity. In the DMTP test, mice that received any of the tested doses of HMB performed better than the control group in the overall test with particularities depending on the dose and the task phase.
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Potenciación a Largo Plazo , Memoria a Corto Plazo , Animales , Suplementos Dietéticos , Hipocampo , Ratones , Ratas , Roedores , ValeratosRESUMEN
Eye blinks provoke a loss of visual information. However, we are not constantly making conscious decisions about the appropriate moment to blink. The presence or absence of eye blinks also denotes levels of attention. We presented three movies with the exact same narrative but different styles of editing and recorded participants' eye blinks. We found that moments of increased or decreased eye blinks by viewers coincided with the same content in the different movie styles. The moments of increased eye blinks corresponded to those when the actor leaves the scene and when the movie repeats the same action for a while. The moments of decreased eye blinks corresponded to actions where visual information was crucial to proper understanding of the scene presented. According to these results, viewers' attention is more related to narrative content than to the style of editing when watching movies.
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Experts apply their experience to the proper development of their routine activities. Their acquired expertise or professionalization is expected to help in the development of those recurring tasks. Media professionals spend their daily work watching narrative contents on screens, so learning how they manage visual perception of those contents could be of interest in an increasingly audiovisual society. Media works require not only the understanding of the storytelling, but also the decoding of the formal rules and presentations. We recorded electroencephalographic (EEG) signals from 36 participants (18 media professionals and 18 non-media professionals) while they were watching audiovisual contents, and compared their eyeblink rate and their brain activity and connectivity. We found that media professionals decreased their blink rate after the cuts, suggesting that they can better manage the loss of visual information that blinks entail by sparing them when new visual information is being presented. Cuts triggered similar activation of basic brain processing in the visual cortex of the two groups, but different processing in medial and frontal cortical areas, where media professionals showed a lower activity. Effective brain connectivity occurred in a more organized way in media professionals-possibly due to a better communication between cortical areas that are coordinated for decoding new visual content after cuts.
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Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.
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Región CA1 Hipocampal/metabolismo , Región CA3 Hipocampal/metabolismo , Plasticidad Neuronal/fisiología , Receptores de Dopamina D2/deficiencia , Memoria Espacial/fisiología , Sinapsis/metabolismo , Animales , Reacción de Prevención/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Interferente Pequeño/administración & dosificación , Receptores de Dopamina D2/genética , Sinapsis/genéticaRESUMEN
In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid-ß (Aß) peptides have been shown to play a causal role. Among different Aß species, Aß25-35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble Aß forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of Aß25-35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. Aß25-35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in Aß25-35 amyloidosis model.
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Astrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.
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Astrocitos/metabolismo , Astrocitos/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Neuronas/patología , Receptor trkB/metabolismo , Índice de Severidad de la Enfermedad , Animales , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/fisiopatología , Eliminación de Gen , Hipocampo/patología , Ácido Kaínico/administración & dosificación , Litio , Locomoción , Ratones Endogámicos C57BL , Neuroprotección , Fenotipo , Pilocarpina , Aprendizaje EspacialRESUMEN
Early in brain development, impaired neuronal signaling during time-sensitive windows triggers the onset of neurodevelopmental disorders. GABA, through its depolarizing and excitatory actions, drives early developmental events including neuronal circuit formation and refinement. BDNF/TrkB signaling cooperates with GABA actions. How these developmental processes influence the formation of neural circuits and affect adult brain function is unknown. Here, we show that early deletion of Ntrk2/Trkb from immature mouse hippocampal dentate granule cells (DGCs) affects the integration and maturation of newly formed DGCs in the hippocampal circuitry and drives a premature shift from depolarizing to hyperpolarizing GABAergic actions in the target of DGCs, the CA3 principal cells of the hippocampus, by reducing the expression of the cation-chloride importer Nkcc1. These changes lead to the disruption of early synchronized neuronal activity at the network level and impaired morphological maturation of CA3 pyramidal neurons, ultimately contributing to altered adult hippocampal synaptic plasticity and cognitive processes.
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Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity.
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Trastornos de la Memoria/etiología , Obesidad/líquido cefalorraquídeo , Palmitatos/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Humanos , Trastornos de la Memoria/patología , Ratones , Obesidad/patologíaRESUMEN
Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-ß (Aß) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aß-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aß pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.
