RESUMEN
Objective: Critical limb ischemia is a major complication of diabetes characterized by insufficient collateral vessel development and proper growth factor signaling unresponsiveness. Although mainly deactivated by hypoxia, phosphatases are important players in the deregulation of proangiogenetic pathways. Previously, SHP-1 (Scr homology 2-containing phosphatase-1) was found to be associated with the downregulation of growth factor actions in the diabetic muscle. Thus, we aimed to gain further understanding of the impact of SHP-1 on smooth muscle cell (SMC) function under hypoxic and diabetic conditions. Approach and Results: Despite being inactivated under hypoxic conditions, high glucose level exposure sustained SHP-1 phosphatase activity in SMC and increased its interaction with PDGFR (platelet-derived growth factor receptor)-ß, thus reducing PDGF proangiogenic actions. Overexpression of an inactive form of SHP-1 fully restored PDGF-induced proliferation, migration, and signaling pathways in SMC exposed to high glucose and hypoxia. Nondiabetic and diabetic mice with deletion of SHP-1 specifically in SMC were generated. Ligation of the femoral artery was performed, and blood flow was measured for 4 weeks. Blood flow reperfusion, vascular density and maturation, and limb survival were all improved while vascular apoptosis was attenuated in diabetic SMC-specific SHP-1 null mice as compared to diabetic mice. Conclusions: Diabetes and high glucose level exposure maintained SHP-1 activity preventing hypoxia-induced PDGF actions in SMC. Specific deletion of SHP-1 in SMC partially restored blood flow reperfusion in the diabetic ischemic limb. Therefore, local modulation of SHP-1 activity in SMC could represent a potential therapeutic avenue to improve the proangiogenic properties of SMC under ischemia and diabetes.
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Inductores de la Angiogénesis/farmacología , Diabetes Mellitus Experimental/enzimología , Angiopatías Diabéticas/enzimología , Miembro Posterior/irrigación sanguínea , Isquemia/enzimología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Animales , Glucemia/metabolismo , Estudios de Casos y Controles , Bovinos , Hipoxia de la Célula , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/fisiopatología , Activación Enzimática , Humanos , Isquemia/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Transducción de SeñalRESUMEN
The goal of this short review is to call attention to a yawning gap of knowledge that separates two processes essential for saccade production. On the one hand, knowledge about the saccade generation circuitry within the brainstem is detailed and precise - push-pull interactions between gaze-shifting and gaze-holding processes control the time of saccade initiation, which begins when omnipause neurons are inhibited and brainstem burst neurons are excited. On the other hand, knowledge about the cortical and subcortical premotor circuitry accomplishing saccade initiation has crystalized around the concept of stochastic accumulation - the accumulating activity of saccade neurons reaching a fixed value triggers a saccade. Here is the gap: we do not know how the reaching of a threshold by premotor neurons causes the critical pause and burst of brainstem neurons that initiates saccades. Why this problem matters and how it can be addressed will be discussed. Closing the gap would unify two rich but curiously disconnected empirical and theoretical domains.
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Movimientos Sacádicos , Colículos Superiores , Animales , Macaca mulatta , Modelos Neurológicos , NeuronasRESUMEN
Brown and brown-like adipocytes (BBAs) control thermogenesis and are detected in adult humans. They express UCP1, which transforms energy into heat. They appear as promising cells to fight obesity. Deciphering the molecular mechanisms leading to the browning of human white adipocytes or the whitening of BBAs represents a goal to properly and safely control the pathways involved in these processes. Here, we analyzed how drugs endowed with therapeutic potential affect the differentiation of human adipose progenitor-cells into BBAs and/or their phenotype. We showed that HIV-protease inhibitors (PI) reduced UCP1 expression in BBAs modifying their metabolic profile and the mitochondria functionality. Lopinavir (LPV) was more potent than darunavir (DRV), a last PI generation. PPARγ and PGC-1α were decreased in a PI or cell-specific manner, thus altering UCP1's constitutive expression. In addition, LPV altered p38 MAPK phosphorylation, blunting then the ß-adrenergic responses. In contrast, low doses of resveratrol stimulated the activatable expression of UCP1 in a p38 MAPK-dependent manner and counteracted the LPV induced loss of UCP1. This effect was independent of the resveratrol-induced sirtuin-1 expression. Altogether our results uncover how drugs impact crucial components of the networks regulating the expression of the thermogenic signature. They provide important information to control the relevant pathways involved in energy expenditure.
