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1.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33808976

RESUMEN

The mammalian hippocampal dentate gyrus is a unique memory circuit in which a subset of neurons is continuously generated throughout the lifespan. Previous studies have shown that the dentate gyrus neuronal population can hold fear memory traces (i.e., engrams) and that adult-born neurons (ABNs) support this process. However, it is unclear whether ABNs themselves hold fear memory traces. Therefore, we analyzed ABN activity at a population level across a fear conditioning paradigm. We found that fear learning did not recruit a distinct ABN population. In sharp contrast, a completely different ABN population was recruited during fear memory retrieval. We further provide evidence that ABN population activity remaps over time during the consolidation period. These results suggest that ABNs support the establishment of a fear memory trace in a different manner to directly holding the memory. Moreover, this activity remapping process in ABNs may support the segregation of memories formed at different times. These results provide new insight into the role of adult neurogenesis in the mammalian memory system.


Asunto(s)
Consolidación de la Memoria/fisiología , Memoria/fisiología , Neurogénesis/genética , Neuronas/metabolismo , Animales , Condicionamiento Psicológico , Giro Dentado/metabolismo , Giro Dentado/fisiología , Miedo/fisiología , Hipocampo/metabolismo , Hipocampo/fisiología , Humanos , Aprendizaje/fisiología , Ratones , Neuronas/fisiología
2.
J Med Case Rep ; 15(1): 185, 2021 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-33883015

RESUMEN

BACKGROUND: Dementia is among the most common chronic noncommunicable neurodegenerative diseases. In the long term, it causes disability and loss of autonomy and independence. It is estimated that there are 35.6 million people with Alzheimer's disease worldwide. Several clinical aspects of this disease have been widely studied, but the main focus of study has been memory loss, which is one of the first symptoms. The present study proposes an innovative intervention that combines cognitive training and multisite transcranial direct current stimulation, which interferes with other clinical aspects of the subject. CASE PRESENTATION: In this study, we present two subjects diagnosed with mild Alzheimer's disease. Subject 1 is an 82-year-old Brazilian Latin American woman with a high school education who was diagnosed with Alzheimer's disease 8 years ago and uses an Exelon patch. Subject 2 is an 88-year-old Brazilian Latin American woman with an incomplete primary education who was diagnosed with Alzheimer's disease 1 year ago and received medical orientation to temporarily discontinue medications for Alzheimer's disease. Both participants were subjected to intermittent cognitive training sessions and concomitant transcranial stimulation in three weekly 30-minute sessions in which a brain area was stimulated every 10 minutes for a total of 24 sessions, with a 2-month follow-up. Transcranial stimulation was applied to six different regions of the cortex: the dorsolateral prefrontal cortex bilaterally, the somatosensory association cortex bilaterally and Broca's and Wernicke's areas. Comparing the results of tests performed before and after the treatment period, a 1-point improvement was observed for both subjects on the Word Recall task of the Alzheimer Disease Assessment Scale, which evaluates symptoms related to the decline of episodic memory. Improvement in the executive functions domain was also observed through the results of the Stroop test, Victoria version. CONCLUSIONS: The results from the two presented cases show that multisite transcranial stimulation associated with cognitive training is an effective adjuvant method for the treatment of patients diagnosed with mild Alzheimer's disease. Its effects can benefit patients' daily routines by reducing cognitive deficits by keeping intact areas active and/or compensating for lost functions. Trial registration NCT02772185. Registered 13 May 2016, http://www.clinicaltrials.gov/ct2/show/NCT02772185 . Retrospectively registered.


Asunto(s)
Enfermedad de Alzheimer/terapia , Cognición/fisiología , Memoria Episódica , Memoria/fisiología , Estimulación Transcraneal de Corriente Directa , Anciano de 80 o más Años , Brasil , Función Ejecutiva , Femenino , Humanos , Resultado del Tratamiento
3.
Nat Commun ; 12(1): 1795, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741933

RESUMEN

Neural computations are often fast and anatomically localized. Yet, investigating such computations in humans is challenging because non-invasive methods have either high temporal or spatial resolution, but not both. Of particular relevance, fast neural replay is known to occur throughout the brain in a coordinated fashion about which little is known. We develop a multivariate analysis method for functional magnetic resonance imaging that makes it possible to study sequentially activated neural patterns separated by less than 100 ms with precise spatial resolution. Human participants viewed five images individually and sequentially with speeds up to 32 ms between items. Probabilistic pattern classifiers were trained on activation patterns in visual and ventrotemporal cortex during individual image trials. Applied to sequence trials, probabilistic classifier time courses allow the detection of neural representations and their order. Order detection remains possible at speeds up to 32 ms between items (plus 100 ms per item). The frequency spectrum of the sequentiality metric distinguishes between sub- versus supra-second sequences. Importantly, applied to resting-state data our method reveals fast replay of task-related stimuli in visual cortex. This indicates that non-hippocampal replay occurs even after tasks without memory requirements and shows that our method can be used to detect such spontaneously occurring replay.


Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodos , Memoria/fisiología , Corteza Visual/diagnóstico por imagen , Corteza Visual/fisiología , Adulto , Algoritmos , Mapeo Encefálico/métodos , Femenino , Humanos , Masculino , Modelos Neurológicos , Análisis Multivariante , Tiempo de Reacción/fisiología , Adulto Joven
4.
Nat Commun ; 12(1): 1458, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674589

RESUMEN

Epitranscriptomic modifications can impact behavior. Here, we used Drosophila melanogaster to study N6-methyladenosine (m6A), the most abundant modification of mRNA. Proteomic and functional analyses confirm its nuclear (Ythdc1) and cytoplasmic (Ythdf) YTH domain proteins as major m6A binders. Assays of short term memory in m6A mutants reveal neural-autonomous requirements of m6A writers working via Ythdf, but not Ythdc1. Furthermore, m6A/Ythdf operate specifically via the mushroom body, the center for associative learning. We map m6A from wild-type and Mettl3 mutant heads, allowing robust discrimination of Mettl3-dependent m6A sites that are highly enriched in 5' UTRs. Genomic analyses indicate that Drosophila m6A is preferentially deposited on genes with low translational efficiency and that m6A does not affect RNA stability. Nevertheless, functional tests indicate a role for m6A/Ythdf in translational activation. Altogether, our molecular genetic analyses and tissue-specific m6A maps reveal selective behavioral and regulatory defects for the Drosophila Mettl3/Ythdf pathway.


Asunto(s)
Adenosina/análogos & derivados , Adenosina/metabolismo , Drosophila melanogaster/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Regiones no Traducidas 5' , Adenosina/genética , Animales , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Femenino , Proteínas Nucleares/metabolismo , Proteómica , Estabilidad del ARN , ARN Mensajero/metabolismo
5.
Int. j. med. surg. sci. (Print) ; 8(1): 1-13, mar. 2021. tab
Artículo en Español | LILACS | ID: biblio-1151562

RESUMEN

Este trabajo busca verificar la relación entre la calidad de vida y los aspectos sociodemográficos y cognitivos de las personas mayores participantes de grupos sociales. El método utilizado para estos fines es el estudio epidemiológico, cuantitativo, de diseño transversal, realizado en grupos de personas mayores residentes en una capital del sur de Brasil. Se utilizaron cuatro cuestionarios referentes a caracterización sociodemográfica, calidad de vida, aspectos cognitivos y queja de memoria subjetiva. Los resultados arrojaron datos respecto a la diferencia significativa en la calidad de vida y sus dominios en términos de edad, educación, ingresos y región de residencia y aspectos cognitivos. Las respuestas obtenidas en las preguntas generales del instrumento mostraron que la calidad de vida fue considerada buena por 176 de los encuestados, equivalentes al 54,83% y 151 encuenstados que representan el 47,04% se consideraron satisfechos en términos de salud en general. Por lo tanto, las conclusiones dan luces sobre los aspectos sociodemográficos, así como los cognitivos, están asociados con la calidad de vida de las personas mayores activas del municipio. Se enfatiza la queja de memoria subjetiva, que mostró relación con todos los aspectos analizados de la calidad de vida. Los datos obtenidos pueden servir como insumos para ampliar las posibilidades de promover la salud y la calidad de vida de la población envejecida.


Objective: To verify the relationship between the quality of life and the socio-demographic and cognitive aspects of the participating elderly people from social groups. Methods: Epidemiological, quantitative, cross-sectional design study, carried out in groups of elderly people living in a capital city in southern Brazil. Four questionnaires were used concerning sociodemographic characterization, quality of life, cognitive aspects and subjective memory complaints. Results: There were significant differences in the quality of life and its domains in terms of age, education, income and region of residence, and cognitive aspects. The answers obtained in the general questions of the instrument showed that the quality of life was considered good by 176 (54.83%) of the respondents and 151 (47.04%) were considered satisfied in terms of overall health. Conclusion: Socio-demographic aspects, as well as cognitive aspects, are associated with the quality of life of active elderly people in the municipality. The complaint of subjective memory is emphasized, which showed a relationship with all the analyzed aspects of the quality of life. The data obtained can serve as inputs to expand the possibilities of promoting the health and quality of life of the elderly population.


Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Calidad de Vida , Cognición/fisiología , Envejecimiento Cognitivo , Apoyo Social , Brasil/epidemiología , Encuestas y Cuestionarios , Memoria/fisiología
6.
Nat Commun ; 12(1): 1115, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602917

RESUMEN

Animals form and update learned associations between otherwise neutral sensory cues and aversive outcomes (i.e., punishment) to predict and avoid danger in changing environments. When a cue later occurs without punishment, this unexpected omission of aversive outcome is encoded as reward via activation of reward-encoding dopaminergic neurons. How such activation occurs remains unknown. Using real-time in vivo functional imaging, optogenetics, behavioral analysis and synaptic reconstruction from electron microscopy data, we identify the neural circuit mechanism through which Drosophila reward-encoding dopaminergic neurons are activated when an olfactory cue is unexpectedly no longer paired with electric shock punishment. Reduced activation of punishment-encoding dopaminergic neurons relieves depression of olfactory synaptic inputs to cholinergic neurons. Synaptic excitation by these cholinergic neurons of reward-encoding dopaminergic neurons increases their odor response, thus decreasing aversiveness of the odor. These studies reveal how an excitatory cholinergic relay from punishment- to reward-encoding dopaminergic neurons encodes the absence of punishment as reward, revealing a general circuit motif for updating aversive memories that could be present in mammals.


Asunto(s)
Dopamina/metabolismo , Drosophila melanogaster/fisiología , Castigo , Recompensa , Animales , Reacción de Prevención/fisiología , Condicionamiento Clásico , Neuronas Dopaminérgicas/fisiología , Memoria/fisiología , Aprendizaje Inverso , Olfato/fisiología , Sinapsis/fisiología
7.
Nat Commun ; 12(1): 1200, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33619256

RESUMEN

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.


Asunto(s)
Miedo/fisiología , Consolidación de la Memoria/fisiología , Memoria/fisiología , Sueño/fisiología , Animales , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Electrodos , Tecnología de Fibra Óptica , Ratones Transgénicos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Optogenética , Privación de Sueño/fisiopatología , Corteza Visual/fisiopatología
8.
Nat Neurosci ; 24(3): 326-330, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33603228

RESUMEN

By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.


Asunto(s)
Condicionamiento Operante/fisiología , Hipocampo/fisiología , Memoria/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Sacarosa/administración & dosificación , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Condicionamiento Operante/efectos de los fármacos , Hipocampo/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Red Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos
9.
PLoS Genet ; 17(1): e1009287, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33465062

RESUMEN

Huntington's disease is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of a large cytoplasmic protein. The Drosophila huntingtin (htt) gene is widely expressed during all developmental stages from embryos to adults. However, Drosophila htt mutant individuals are viable with no obvious developmental defects. We asked if such defects could be detected in htt mutants in a background that had been genetically sensitized to reveal cryptic developmental functions. Amyloid precursor protein (APP) is linked to Alzheimer's disease. Appl is the Drosophila APP ortholog and Appl signaling modulates axon outgrowth in the mushroom bodies (MBs), the learning and memory center in the fly, in part by recruiting Abl tyrosine kinase. Here, we find that htt mutations suppress axon outgrowth defects of αß neurons in Appl mutant MB by derepressing the activity of Abl. We show that Abl is required in MB αß neurons for their axon outgrowth. Importantly, both Abl overexpression and lack of expression produce similar phenotypes in the MBs, indicating the necessity of tightly regulating Abl activity. We find that Htt behaves genetically as a repressor of Abl activity, and consistent with this, in vivo FRET-based measurements reveal a significant increase in Abl kinase activity in the MBs when Htt levels are reduced. Thus, Appl and Htt have essential but opposing roles in MB development, promoting and suppressing Abl kinase activity, respectively, to maintain the appropriate intermediate level necessary for axon growth.