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Reacción de Prevención/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Potenciación a Largo Plazo/fisiología , Memoria a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Serina Endopeptidasas/metabolismo , Transducción de Señal/fisiología , Tauopatías/metabolismo , Tauopatías/fisiopatología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Proteína ReelinaRESUMEN
AIM: Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. METHODS: Adult rats were implanted with GC cells and checked 10 weeks later, when a GH/IGF-I-secreting tumour was already formed. RESULTS: Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. CONCLUSION: Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.
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Diferenciación Celular , Cognición , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Potenciación a Largo Plazo , Neuronas/citología , Animales , Femenino , Ratas , Ratas Endogámicas WFRESUMEN
BACKGROUND AND PURPOSE: Excessive GABAergic inhibition contributes to cognitive dysfunctions in Down syndrome (DS). Selective negative allosteric modulators (NAMs) of α5-containing GABAA receptors such as the α5 inverse agonist (α5IA) restore learning and memory deficits in Ts65Dn mice, a model of DS. In this study we have assessed the long-lasting effects of α5IA on in vivo LTP and behaviour in Ts65Dn mice. EXPERIMENTAL APPROACH: We made in vivo LTP recordings for six consecutive days in freely moving Ts65Dn mice and their wild-type littermates, treated with vehicle or α5IA. In parallel, Ts65Dn mice were assessed by various learning and memory tests (Y maze, Morris water maze, or the novel object recognition) for up to 7 days, following one single injection of α5IA or vehicle. KEY RESULTS: LTP was not evoked in vivo in Ts65Dn mice at hippocampal CA3-CA1 synapses. However, this deficit was sustainably reversed for at least six consecutive days following a single injection of α5IA. This long-lasting effect of α5IA was also observed when assessing working and long-term memory deficits in Ts65Dn mice. CONCLUSION AND IMPLICATIONS: We show for the first time in vivo LTP deficits in Ts65Dn mice. These deficits were restored for at least 6 days following acute treatment with α5IA and might be the substrate for the long-lasting pharmacological effects of α5IA on spatial working and long-term recognition and spatial memory tasks. Our results demonstrate the relevance of negative allosteric modulators of α5-containing GABAA receptors to the treatment of cognitive deficits associated with DS.
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Disfunción Cognitiva , Síndrome de Down , Agonistas de Receptores de GABA-A/farmacología , Potenciación a Largo Plazo , Animales , Cognición , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Aprendizaje por Laberinto , Ratones , Receptores de GABA-A , Ácido gamma-AminobutíricoRESUMEN
The capacity to understand another person's emotions, intentions, beliefs and personality traits, based on observed or communicated behaviors, is termed social cognition. During the last decade, social neuroscience has made great progress in understanding the neural correlates of social cognition. However, because the cerebellum is traditionally viewed as only involved in motor processing, the contribution of this major part of the brain in social processing has been largely ignored and its specific role in social cognition remains unclear. Nevertheless, recent meta-analyses have made its crucial contribution to social cognition evident. This raises the question: What is the exact function of the cerebellum in social cognition? We hypothesize that the cerebellum builds internal action models of our social inter-actions to predict how other people's actions will be executed, what our most likely responses are to these actions, so that we can automatize our interactions and instantly detect disruptions in these action sequences. This mechanism likely allows to better anticipate action sequences during social interactions in an automatic and intuitive way and to fine-tune these anticipations, making it easier to understand behaviors and to detect violations. This hypothesis has major implications in neurological disorders affecting the cerebellum such as autism, with detrimental effects on social functionality, especially on more complex and abstract social cognitive processes. Because the fundamental anatomical organization of the cerebellum is identical in many species (cerebellar microcomplexes), this hypothesis could have major impacts to elucidate social interactions in social animals.
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Cerebelo/fisiología , Cognición/fisiología , Conducta Social , Animales , Trastorno del Espectro Autista/fisiopatología , Conducta Animal , Encéfalo , Mapeo Encefálico , Cerebro/fisiología , Comunicación , Condicionamiento Operante , Emociones/fisiología , Humanos , Relaciones Interpersonales , Imagen por Resonancia Magnética , Memoria , Mentalización/fisiología , Neuronas Espejo/fisiología , Vías Nerviosas/fisiología , Neurociencias , Ratas , RecompensaRESUMEN
Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer's disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3â»CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-ß (Aß) or GirK channel modulators impaired ionotropic (GABAA-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented Aß-induced changes in GABAA components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABAA and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes.