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Adipocitos/efectos de los fármacos , Darunavir/farmacología , Resveratrol/farmacología , Proteína Desacopladora 1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adipocitos/metabolismo , Antioxidantes/farmacología , Línea Celular , Colforsina , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Compuestos Orgánicos/farmacología , Fosforilación , Proteína Desacopladora 1/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: Cancer cells cooperate with cells that compose their environment to promote tumor growth and invasion. Among them, adipocytes provide lipids used as a source of energy by cancer cells and adipokines that contribute to tumor expansion. Mechanisms supporting the dynamic interactions between cancer cells and stromal adipocytes, however, remain unclear. METHODS: We set-up a co-culture model with breast cancer cells grown in 3D as mammospheres and human adipocytes to accurately recapitulate intrinsic features of tumors, such as hypoxia and cancer cell-adipocytes interactions. RESULTS: Herein, we observed that the lipid droplets' size was reduced in adipocytes adjacent to the mammospheres, mimicking adipocyte morphology on histological sections. We showed that the uncoupling protein UCP1 was expressed in adipocytes close to tumor cells on breast cancer histological sections as well as in adipocytes in contact with the mammospheres. Mammospheres produced adrenomedullin (ADM), a multifactorial hypoxia-inducible peptide while ADM receptors were detected in adipocytes. Stimulation of adipocytes with ADM promoted UCP1 expression and increased HSL phosphorylation, which activated lipolysis. Invalidation of ADM in breast cancer cells dramatically reduced UCP1 expression in adipocytes. CONCLUSIONS: Breast tumor cells secreted ADM that modified cancer-associated adipocytes through paracrine signaling, leading to metabolic changes and delipidation. Hence, ADM appears to be crucial in controlling the interactions between cancer cells and adipocytes and represents an excellent target to hinder them.
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Adipocitos/patología , Adrenomedulina/metabolismo , Neoplasias de la Mama/patología , Comunicación Paracrina , Esferoides Celulares/metabolismo , Adipocitos/citología , Mama/citología , Mama/patología , Hipoxia de la Célula , Técnicas de Cocultivo , Femenino , Humanos , Gotas Lipídicas/metabolismo , Lipólisis , Células MCF-7 , Microambiente Tumoral , Proteína Desacopladora 1/metabolismoRESUMEN
The storage limitations of visual working memory have been the subject of intense research interest for several decades, but few studies have systematically investigated the dependence of these limitations on memory load that exceeds our retention abilities. Under this real-world scenario, performance typically declines beyond a critical load among low-performing subjects, a phenomenon known as working memory overload. We used a frontoparietal cortical model to test the hypothesis that high-performing subjects select a manageable number of items for storage, thereby avoiding overload. The model accounts for behavioral and electrophysiological data from high-performing subjects in a parameter regime where competitive encoding in its prefrontal network selects items for storage, interareal projections sustain their representations after stimulus offset, and weak dynamics in its parietal network limit their mutual interference. Violation of these principles accounts for these data among low-performing subjects, implying that poor visual working memory performance reflects poor control over frontoparietal circuitry, making testable predictions for experiments.
