Neuronal activity in posterior parietal cortex area LIP is not sufficient for saccadic eye movement production.

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.

Diabetes Impaired Ischemia-Induced PDGF (Platelet-Derived Growth Factor) Signaling Actions and Vessel Formation Through the Activation of Scr Homology 2-Containing Phosphatase-1.

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.

The unknown but knowable relationship between Presaccadic Accumulation of activity and Saccade initiation.

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.

Breast cancer mammospheres secrete Adrenomedullin to induce lipolysis and browning of adjacent adipocytes.

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.

Resveratrol and HIV-protease inhibitors control UCP1 expression through opposite effects on p38 MAPK phosphorylation in human adipocytes.

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.

Hierarchical recruitment of competition alleviates working memory overload in a frontoparietal model.

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.

A consensus guide to capturing the ability to inhibit actions and impulsive behaviors in the stop-signal task.

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.

Slot-like capacity and resource-like coding in a neural model of multiple-item working memory.

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.

Forty Years After Hearing Lips and Seeing Voices: the McGurk Effect Revisited.

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.

Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors.

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.

Contextual response time adaptation in the countermanding performance of rats.

Humans and non-human primates are known to lengthen their response time (RT) to a go signal when they occasionally must cancel their responses following a stop signal in a countermanding task as well as to adjust their RT adaptively on a trial-by-trial basis. Less is clear regarding the adaptive RT adjustments in the countermanding performance of rodents. To investigate this question, male Wistar rats (N=12) were trained with food reward to press a lever directly below an illuminated light (go signal), but to countermand the lever press subsequent to a tone (stop signal) presented infrequently (25% of trials) at variable delays. Rats were then tested in a standard responding task (0% stop trials) or a countermanding task with a 10-s or 1-s TO interval following errors. Rats exhibited significant RT lengthening in the countermanding task, compared with the standard responding task, and RT shortening following consecutive correct go trials. They also show RT lengthening following both error trials in the standard responding task and unrewarded, non-canceled stop trials in the countermanding task. RT lengthening following erroneous stop trials was observed in sessions with a 10-s TO interval, but not with a 1-s TO interval. Analyses of RT distributions suggest that RT lengthening results largely from reduced sensitivity to the go signal, but also from reduced readiness. These findings indicate that rats exert control in the countermanding task by lengthening RT in anticipation of stop trials to avoid long, unrewarded TO intervals.

Lifespan Changes in the Countermanding Performance of Young and Middle Aged Adult Rats.

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.

Spatial Frequency Requirements and Gaze Strategy in Visual-Only and Audiovisual Speech Perception.

PURPOSE: The aim of this article is to examine the effects of visual image degradation on performance and gaze behavior in audiovisual and visual-only speech perception tasks. METHOD: We presented vowel-consonant-vowel utterances visually filtered at a range of frequencies in visual-only, audiovisual congruent, and audiovisual incongruent conditions (Experiment 1; N = 66). In Experiment 2 (N = 20), participants performed a visual-only speech perception task and in Experiment 3 (N = 20) an audiovisual task while having their gaze behavior monitored using eye-tracking equipment. RESULTS: In the visual-only condition, increasing image resolution led to monotonic increases in performance, and proficient speechreaders were more affected by the removal of high spatial information than were poor speechreaders. The McGurk effect also increased with increasing visual resolution, although it was less affected by the removal of high-frequency information. Observers tended to fixate on the mouth more in visual-only perception, but gaze toward the mouth did not correlate with accuracy of silent speechreading or the magnitude of the McGurk effect. CONCLUSIONS: The results suggest that individual differences in silent speechreading and the McGurk effect are not related. This conclusion is supported by differential influences of high-resolution visual information on the 2 tasks and differences in the pattern of gaze.

Methylphenidate does not enhance visual working memory but benefits motivation in macaque monkeys.

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.

High visual resolution matters in audiovisual speech perception, but only for some.

