Starvation-resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity.

Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that although surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Furthermore, down-regulation of FATP2 in Drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionarily conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.

Starvation resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity.

Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that while surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Further, down-regulation of FATP2 in drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionary conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.

Ptth regulates lifespan through innate immunity pathway in Drosophila.

The prothoracicotropic hormone (Ptth) is well-known for its important role in controlling insect developmental timing and body size by promoting the biosynthesis and release of ecdysone. However, the role of Ptth in adult physiology is largely unexplored. Here we show that Ptth null mutants (both males and females) show extended lifespan and healthspan, and exhibit increased resistance to oxidative stress. Transcriptomic analysis reveals that age-dependent upregulation of innate immunity pathway is attenuated by Ptth mutants. Intriguingly, we find that Ptth regulates the innate immunity pathway, specifically in fly oenocytes, the homology of mammalian hepatocytes. We further show that oenocyte-specific overexpression of Relish shortens the lifespan, while oenocyte-specific downregulation of ecdysone signaling extends lifespan. Consistently, knocking down torso, the receptor of Ptth in the prothoracic gland also promotes longevity of the flies. Thus, our data reveal a novel function of the insect hormone Ptth in longevity regulation and innate immunity in adult Drosophila.

Phasic alertness boosts representational momentum.

The final location of a moving object is always misremembered in the direction of the object's motion; this occurrence is called representational momentum. Three experiments were conducted to investigate the effects of phasic alertness on representational momentum by presenting a visual or auditory warning cue. In experiment 1, the mouse pointer paradigm was used, and the results showed that external warning cues increased forward displacement. Experiment 2 indicated that the effects of phasic alertness and speed of motion on representational momentum were independent. In experiment 3, the probe paradigm was used, and the results showed that external warning cues increased forward displacement as well as participants' sensitivity to the difference between the target and probe positions. These findings prove that phasic alertness boosts rather than reduces representational momentum. We propose that phasic alertness might influence representational momentum by modulating the process of executive control in the retention interval.

mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila.

High-fat diet (HFD)-induced obesity has become the major risk factor for the development of cardiovascular diseases, but the underlying mechanisms remain poorly understood. Here, we use Drosophila as a model to study the role of mTORC2 in HFD-induced mitochondrial fission and cardiac dysfunction. We find that knockdown of mTORC2 subunit rictor blocks HFD-induced mitochondrial fragmentation and Drp1 recruitment. Knockdown of rictor further impairs cardiac contractile function under HFD treatment. Surprisingly, knockdown of Akt, the major effector of mTORC2, did not affect HFD-induced mitochondrial fission. Similar to mTORC2 inhibition, knockdown of Drp1 blocks HFD-induced mitochondrial fragmentation and induces contractile defects. Furthermore, overexpression of Drp1 restored HFD-induced mitochondrial fragmentation in rictor knockdown flies. Thus, we uncover a novel function of mTORC2 in protecting the heart from HFD treatment through Drp1-dependent mitochondrial fission.

Task compliance predicts suppression-induced forgetting in a large sample.

Suppression-induced forgetting (SIF) refers to a memory impairment resulting from repeated attempts to stop the retrieval of unwanted memory associates. SIF has become established in the literature through a growing number of reports built upon the Think/No-Think (TNT) paradigm. Not all individuals and not all reported experiments yield reliable forgetting, however. Given the reliance on task instructions to motivate participants to suppress target memories, such inconsistencies in SIF may reasonably owe to differences in compliance or expectations as to whether they will again need to retrieve those items (on, say, a final test). We tested these possibilities on a large (N = 497) sample of TNT participants. In addition to successfully replicating SIF, we found that the magnitude of the effect was significantly and negatively correlated with participants' reported compliance during the No-Think trials. This pattern held true on both same- and independent-probe measures of forgetting, as well as when the analysis was conditionalized on initial learning. In contrast, test expectancy was not associated with SIF. Supporting previous intuition and more limited post-hoc examinations, this study provides robust evidence that a lack of compliance with No-Think instructions significantly compromises SIF. As such, it suggests that diminished effects in some studies may owe, at least in part, to non-compliance-a factor that should be carefully tracked and/or controlled. Motivated forgetting is possible, provided that one is sufficiently motivated and capable of following the task instructions.