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Cognición/fisiología , Memoria a Corto Plazo/fisiología , Modelos Neurológicos , Lóbulo Parietal/fisiología , Corteza Prefrontal/fisiología , Adulto , Femenino , Humanos , Masculino , Transmisión SinápticaRESUMEN
For the past decade, research on the storage limitations of working memory has been dominated by two fundamentally different hypotheses. On the one hand, the contents of working memory may be stored in a limited number of "slots," each with a fixed resolution. On the other hand, any number of items may be stored but with decreasing resolution. These two hypotheses have been invaluable in characterizing the computational structure of working memory, but neither provides a complete account of the available experimental data or speaks to the neural basis of the limitations it characterizes. To address these shortcomings, we simulated a multiple-item working memory task with a cortical network model, the cellular resolution of which allowed us to quantify the coding fidelity of memoranda as a function of memory load, as measured by the discriminability, regularity, and reliability of simulated neural spiking. Our simulations account for a wealth of neural and behavioral data from human and nonhuman primate studies, and they demonstrate that feedback inhibition lowers both capacity and coding fidelity. Because the strength of inhibition scales with the number of items stored by the network, increasing this number progressively lowers fidelity until capacity is reached. Crucially, the model makes specific, testable predictions for neural activity on multiple-item working memory tasks. NEW & NOTEWORTHY Working memory is the ability to keep information in mind and is fundamental to cognition. It is actively debated whether the storage limitations of working memory reflect a small number of storage units (slots) or a decrease in coding resolution as a limited resource is allocated to more items. In a cortical model, we found that slot-like capacity and resource-like neural coding resulted from the same mechanism, offering an integrated explanation for storage limitations.
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Memoria a Corto Plazo , Modelos Neurológicos , Animales , Encéfalo/citología , Encéfalo/fisiología , Excitabilidad Cortical , Haplorrinos , Humanos , Neuronas/fisiologíaRESUMEN
Searching for a visual object naturally involves sequences of gaze fixations, during which the current foveal image is analyzed and the next object to inspect is selected as a saccade target. Fixation durations during such sequences are short, suggesting that saccades may be concurrently processed. Therefore, the selection of the next saccade target may occur before the current saccade target is acquired. To test this hypothesis, we trained four female rhesus monkeys (Macaca mulatta) to perform a multiple-fixation visual conjunction search task. We simultaneously recorded the activity of sensorimotor neurons in the midbrain superior colliculus (SC) in two monkeys. In this task, monkeys made multiple fixations before foveating the target. Fixation durations were significantly shorter than the latency of the initial responses to the search display, with approximately one-quarter being shorter than the shortest response latencies. The time at which SC sensorimotor activity discriminated the target from distracters occurred significantly earlier for the selection of subsequent fixations than for the selection of the first fixation. Target selection during subsequent fixations occurred even before the visual afferent delay in more than half of the neuronal sample, suggesting that the process of selection can encompass at least two future saccade targets. This predictive selection was present even when differences in saccade latencies were taken into account. Altogether, these findings demonstrate how neural representations on the visual salience map are processed in parallel, thus facilitating visual search.
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Atención/fisiología , Conducta de Elección/fisiología , Fijación Ocular/fisiología , Movimientos Sacádicos/fisiología , Colículos Superiores/fisiología , Percepción Visual/fisiología , Potenciales de Acción/fisiología , Animales , Femenino , Macaca mulatta , Neuronas/fisiología , Estimulación Luminosa , Valor Predictivo de las Pruebas , Curva ROC , Tiempo de Reacción , Detección de Señal Psicológica , Colículos Superiores/citologíaRESUMEN
It is widely recognized that the posterior parietal cortex (PPC) plays a role in active exploration with eye movements, arm reaching, and hand grasping. Whether this role is causal in nature is largely unresolved. One region of the PPC appears dedicated to the control of saccadic eye movement-lateral intraparietal (LIP) area. This area LIP possesses direct projections to well-established oculomotor centers and contains neurons with movement-related activity. In this study, we tested whether these neurons are implicated in saccade initiation and production. The movement-related activity of LIP neurons was tested by recording these neurons while monkeys performed a countermanding task. We found that LIP neuronal activity is not different before the execution or the cancelation of commanded saccades and thereby is not sufficient for the initiation and production of saccades. Consistent with the evolutionarily late emergence of the PPC, this finding relegates the role of this PPC area to processes that can regulate but not trigger eye movements.