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Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/administración & dosificación , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Sinapsis/fisiología , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/agonistas , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/antagonistas & inhibidores , Inyecciones , Potenciación a Largo Plazo , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
Stroke is one of the main causes of death, neurological dysfunctions or disability in elderly. Neuroprotective drugs have been proposed to improve long-term recovery after stroke, but failed to reach clinical effectiveness. Hence, recent studies suggested that restorative therapies should combine neuroprotection and remyelination. Montelukast, an anti-asthmatic drug, was shown to exert neuroprotection in animal models of CNS injuries, but its ability to affect oligodendrocytes, restoring fiber connectivity, remains to be determined. In this study, we evaluated whether montelukast induces long-term repair by promoting fiber connectivity up to 8 weeks after middle cerebral artery occlusion (MCAo), using different experimental approaches such as in vivo diffusion magnetic resonance imaging (MRI), electrophysiological techniques, ex vivo diffusion tensor imaging (DTI)-based fiber tracking and immunohistochemistry. We found that, in parallel with a reduced evolution of ischemic lesion and atrophy, montelukast increased the DTI-derived axial diffusivity and number of myelin fibers, the density of myelin binding protein (MBP) and the number of GSTpi+ mature oligodendrocytes. Together with the rescue of MCAo-induced impairments of local field potentials in ischemic cortex, the data suggest that montelukast may improve fibers reorganization. Thus, to ascertain whether this effect involved changes of oligodendrocyte precursor cells (OPCs) activation and maturation, we used the reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice that allowed us to trace the fate of OPCs throughout animal's life. Our results showed that montelukast enhanced the OPC recruitment and proliferation at acute phase, and increased their differentiation to mature oligodendrocytes at chronic phase after MCAo. Considering the crosstalk between OPCs and microglia has been widely reported in the context of demyelinating insults, we also assessed microglia activation. We observed that montelukast influenced the phenotype of microglial cells, increasing the number of M2 polarized microglia/macrophages, over the M1 phenotype, at acute phase after MCAo. In conclusion, we demonstrated that montelukast improves fiber re-organization and long-term functional recovery after brain ischemia, enhancing recruitment and maturation of OPCs. The present data suggest that montelukast, an already approved drug, could be "repositioned "as a protective drug in stroke acting also on fiber re-organization.
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Acetatos/uso terapéutico , Antiasmáticos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Quinolinas/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Ciclopropanos , Infarto de la Arteria Cerebral Media/fisiopatología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Microglía/efectos de los fármacos , Accidente Cerebrovascular/fisiopatología , SulfurosRESUMEN
It has been well documented that neurotrophins, including brain-derived neurotrophic factor (BDNF), are severely affected in Alzheimer's disease (AD), but their administration faces a myriad of technical challenges. Here we took advantage of the early astrogliosis observed in an amyloid mouse model of AD (5xFAD) and used it as an internal sensor to administer BDNF conditionally and locally. We first demonstrate the relevance of BDNF release from astrocytes by evaluating the effects of coculturing WT neurons and BDNF-deficient astrocytes. Next, we crossed 5xFAD mice with pGFAP:BDNF mice (only males were used) to create 5xFAD mice that overexpress BDNF when and where astrogliosis is initiated (5xF:pGB mice). We evaluated the behavioral phenotype of these mice. We first found that BDNF from astrocytes is crucial for dendrite outgrowth and spine number in cultured WT neurons. Double-mutant 5xF:pGB mice displayed improvements in cognitive tasks compared with 5xFAD littermates. In these mice, there was a rescue of BDNF/TrkB downstream signaling activity associated with an improvement of dendritic spine density and morphology. Clusters of synaptic markers, PSD-95 and synaptophysin, were also recovered in 5xF:pGB compared with 5xFAD mice as well as the number of presynaptic vesicles at excitatory synapses. Additionally, experimentally evoked LTP in vivo was increased in 5xF:pGB mice. The beneficial effects of conditional BDNF production and local delivery at the location of active neuropathology highlight the potential to use endogenous biomarkers with early onset, such as astrogliosis, as regulators of neurotrophic therapy in AD.SIGNIFICANCE STATEMENT Recent evidence places astrocytes as pivotal players during synaptic plasticity and memory processes. In the present work, we first provide evidence that astrocytes are essential for neuronal morphology via BDNF release. We then crossed transgenic mice (5xFAD mice) with the transgenic pGFAP-BDNF mice, which express BDNF under the GFAP promoter. The resultant double-mutant mice 5xF:pGB mice displayed a full rescue of hippocampal BDNF loss and related signaling compared with 5xFAD mice and a significant and specific improvement in all the evaluated cognitive tasks. These improvements did not correlate with amelioration of ß amyloid load or hippocampal adult neurogenesis rate but were accompanied by a dramatic recovery of structural and functional synaptic plasticity.