The basis for individual differences in the degree to which visual speech input enhances comprehension of acoustically degraded speech is largely unknown. Previous research indicates that fine facial detail is not critical for visual enhancement when auditory information is available; however, these studies did not examine individual differences in ability to make use of fine facial detail in relation to audiovisual speech perception ability. Here, we compare participants based on their ability to benefit from visual speech information in the presence of an auditory signal degraded with noise, modulating the resolution of the visual signal through low-pass spatial frequency filtering and monitoring gaze behavior. Participants who benefited most from the addition of visual information (high visual gain) were more adversely affected by the removal of high spatial frequency information, compared to participants with low visual gain, for materials with both poor and rich contextual cues (i.e., words and sentences, respectively). Differences as a function of gaze behavior between participants with the highest and lowest visual gains were observed only for words, with participants with the highest visual gain fixating longer on the mouth region. Our results indicate that the individual variance in audiovisual speech in noise performance can be accounted for, in part, by better use of fine facial detail information extracted from the visual signal and increased fixation on mouth regions for short stimuli. Thus, for some, audiovisual speech perception may suffer when the visual input (in addition to the auditory signal) is less than perfect.

PKC-ß activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis.

AIMS: Clinical observations showed a correlation between accelerated atherosclerosis in diabetes and high plasmatic level of IL-18, a pro-inflammatory cytokine. IL-18 enhances the production of inflammatory cytokines and cellular adhesion molecules contributing to atherosclerotic plaque formation and instability. Previous studies indicated that protein kinase C (PKC)-ß inhibition prevented macrophage-induced cytokine expression involved in diabetic (DM) atherosclerotic plaque development. However, the role of PKC-ß activation on IL-18/IL-18-binding protein (IL-18BP) pathway causing endothelial dysfunction and monocyte adhesion in diabetes has never been explored. METHODS AND RESULTS: Apoe(-/-) mice were rendered DM and fed with western diet containing ruboxistaurin (RBX), a PKC-ß inhibitor. After 20 weeks, atherosclerotic plaque composition was quantified. Compared with non-diabetic, DM mice exhibited elevated atherosclerotic plaque formation, cholestoryl ester content and macrophage infiltration, as well as reduced IL-18BP expression in the aorta which was prevented with RBX treatment. Endothelial cells (ECs) and macrophages were exposed to normal or high glucose (HG) levels with or without palmitate and recombinant IL-18 for 24 h. The combined HG and palmitate condition was required to increase IL-18 expression and secretion in macrophages, while it reduced IL-18BP expression in EC causing up-regulation of the vascular cell adhesion molecule (VCAM)-1 and monocyte adhesion. Elevated VCAM-1 expression and monocyte adherence were prevented by siRNA, RBX, and IL-18 neutralizing antibody. CONCLUSION: Our study unrevealed a new mechanism by which PKC-ß activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.

Predictive saccade target selection in superior colliculus during visual search.

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.

PKCδ impaired vessel formation and angiogenic factor expression in diabetic ischemic limbs.

Decreased collateral vessel formation in diabetic peripheral limbs is characterized by abnormalities of the angiogenic response to ischemia. Hyperglycemia is known to activate protein kinase C (PKC), affecting the expression and activity of growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The current study investigates the role of PKCδ in diabetes-induced poor collateral vessel formation and inhibition of angiogenic factors expression and actions. Ischemic adductor muscles of diabetic Prkcd(+/+) mice exhibited reduced blood reperfusion, vascular density, and number of small vessels compared with nondiabetic Prkcd(+/+) mice. By contrast, diabetic Prkcd(-/-) mice showed significant increased blood flow, capillary density, and number of capillaries. Although expression of various PKC isoforms was unchanged, activation of PKCδ was increased in diabetic Prkcd(+/+) mice. VEGF and PDGF mRNA and protein expression were decreased in the muscles of diabetic Prkcd(+/+) mice and were normalized in diabetic Prkcd(-/-) mice. Furthermore, phosphorylation of VEGF receptor 2 (VEGFR2) and PDGF receptor-ß (PDGFR-ß) were blunted in diabetic Prkcd(+/+) mice but elevated in diabetic Prkcd(-/-) mice. The inhibition of VEGFR2 and PDGFR-ß activity was associated with increased SHP-1 expression. In conclusion, our data have uncovered the mechanisms by which PKCδ activation induced poor collateral vessel formation, offering potential novel targets to regulate angiogenesis therapeutically in diabetic patients.

Neural basis of adaptive response time adjustment during saccade countermanding.

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.

Investigating the role of the superior colliculus in active vision with the visual search paradigm.

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.