RESUMEN
Humans and macaque monkeys adjust their response time adaptively in stop-signal (countermanding) tasks, responding slower after stop-signal trials than after control trials with no stop signal. We investigated the neural mechanism underlying this adaptive response time adjustment in macaque monkeys performing a saccade countermanding task. Earlier research showed that movements are initiated when the random accumulation of presaccadic movement-related activity reaches a fixed threshold. We found that a systematic delay in response time after stop-signal trials was accomplished not through a change of threshold, baseline, or accumulation rate, but instead through a change in the time when activity first began to accumulate. The neurons underlying movement initiation have been identified with stochastic accumulator models of response time performance. Therefore, this new result provides surprising new insights into the neural instantiation of stochastic accumulator models and the mechanisms through which executive control can be exerted.
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Potenciales de Acción/fisiología , Adaptación Fisiológica/fisiología , Neuronas/fisiología , Tiempo de Reacción/fisiología , Movimientos Sacádicos/fisiología , Animales , Potenciales Evocados Visuales/fisiología , Fijación Ocular/fisiología , Inhibición Psicológica , Modelos Lineales , Macaca mulatta , Masculino , Modelos Neurológicos , Movimiento , Neuronas/clasificación , Pruebas Neuropsicológicas , Estimulación Luminosa/métodosRESUMEN
The ability of sensory-motor circuits to integrate sensory evidence over time is thought to underlie the process of decision-making in perceptual discrimination. Recent work has suggested that the NMDA receptor contributes to mediating neural activity integration. To test this hypothesis, we trained three female rhesus monkeys (Macaca mulatta) to perform a visual search task, in which they had to make a saccadic eye movement to the location of a target stimulus presented among distracter stimuli of lower luminance. We manipulated NMDA-receptor function by administering an intramuscular injection of the noncompetitive NMDA antagonist ketamine and assessed visual search performance before and after manipulation. Ketamine was found to lengthen response latency in a dose-dependent fashion. Surprisingly, it was also observed that response accuracy was significantly improved when lower doses were administered. These findings suggest that NMDA receptors play a crucial role in the process of decision-making in perceptual discrimination. They also further support the idea that multiple neural representations compete with one another through mutual inhibition, which may explain the speed-accuracy trade-off rule that shapes discrimination behavior: lengthening integration time helps resolve small differences between choice alternatives, thereby improving accuracy.
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Toma de Decisiones/efectos de los fármacos , Ketamina/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Percepción Visual/efectos de los fármacos , Animales , Discriminación en Psicología/efectos de los fármacos , Femenino , Fijación Ocular/efectos de los fármacos , Macaca mulatta , Estimulación Luminosa , Tiempo de Reacción/efectos de los fármacos , Movimientos Sacádicos/efectos de los fármacosRESUMEN
We review here both the evidence that the functional visuomotor organization of the optic tectum is conserved in the primate superior colliculus (SC) and the evidence for the linking proposition that SC discriminating activity instantiates saccade target selection. We also present new data in response to questions that arose from recent SC visual search studies. First, we observed that SC discriminating activity predicts saccade initiation when monkeys perform an unconstrained search for a target defined by either a single visual feature or a conjunction of two features. Quantitative differences between the results in these two search tasks suggest, however, that SC discriminating activity does not only reflect saccade programming. This finding concurs with visual search studies conducted in posterior parietal cortex and the idea that, during natural active vision, visual attention is shifted concomitantly with saccade programming. Second, the analysis of a large neuronal sample recorded during feature search revealed that visual neurons in the superficial layers do possess discriminating activity. In addition, the hypotheses that there are distinct types of SC neurons in the deeper layers and that they are differently involved in saccade target selection were not substantiated. Third, we found that the discriminating quality of single-neuron activity substantially surpasses the ability of the monkeys to discriminate the target from distracters, raising the possibility that saccade target selection is a noisy process. We discuss these new findings in light of the visual search literature and the view that the SC is a visual salience map for orienting eye movements.