Asunto(s)
Aciltransferasas/genética , Axones/metabolismo , Proteínas de Drosophila/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Transporte Axonal/genética , Axones/patología , Drosophila melanogaster/genética , Desarrollo Embrionario/genética , Humanos , Enfermedad de Huntington/patología , Aprendizaje/fisiología , Memoria/fisiología , Cuerpos Pedunculados/crecimiento & desarrollo , Cuerpos Pedunculados/patología , Mutación/genética , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Transducción de Señal/genética
10.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467450

RESUMEN

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.


Asunto(s)
Amígdala del Cerebelo/fisiología , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Células Piramidales/fisiología , Transcriptoma/genética , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/metabolismo , Animales , Fenómenos Electrofisiológicos , Potenciales Postsinápticos Excitadores/fisiología , Miedo/psicología , Masculino , Memoria/fisiología , Ratones Transgénicos , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Optogenética/métodos , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Células Piramidales/metabolismo , Transmisión Sináptica/fisiología
11.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445678

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid ß (Aß) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.


Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/patología , Región CA1 Hipocampal/patología , Potenciación a Largo Plazo/fisiología , Red Nerviosa/patología , Neuronas/patología , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Interneuronas/metabolismo , Interneuronas/patología , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Transgénicos , Red Nerviosa/metabolismo , Neurregulina-1/metabolismo , Neuronas/metabolismo , Parvalbúminas/metabolismo , Receptor ErbB-4/metabolismo , Transducción de Señal/fisiología , Transmisión Sináptica/fisiología
12.
J Neurosci ; 41(5): 873-882, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33446519

RESUMEN

A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use disorder. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epigenome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.


Asunto(s)
Encéfalo/metabolismo , Cromatina/metabolismo , Epigénesis Genética/fisiología , Salud Mental/tendencias , Red Nerviosa/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Animales , Cromatina/genética , Humanos , Memoria/fisiología , Trastornos Relacionados con Sustancias/genética
13.
J Vis Exp ; (167)2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33491674

RESUMEN

Fear- and anxiety-related behaviors significantly contribute to an organism's survival. However, exaggerated defensive responses to perceived threat are characteristic of various anxiety disorders, which are the most prevalent form of mental illness in the United States. Discovering the neurobiological mechanisms responsible for defensive behaviors will aid in the development of novel therapeutic interventions. Pavlovian fear conditioning is a widely used laboratory paradigm to study fear-related learning and memory. A major limitation of traditional Pavlovian fear conditioning paradigms is that freezing is the only defensive behavior monitored. We recently developed a modified Pavlovian fear conditioning paradigm that allows us to study both conditioned freezing and flight (also known as escape) behavior within individual subjects. This model employs higher intensity footshocks and a greater number of pairings between the conditioned stimulus and unconditioned stimulus. Additionally, this conditioned flight paradigm utilizes serial presentation of pure tone and white noise auditory stimuli as the conditioned stimulus. Following conditioning in this paradigm, mice exhibit freezing behavior in response to the tone stimulus, and flight responses during the white noise. This conditioning model can be applied to the study of rapid and flexible transitions between behavioral responses necessary for survival.


Asunto(s)
Conducta Animal , Condicionamiento Clásico/fisiología , Reacción de Fuga/fisiología , Miedo/fisiología , Reacción Cataléptica de Congelación/fisiología , Animales , Extinción Psicológica , Femenino , Congelación , Masculino , Memoria/fisiología , Ratones Endogámicos C57BL , Grabación en Video
14.
Nat Commun ; 12(1): 628, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504795

RESUMEN

Consolidated memory can be preserved or updated depending on the environmental change. Although such conflicting regulation may happen during memory updating, the flexibility of memory updating may have already been determined in the initial memory consolidation process. Here, we explored the gating mechanism for activity-dependent transcription in memory consolidation, which is unexpectedly linked to the later memory updating in Drosophila. Through proteomic analysis, we discovered that the compositional change in the transcriptional repressor, which contains the histone deacetylase Rpd3 and CoRest, acts as the gating mechanism that opens and closes the time window for activity-dependent transcription. Opening the gate through the compositional change in Rpd3/CoRest is required for memory consolidation, but closing the gate through Rpd3/CoRest is significant to limit future memory updating. Our data indicate that the flexibility of memory updating is determined through the initial activity-dependent transcription, providing a mechanism involved in defining memory state.


