RESUMEN
Older adults experience deficits in working memory (WM) that are acutely exacerbated by the presence of distracting information. Human neurophysiological studies have revealed that these changes are accompanied by a diminished ability to suppress visual cortical activity associated with task-irrelevant information. Although this is often attributed to deficits in top-down control from a prefrontal cortical source, this has not yet been directly demonstrated. Here we evaluate the neural basis of distraction's negative impact on WM and the impairment in neural suppression in older adults by performing structural and functional MRIs while older participants engage in tasks that require remembering relevant visual stimuli in the context of overlapping irrelevant stimuli. Analysis supports both an age-related distraction effect and neural suppression deficit, and extends our understanding by revealing an alteration in functional connectivity between visual cortices and a region in the default network, the medial prefrontal cortex (mPFC). Moreover, within the older population, the magnitude of WM distractibility and neural suppression are both associated with individual differences in cortical volume and activity of the mPFC, as well as its associated white-matter tracts.
Asunto(s)
Envejecimiento/fisiología , Corteza Prefrontal/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria a Corto Plazo , Persona de Mediana Edad , Corteza Prefrontal/diagnóstico por imagen , Radiografía , Tiempo de Reacción , Corteza Visual/diagnóstico por imagen , Corteza Visual/fisiología , Adulto JovenRESUMEN
Alpha band (8-12 Hz) phase dynamics in the visual cortex are thought to reflect fluctuations in cortical excitability that influences perceptual processing. As such, visual stimuli are better detected when their onset is concurrent with specific phases of the alpha cycle. However, it is unclear whether alpha phase differentially influences cognitive performance at specific times relative to stimulus onset (i.e., is the influence of phase maximal before, at, or after stimulus onset?). To address this, participants performed a delayed-recognition, working memory (WM) task for visual motion direction during two separate visits. The first visit utilized functional magnetic resonance (fMRI) imaging to identify neural regions associated with task performance. Replicating previous studies, fMRI data showed engagement of visual cortical area V5, as well as a prefrontal cortical region, the inferior frontal junction (IFJ). During the second visit, transcranial magnetic stimulation (TMS) was applied separately to both the right IFJ and right V5 (with the vertex as a control region) while electroencephalography (EEG) was simultaneously recorded. During each trial, a single pulse of TMS (spTMS) was applied at one of six time points (-200, -100, -50, 0, 80, 160 ms) relative to the encoded stimulus onset. Results demonstrated a relationship between the phase of the posterior alpha signal prior to stimulus encoding and subsequent response times to the memory probe two seconds later. Specifically, spTMS to V5, and not the IFJ or vertex, yielded faster response times, indicating improved WM performance, when delivered during the peak, compared to the trough, of the alpha cycle, but only when spTMS was applied 100 ms prior to stimulus onset. These faster responses to the probe correlated with decreased early event related potential (ERP) amplitudes (i.e., P1) to the probe stimuli. Moreover, participants that were least affected by spTMS exhibited greater functional connectivity between V5 and fronto-parietal regions. These results suggest that posterior alpha phase indexes a critical time period for motion processing in the context of WM encoding goals, which occurs in anticipation of stimulus onset.
Asunto(s)
Ritmo alfa/fisiología , Anticipación Psicológica/fisiología , Encéfalo/fisiología , Memoria a Corto Plazo/fisiología , Percepción Visual/fisiología , Adulto , Mapeo Encefálico , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Reconocimiento en Psicología/fisiología , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
Despite the human brain's ability to rapidly reorganize neuronal activity patterns in response to interactions with the environment (e.g., learning), it remains unclear whether compensatory mechanisms occur, on a similar time scale, in response to exogenous cortical perturbations. To investigate this, we disrupted normal neural function via repetitive transcranial magnetic stimulation and assessed, using fMRI, activity changes associated with performance on a working memory task. Although transcranial magnetic stimulation disrupted neural activity in task-related brain regions, performance was not affected. Critically, another brain region not previously engaged by the task was recruited to uphold memory performance. Thus, functional reorganization of cortical activity can occur within minutes of neural disruption to maintain cognitive abilities.
Asunto(s)
Corteza Cerebral/fisiología , Plasticidad Neuronal/fisiología , Adulto , Mapeo Encefálico , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Aprendizaje/fisiología , Imagen por Resonancia Magnética , Masculino , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
Learning to fear and avoid life-threatening stimuli are critical survival skills but are maladaptive when they persist in the absence of a direct threat. Thus, it is important to detect when a situation is safe and to increase behaviors leading to naturally rewarding actions, such as feeding and mating. It is unclear how the brain distinguishes between dangerous and safe situations. Here, we present a novel protocol designed to investigate the processing of cues that predict danger, safety, or reward (sucrose). In vivo single unit recordings were obtained in the basal amygdala of freely behaving rats undergoing simultaneous reward, fear, and safety conditioning. We observed a population of neurons that did not respond to a Fear Cue but did change their firing rate during the combined presentation of a fear cue simultaneous with a second, safety, cue; this combination of Fear + Safety Cues signified "no shock." This neural population consisted of two subpopulations: neurons that responded to the Fear + Safety Cue but not the Fear or Reward Cue ("safety" neurons), and neurons that responded to the Fear + Safety and Reward Cue but not the Fear Cue ("safety + reward" neurons). These data demonstrate the presence of neurons in the basal amygdala that are selectively responsive to Safety Cues. Furthermore, these data suggest that safety and reward learning use overlapping mechanisms in the basal amygdala.