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Movimientos Oculares/fisiología , Colículos Superiores/fisiología , Visión Ocular/fisiología , Percepción Visual/fisiología , Animales , Haplorrinos , Neuronas/fisiologíaRESUMEN
A core aspect of working memory is that only a limited amount of information can be held at one time, but the investigations of its underlying neural mechanisms in animal models have been dominated by paradigms requiring the retention of a single memorandum. In humans, the information processing limitations of visual working memory have been studied extensively using a sequential comparison procedure, in which subjects detect a change in a multiple-item array following a retention interval. Here, we adopted this approach to study the working memory ability of the macaque monkey. We trained two female rhesus monkeys (Macaca mulatta) to perform a change detection task, in which they were required to report with a saccadic eye movement which one of several items (two to five colored stimuli) in a array had changed color after a 1-s retention interval. Performance gradually declined as a function of set size but always exceeded chance probability. These results show that monkeys possess sufficient information processing capability to perform a visual working memory task requiring the simultaneous maintenance of mnemonic representations of multiple items and validate this animal model for investigation of the neural mechanisms underlying the temporary retention of more than one memorandum.
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Macaca mulatta/psicología , Memoria a Corto Plazo/fisiología , Procesos Mentales/fisiología , Visión Ocular , Animales , Color , Femenino , Retención en Psicología , Movimientos SacádicosRESUMEN
Flexible behavior depends on the brain's ability to suppress a habitual response or to cancel a planned movement whenever needed. Such inhibitory control has been studied using the countermanding paradigm in which subjects are required to withhold an imminent movement when a stop signal appears infrequently in a fraction of trials. To elucidate the circuit mechanism of inhibitory control of action, we developed a recurrent network model consisting of spiking movement (GO) neurons and fixation (STOP) neurons, based on neurophysiological observations in the frontal eye field and superior colliculus of behaving monkeys. The model places a premium on the network dynamics before the onset of a stop signal, especially the experimentally observed high baseline activity of fixation neurons, which is assumed to be modulated by a persistent top-down control signal, and their synaptic interaction with movement neurons. The model simulated observed neural activity and fit behavioral performance quantitatively. In contrast to a race model in which the STOP process is initiated at the onset of a stop signal, in our model whether a movement will eventually be canceled is determined largely by the proactive top-down control and the stochastic network dynamics, even before the appearance of the stop signal. A prediction about the correlation between the fixation neural activity and the behavioral outcome was verified in the neurophysiological data recorded from behaving monkeys. The proposed mechanism for adjusting control through tonically active neurons that inhibit movement-producing neurons has significant implications for exploring the basis of impulsivity associated with psychiatric disorders.
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Potenciales de Acción/fisiología , Redes Neurales de la Computación , Neuronas/fisiología , Dinámicas no Lineales , Inhibición Proactiva , Animales , Conducta Animal/fisiología , Encéfalo/citología , Simulación por Computador , Fijación Ocular/fisiología , Macaca mulatta , Modelos Neurológicos , Movimiento/fisiología , Inhibición Neural/fisiología , Neuronas/clasificación , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología , Factores de Tiempo , Campos Visuales/fisiología , Vías Visuales/fisiologíaRESUMEN
Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis.