Asunto(s)
Proteínas Co-Represoras/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Histona Desacetilasa 1/metabolismo , Memoria/fisiología , Transcripción Genética , Acetilación , Animales , Conducta Animal , Encéfalo/fisiología , Sitios Genéticos , Cuerpos Pedunculados/inervación , Unión Proteica , Mapeo de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , ARN Mensajero/genética , ARN Mensajero/metabolismo
15.
Rev. neurol. (Ed. impr.) ; 72(2): 35-42, 16 ene., 2021. graf, tab
Artículo en Español | IBECS | ID: ibc-199582

RESUMEN

INTRODUCCIÓN: El test de aprendizaje verbal de Hopkins revisado (HVLT-R) se creó originalmente con el objetivo de proporcionar un test de aprendizaje y memoria verbal corto y con seis versiones paralelas que permitieran su readministración. OBJETIVO: Obtener datos normativos y estandarizados para el HVLT-R adaptado a las características sociodemográficas de la población española actual. Sujetos y métodos: El estudio se enmarca dentro del proyecto Normacog, para el cual se evaluó a 700 participantes (rango de edad: 18-90 años). Se analizó el efecto de la edad, el nivel educativo y el sexo sobre el rendimiento del HVLT-R, y se crearon los percentiles y las puntuaciones escalares ajustadas por edad y nivel educativo. RESULTADOS: Se observó un efecto significativo de la edad y el nivel educativo sobre las variables analizadas del test, que explicaba entre el 15 y el 29% de la varianza (ensayo 1, recuerdo total, ensayo 4, índice de discriminación). Como era de esperar, a mayor edad y menor nivel educativo, el rendimiento en el HVLT-R fue menor en todas las variables analizadas. Sin embargo, el sexo presentó un efecto significativo únicamente en las variables ensayo 1, recuerdo total e índice de discriminación. CONCLUSIÓN: Este estudio presenta baremos estandarizados y normalizados para el HVLT-R para población española, y ofrece normas actuales para los clínicos e investigadores. Los resultados confirman la influencia de la edad y la educación en todos los indicadores del test, por lo que se aportan datos que permiten corregir el HVLT-R teniendo en cuenta dichas características


INTRODUCTION: The Hopkins Verbal Learning Test-revised (HVLT-R) was originally created with the objective of providing a short verbal memory and learning test with six alternative forms that allow the re-administration. AIM: To obtain normative and standardized data for the HVLT-R taking into account the sociodemographic characteristics of the current Spanish population. SUBJECTS AND METHODS: The study is part of the Normacog Project. Seven hundred participants (18 to 90 years old) were assessed. The effect of age, level of education and gender on the performance of HVLT-R were analyzed, and percentiles and scalar scores adjusted by age and level of education were created. RESULTS: A significant effect of age and educational level on the analyzed variables of the test was observed, explaining from 15% to 29% of the variance (trial 1, total recall, trial 4, discrimination index). As expected, the older and less educated obtained lower performance in all the analyzed variables of the HVLT-R. However, sex only had a significant effect on the variables trial 1, total recall and discrimination index. CONCLUSION. This study provides standardized and normalized data for the HVLT-R for the Spanish population, offering current norms to clinicians and researchers. The results confirm the influence of age and level of education on all the indicators of the test, so normative data are provided to correct the HVLT-R taking into account these characteristics


Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Aprendizaje Verbal/fisiología , Evaluación Educacional/normas , Disfunción Cognitiva/terapia , Memoria/fisiología , Pruebas Neuropsicológicas/normas , Escolaridad , España , Estándares de Referencia , Análisis Estadístico , Análisis de Varianza , Recuerdo Mental/fisiología
16.
Nature ; 590(7847): 612-617, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33361813

RESUMEN

In the adult hippocampus, synapses are constantly formed and eliminated1,2. However, the exact function of synapse elimination in the adult brain, and how it is regulated, are largely unknown. Here we show that astrocytic phagocytosis3 is important for maintaining proper hippocampal synaptic connectivity and plasticity. By using fluorescent phagocytosis reporters, we find that excitatory and inhibitory synapses are eliminated by glial phagocytosis in the CA1 region of the adult mouse hippocampus. Unexpectedly, we found that astrocytes have a major role in the neuronal activity-dependent elimination of excitatory synapses. Furthermore, mice in which astrocytes lack the phagocytic receptor MEGF10 show a reduction in the elimination of excitatory synapses; as a result, excessive but functionally impaired synapses accumulate. Finally, Megf10-knockout mice show defective long-term synaptic plasticity and impaired formation of hippocampal memories. Together, our data provide strong evidence that astrocytes eliminate unnecessary excitatory synaptic connections in the adult hippocampus through MEGF10, and that this astrocytic function is crucial for maintaining circuit connectivity and thereby supporting cognitive function.