Asunto(s)
Amígdala del Cerebelo/fisiología , Reacción de Prevención/fisiología , Miedo , Neuronas/fisiología , Recompensa , Estimulación Acústica , Potenciales de Acción/fisiología , Amígdala del Cerebelo/citología , Análisis de Varianza , Animales , Señales (Psicología) , Electrochoque/efectos adversos , Preferencias Alimentarias/fisiología , Masculino , Neuronas/clasificación , Ratas , Ratas Long-Evans , Tiempo de Reacción/fisiologíaRESUMEN
The relationship between top-down enhancement and suppression of sensory cortical activity and large-scale neural networks remains unclear. Functional connectivity analysis of human functional magnetic resonance imaging data revealed that visual cortical areas that selectively process relevant information are functionally connected with the frontal-parietal network, whereas those that process irrelevant information are simultaneously coupled with the default network. This indicates that sensory cortical regions are differentially and dynamically coupled with distinct networks on the basis of task goals.
Asunto(s)
Mapeo Encefálico , Lóbulo Frontal/fisiología , Objetivos , Lóbulo Parietal/fisiología , Corteza Visual/fisiología , Adolescente , Adulto , Análisis de Varianza , Femenino , Lóbulo Frontal/irrigación sanguínea , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Memoria a Corto Plazo/fisiología , Neurología/métodos , Oxígeno/sangre , Lóbulo Parietal/irrigación sanguínea , Reconocimiento Visual de Modelos/fisiología , Estimulación Luminosa/métodos , Tiempo de Reacción , Factores de Tiempo , Corteza Visual/irrigación sanguínea , Vías Visuales/irrigación sanguínea , Vías Visuales/fisiología , Adulto JovenRESUMEN
Selective attention confers a behavioral benefit on both perceptual and working memory (WM) performance, often attributed to top-down modulation of sensory neural processing. However, the direct relationship between early activity modulation in sensory cortices during selective encoding and subsequent WM performance has not been established. To explore the influence of selective attention on WM recognition, we used electroencephalography to study the temporal dynamics of top-down modulation in a selective, delayed-recognition paradigm. Participants were presented with overlapped, "double-exposed" images of faces and natural scenes, and were instructed to either remember the face or the scene while simultaneously ignoring the other stimulus. Here, we present evidence that the degree to which participants modulate the early P100 (97-129 msec) event-related potential during selective stimulus encoding significantly correlates with their subsequent WM recognition. These results contribute to our evolving understanding of the mechanistic overlap between attention and memory.
Asunto(s)
Atención/fisiología , Corteza Cerebral/fisiología , Memoria a Corto Plazo/fisiología , Reconocimiento en Psicología/fisiología , Vías Visuales/fisiología , Percepción Visual/fisiología , Adolescente , Adulto , Análisis de Varianza , Mapeo Encefálico , Electroencefalografía , Potenciales Evocados Visuales/fisiología , Femenino , Humanos , Masculino , Estimulación Luminosa , Desempeño Psicomotor/fisiología , Tiempo de Reacción/fisiología , Procesamiento de Señales Asistido por ComputadorRESUMEN
Biochemical evidence suggesting that the predominant form of Mediator in the yeast Saccharomyces cerevisiae might be one in which the complex is associated with RNA polymerase II to form a holoenzyme has led to the proposition of a holoenzyme-based model for transcription initiation. We report that polymerase-free Mediator, isolated early on during a whole-cell extract fractionation protocol, is in fact the most abundant form of the Mediator complex. The existence of free Mediator would make possible independent recruitment of Mediator and RNA polymerase II to the pre-initiation complex. This is in agreement with reports from in vivo studies of time and spatial independence of Mediator and RNA polymerase II promoter interaction, with current models of pre-initiation complex structure in which promoter DNA upstream of the transcription start site is positioned between Mediator and polymerase, and with the proposed role of Mediator as the major component of the Scaffold complex involved in transcription reinitiation.
Asunto(s)
Regulación Fúngica de la Expresión Génica , ARN Polimerasa II/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transcripción Genética , Fraccionamiento Celular , Estabilidad de Enzimas , Sustancias Macromoleculares , Modelos Moleculares , Regiones Promotoras Genéticas , Estructura Cuaternaria de Proteína , ARN Polimerasa II/genética , ARN Polimerasa II/aislamiento & purificación , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/aislamiento & purificaciónRESUMEN
Mediator, a macromolecular complex comprising approximately 20 different protein components, is largely responsible for the tight control of transcription that underpins cell development, differentiation, and maintenance in eukaryotes from yeast to human. In the past five years, macromolecular electron microscopy has been used to characterize the structure of Mediator, and of the complexes it forms with other components of the transcription machinery. The results reveal how Mediator interacts with RNA polymerase II, and suggest that regulatory information could be conveyed through changes in Mediator conformation that would influence the transcription initiation process.
Asunto(s)
Células Eucariotas , Estructura Cuaternaria de Proteína , Subunidades de Proteína/química , Animales , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Regulación de la Expresión Génica , Humanos , Modelos Genéticos , Complejos Multiproteicos/química , Subunidades de Proteína/metabolismo , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
De novo synthesis of fatty acids in the cytosol of animal cells is carried out by the multifunctional, homodimeric fatty acid synthase (FAS). Cryo-EM analysis of single FAS particles imaged under conditions that limit conformational variability, combined with gold labeling of the N termini and structural analysis of the FAS monomers, reveals two coiled monomers in an overlapping arrangement. Comparison of dimeric FAS structures related to different steps in the fatty acid synthesis process indicates that only limited local rearrangements are required for catalytic interaction among different functional domains. Monomer coiling probably contributes to FAS efficiency and provides a structural explanation for the reported activity of a FAS monomer dimerized to a catalytically inactive partner. The new FAS structure provides a new paradigm for understanding the architecture of FAS and the related modular polyketide synthases.