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Consenso , Conducta Impulsiva/fisiología , Inhibición Psicológica , Desempeño Psicomotor/fisiología , Animales , Toma de Decisiones , Función Ejecutiva/fisiología , Humanos , Modelos Animales , Modelos Psicológicos , Pruebas Neuropsicológicas , Tiempo de ReacciónRESUMEN
Since its discovery 40 years ago, the McGurk illusion has been usually cited as a prototypical paradigmatic case of multisensory binding in humans, and has been extensively used in speech perception studies as a proxy measure for audiovisual integration mechanisms. Despite the well-established practice of using the McGurk illusion as a tool for studying the mechanisms underlying audiovisual speech integration, the magnitude of the illusion varies enormously across studies. Furthermore, the processing of McGurk stimuli differs from congruent audiovisual processing at both phenomenological and neural levels. This questions the suitability of this illusion as a tool to quantify the necessary and sufficient conditions under which audiovisual integration occurs in natural conditions. In this paper, we review some of the practical and theoretical issues related to the use of the McGurk illusion as an experimental paradigm. We believe that, without a richer understanding of the mechanisms involved in the processing of the McGurk effect, experimenters should be really cautious when generalizing data generated by McGurk stimuli to matching audiovisual speech events.
RESUMEN
The stop-signal or countermanding task probes the ability to control action by requiring subjects to withhold a planned movement in response to an infrequent stop signal which they do with variable success depending on the delay of the stop signal. We investigated whether performance of humans and macaque monkeys in a saccade countermanding task was influenced by stimulus and performance history. In spite of idiosyncrasies across subjects several trends were evident in both humans and monkeys. Response time decreased after successive trials with no stop signal. Response time increased after successive trials with a stop signal. However, post-error slowing was not observed. Increased response time was observed mainly or only after cancelled (signal inhibit) trials and not after noncancelled (signal respond) trials. These global trends were based on rapid adjustments of response time in response to momentary fluctuations in the fraction of stop signal trials. The effects of trial sequence on the probability of responding were weaker and more idiosyncratic across subjects when stop signal fraction was fixed. However, both response time and probability of responding were influenced strongly by variations in the fraction of stop signal trials. These results indicate that the race model of countermanding performance requires extension to account for these sequential dependencies and provide a basis for physiological studies of executive control of countermanding saccade performance.
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Movimientos Sacádicos/fisiología , Animales , Cognición/fisiología , Fijación Ocular/fisiología , Humanos , Macaca mulatta , Macaca radiata , Masculino , Modelos Neurológicos , Inhibición Neural/fisiología , Estimulación Luminosa/métodos , Desempeño Psicomotor/fisiología , Tiempo de Reacción , Percepción Visual/fisiologíaRESUMEN
Although we know that the process of saccade target selection is reflected in the activity of sensory-motor neurons within saccade executive centers, the description of this process at the neural level has yet to fully account for all selection outcomes. The current study sought to determine how neuronal activity in the intermediate layers of the superior colliculus (SC) determines correct saccade target selection by examining the activity of visuomovement neurons during both correct and error trials of monkeys performing a relatively difficult visual conjunction search task. We found that a stimulus presented in a neuron's response field, but not foveated, was associated with greater activity if it was the search target instead of a distractor, indicating that SC neurons could represent stimulus identity. Nevertheless, activity was greater when a saccade was made to a stimulus than when it was not, further implicating these neurons in selecting the saccade goal. Together with the related observation that, when the target fell in their response fields, SC neurons discharged significantly more if the monkey correctly selected it instead of a distractor, these results suggest that visual stimuli are selected when these neurons reach a critical activation level. Our findings show that the outcome of all visual search trials, regardless of the stimulus being selected, is predicted by SC neuronal activity.