Asunto(s)
Envejecimiento , Astrocitos/citología , Región CA1 Hipocampal/citología , Homeostasis , Vías Nerviosas , Fagocitosis , Sinapsis/metabolismo , Animales , Potenciales Postsinápticos Excitadores , Femenino , Potenciales Postsinápticos Inhibidores , Masculino , Proteínas de la Membrana/metabolismo , Memoria/fisiología , Ratones , Plasticidad Neuronal/fisiología
17.
J Neurosci ; 41(6): 1191-1206, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33328293

RESUMEN

The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of Tiam1 in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG granule cell dendrites and synapses develop normally in Tiam1 KO mice, resembling WT mice at postnatal day 21 (P21), but fail to stabilize, leading to dendrite and synapse loss by P42. These results indicate that Tiam1 promotes DG granule cell dendrite and synapse stabilization late in development. Tiam1 loss also increases the survival, but not the production, of adult-born DG granule cells, possibly because of greater circuit integration as a result of decreased competition with mature granule cells for synaptic inputs. Strikingly, both male and female mice lacking Tiam1 exhibit enhanced contextual fear memory and context discrimination. Together, these results suggest that Tiam1 is a key regulator of DG granule cell stabilization and function within hippocampal circuits. Moreover, based on the enhanced memory phenotype of Tiam1 KO mice, Tiam1 may be a potential target for the treatment of disorders involving memory impairments.SIGNIFICANCE STATEMENT The dentate gyrus (DG) is important for learning, memory, pattern separation, and spatial navigation, and its dysfunction is associated with neuropsychiatric disorders. However, the molecular mechanisms controlling DG formation and function remain elusive. By characterizing mice lacking the Rac-GEF Tiam1, we demonstrate that Tiam1 promotes the stabilization of DG granule cell dendritic arbors, spines, and synapses, whereas it restricts the survival of adult-born DG granule cells, which compete with mature granule cells for synaptic integration. Notably, mice lacking Tiam1 also exhibit enhanced contextual fear memory and context discrimination. These findings establish Tiam1 as an essential regulator of DG granule cell development, and identify it as a possible therapeutic target for memory enhancement.


Asunto(s)
Dendritas/metabolismo , Giro Dentado/metabolismo , Memoria/fisiología , Neurogénesis/fisiología , Sinapsis/metabolismo , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/deficiencia , Animales , Dendritas/genética , Giro Dentado/citología , Femenino , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Sinapsis/genética , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/genética
18.
Neurosci Lett ; 743: 135555, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33352288

RESUMEN

Stress enhances cocaine craving. We recently reported that acute restraint stress increases cocaine conditioned place preference (CPP) in mice; however, the underlying mechanisms remain unclear. This study aimed to examine the role of serotonergic transmission in the medial prefrontal cortex (mPFC) in cocaine CPP enhancement by acute restraint stress, which increases extracellular serotonin (5-HT) levels in the mPFC. Intra-mPFC infusion of the selective serotonin reuptake inhibitor (S)-citalopram prior to the test session significantly increased the cocaine CPP score under non-stressed conditions. This is indicative of the substantial role of increased mPFC 5-HT levels in cocaine CPP enhancement. Moreover, intra-mPFC and systemic administration of the 5-HT1A receptor antagonist WAY100635 immediately before restraint stress exposure significantly attenuated stress-induced cocaine CPP enhancement. Our findings suggest that enhanced serotonergic transmission via 5-HT1A receptors in the mPFC is involved in acute stress-induced augmentation of rewarding memory of cocaine; moreover, the 5-HT1A receptor could be a therapeutic target for stress-induced cocaine craving.