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Atención/fisiología , Objetivos , Neuronas/fisiología , Movimientos Sacádicos/fisiología , Colículos Superiores/fisiología , Percepción Visual/fisiología , Animales , Conducta Animal , Umbral Diferencial , Discriminación en Psicología/fisiología , Femenino , Fóvea Central/fisiología , Macaca mulatta , Estimulación Luminosa/métodos , Detección de Señal Psicológica , Colículos Superiores/citologíaRESUMEN
Maintenance of the adipose tissue requires a proper balance between self-renewal and differentiation of adipose progenitors (AP). Any deregulation leads either to fat overexpansion and obesity or fat loss and consequent lipodystrophies. Depending on the fat pad location, APs and adipocytes are heterogeneous. However, information on the pharmacological sensitivity of distinct APs to drugs known to alter the function of adipose tissue, especially HIV protease inhibitors (PIs) is scant. Here we show that PIs decreased proliferation and clonal expansion of APs, modifying their self-renewal potential. Lopinavir was the most potent PI tested. Decrease in self-renewal was accompanied by a reduced expression of the immediate early response gene IER3, a gene associated with tissue expansion. It was more pronounced in chin-derived APs than in knee-derived APs. Furthermore, lopinavir lowered the activin A-induced ERK1/2 phosphorylation. Expressions of the transcription factor EGR1 and its targets, including INHBA were subsequently altered. Therefore, activin A secretion was reduced leading to a dramatic impairment of APs self-renewal sustained by the activin A autocrine loop. All together, these observations highlight the activin A autocrine loop as a crucial effector to maintain APs self-renewal. Targeting this pathway by HIV-PIs may participate in the induction of unwanted side effects.
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Activinas/antagonistas & inhibidores , Tejido Adiposo/citología , Proliferación Celular/efectos de los fármacos , Inhibidores de la Proteasa del VIH/efectos adversos , Lopinavir/efectos adversos , Células Madre/fisiología , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mapas de Interacción de Proteínas/efectos de los fármacos , Células Madre/efectos de los fármacosRESUMEN
Working memory is a limited-capacity cognitive process that retains relevant information temporarily to guide thoughts and behavior. A large body of work has suggested that catecholamines exert a major modulatory influence on cognition, but there is only equivocal evidence of a direct influence on working memory ability, which would be reflected in a dependence on working memory load. Here we tested the contribution of catecholamines to working memory by administering a wide range of acute oral doses of the dopamine and norepinephrine reuptake inhibitor methylphenidate (MPH, 0.1-9 mg/kg) to three female macaque monkeys (Macaca mulatta), whose working memory ability was measured from their performance in a visual sequential comparison task. This task allows the systematic manipulation of working memory load, and we therefore tested the specific hypothesis that MPH modulates performance in a manner that depends on both dose and memory load. We found no evidence of a dose- or memory load-dependent effect of MPH on performance. In contrast, significant effects on measures of motivation were observed. These findings suggest that an acute increase in catecholamines does not seem to affect the retention of visual information per se. As such, these results help delimit the effects of MPH on cognition.
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Inhibidores de Captación de Dopamina/administración & dosificación , Memoria a Corto Plazo/efectos de los fármacos , Metilfenidato/administración & dosificación , Motivación/efectos de los fármacos , Percepción Visual/efectos de los fármacos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Macaca mulatta , Memoria a Corto Plazo/fisiología , Motivación/fisiología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Percepción Visual/fisiologíaRESUMEN
Inhibitory control can be investigated with the countermanding task, which requires subjects to make a response to a go signal and cancel that response when a stop signal is presented occasionally. Adult humans performing the countermanding task typically exhibit impaired response time (RT), stop signal response time (SSRT) and response accuracy as they get older, but little change in post-error slowing. Rodent models of the countermanding paradigm have been developed recently, yet none have directly examined age-related changes in performance throughout the lifespan. Male Wistar rats (N = 16) were trained to respond to a visual stimulus (go signal) by pressing a lever directly below an illuminated light for food reward, but to countermand the lever press subsequent to a tone (stop signal) that was presented occasionally (25% of trials) at a variable delay. Subjects were tested in 1 h sessions at approximately 7 and 12 months of age with intermittent training in between. Rats demonstrated longer go trial RT, a higher proportion of go trial errors and performed less total trials at 12, compared to 7 months of age. Consistent SSRT and post-error slowing were observed for rats at both ages. These results suggest that the countermanding performance of rats does vary throughout the lifespan, in a manner similar to humans, suggesting that rodents may provide a suitable model for behavioral impairment related to normal aging. These findings also highlight the importance of indicating the age at which rodents are tested in countermanding investigations.