Asunto(s)
Cocaína/administración & dosificación , Memoria/fisiología , Corteza Prefrontal/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Recompensa , Estrés Psicológico/metabolismo , Animales , Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/metabolismo , Conducta Adictiva/psicología , Inhibidores de Captación de Dopamina/administración & dosificación , Infusiones Intraventriculares , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Piperazinas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Piridinas/administración & dosificación , Restricción Física/efectos adversos , Restricción Física/psicología , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/administración & dosificación , Estrés Psicológico/psicología
19.
J Neurosci ; 41(7): 1505-1515, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33310755

RESUMEN

Integrating information across different senses is a central feature of human perception. Previous research suggests that multisensory integration is shaped by a context-dependent and largely adaptive interplay between stimulus-driven bottom-up and top-down endogenous influences. One critical question concerns the extent to which this interplay is sensitive to the amount of available cognitive resources. In the present study, we investigated the influence of limited cognitive resources on audiovisual integration by measuring high-density electroencephalography (EEG) in healthy participants performing the sound-induced flash illusion (SIFI) and a verbal n-back task (0-back, low load and 2-back, high load) in a dual-task design. In the SIFI, the integration of a flash with two rapid beeps can induce the illusory perception of two flashes. We found that high compared with low load increased illusion susceptibility and modulated neural oscillations underlying illusion-related crossmodal interactions. Illusion perception under high load was associated with reduced early ß power (18-26 Hz, ∼70 ms) in auditory and motor areas, presumably reflecting an early mismatch signal and subsequent top-down influences including increased frontal θ power (7-9 Hz, ∼120 ms) in mid-anterior cingulate cortex (ACC) and a later ß power suppression (13-22 Hz, ∼350 ms) in prefrontal and auditory cortex. Our study demonstrates that integrative crossmodal interactions underlying the SIFI are sensitive to the amount of available cognitive resources and that multisensory integration engages top-down θ and ß oscillations when cognitive resources are scarce.SIGNIFICANCE STATEMENT The integration of information across multiple senses, a remarkable ability of our perceptual system, is influenced by multiple context-related factors, the role of which is highly debated. It is, for instance, poorly understood how available cognitive resources influence crossmodal interactions during multisensory integration. We addressed this question using the sound-induced flash illusion (SIFI), a phenomenon in which the integration of two rapid beeps together with a flash induces the illusion of a second flash. Replicating our previous work, we demonstrate that depletion of cognitive resources through a working memory (WM) task increases the perception of the illusion. With respect to the underlying neural processes, we show that when available resources are limited, multisensory integration engages top-down θ and ß oscillations.


Asunto(s)
Memoria/fisiología , Neuronas/fisiología , Percepción/fisiología , Sensación/fisiología , Estimulación Acústica , Adulto , Corteza Auditiva/fisiología , Percepción Auditiva/fisiología , Ritmo beta/fisiología , Electroencefalografía , Femenino , Humanos , Ilusiones , Masculino , Memoria a Corto Plazo/fisiología , Estimulación Luminosa , Corteza Prefrontal/fisiología , Tiempo de Reacción/fisiología , Ritmo Teta/fisiología , Percepción Visual/fisiología , Adulto Joven
20.
Neural Netw ; 135: 38-54, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33341513

RESUMEN

The ability of artificial agents to increment their capabilities when confronted with new data is an open challenge in artificial intelligence. The main challenge faced in such cases is catastrophic forgetting, i.e., the tendency of neural networks to underfit past data when new ones are ingested. A first group of approaches tackles forgetting by increasing deep model capacity to accommodate new knowledge. A second type of approaches fix the deep model size and introduce a mechanism whose objective is to ensure a good compromise between stability and plasticity of the model. While the first type of algorithms were compared thoroughly, this is not the case for methods which exploit a fixed size model. Here, we focus on the latter, place them in a common conceptual and experimental framework and propose the following contributions: (1) define six desirable properties of incremental learning algorithms and analyze them according to these properties, (2) introduce a unified formalization of the class-incremental learning problem, (3) propose a common evaluation framework which is more thorough than existing ones in terms of number of datasets, size of datasets, size of bounded memory and number of incremental states, (4) investigate the usefulness of herding for past exemplars selection, (5) provide experimental evidence that it is possible to obtain competitive performance without the use of knowledge distillation to tackle catastrophic forgetting and (6) facilitate reproducibility by integrating all tested methods in a common open-source repository. The main experimental finding is that none of the existing algorithms achieves the best results in all evaluated settings. Important differences arise notably if a bounded memory of past classes is allowed or not.


Asunto(s)
Algoritmos , Inteligencia Artificial , Redes Neurales de la Computación , Desempeño Psicomotor , Percepción Visual , Inteligencia Artificial/tendencias , Humanos , Memoria/fisiología , Desempeño Psicomotor/fisiología , Reproducibilidad de los Resultados , Percepción Visual/fisiología
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