The Second Annual Symposium of the Midwest Aging Consortium: The Future of Aging Research in the Midwestern United States.

While the average human life span continues to increase, there is little evidence that this is leading to a contemporaneous increase in "healthy years" experienced by our aging population. Consequently, many scientists focus their research on understanding the process of aging and trialing interventions that can promote healthspan. The 2021 Midwest Aging Consortium consensus statement is to develop and further the understanding of aging and age-related disease using the wealth of expertise across universities in the Midwestern United States. This report summarizes the cutting-edge research covered in a virtual symposium held by a consortium of researchers in the Midwestern United States, spanning topics such as senescence biomarkers, serotonin-induced DNA protection, immune system development, multisystem impacts of aging, neural decline following severe infection, the unique transcriptional impact of calorie restriction of different fat depots, the pivotal role of fasting in calorie restriction, the impact of peroxisome dysfunction, and the influence of early life trauma on health. The symposium speakers presented data from studies conducted in a variety of common laboratory animals as well as less-common species, including Caenorhabditis elegans, Drosophila, mice, rhesus macaques, elephants, and humans. The consensus of the symposium speakers is that this consortium highlights the strength of aging research in the Midwestern United States as well as the benefits of a collaborative and diverse approach to geroscience.

Memory Suppression Ability can be Robustly Predicted by the Internetwork Communication of Frontoparietal Control Network.

Memory suppression (MS) is essential for mental well-being. However, no studies have explored how intrinsic resting-state functional connectivity (rs-FC) predicts this ability. Here, we adopted the connectome-based predictive modeling (CPM) based on the resting-state fMRI data to investigate whether and how rs-FC profiles in predefined brain networks (the frontoparietal control networks or FPCN) can predict MS in healthy individuals with 497 participants. The MS ability was assessed by MS-induced forgetting during the think/no-think paradigm. The results showed that FPCN network was especially informative for generating the prediction model for MS. Some regions of FPCN, such as middle frontal gyrus, superior frontal gyrus and inferior parietal lobe were critical in predicting MS. Moreover, functional interplay between FPCN and multiple networks, such as dorsal attention network (DAN), ventral attention network (VAN), default mode network (DMN), the limbic system and subcortical regions, enabled prediction of MS. Crucially, the predictive FPCN networks were stable and specific to MS. These results indicated that FPCN flexibility interacts with other networks to underpin the ability of MS. These would also be beneficial for understanding how compromises in these functional networks may have led to the intrusive thoughts and memories characterized in some mental disorders.

The functional connectome predicts feeling of stress on regular days and during the COVID-19 pandemic.

Although many studies have explored the neural mechanism of the feeling of stress, to date, no effort has been made to establish a model capable of predicting the feeling of stress at the individual level using the resting-state functional connectome. Although individuals may be confronted with multidimensional stressors during the coronavirus disease 2019 (COVID-19) pandemic, their appraisal of the impact and severity of these events might vary. In this study, connectome-based predictive modeling (CPM) with leave-one-out cross-validation was conducted to predict individual perceived stress (PS) from whole-brain functional connectivity data from 817 participants. The results showed that the feeling of stress could be predicted by the interaction between the default model network and salience network, which are involved in emotion regulation and salience attribution, respectively. Key nodes that contributed to the prediction model comprised regions mainly located in the limbic systems and temporal lobe. Critically, the CPM model of PS based on regular days can be generalized to predict individual PS levels during the COVID-19 pandemic, which is a multidimensional, uncontrollable stressful situation. The stability of the results was demonstrated by two independent datasets. The present work not only expands existing knowledge regarding the neural mechanism of PS but also may help identify high-risk individuals in healthy populations.

Behavioral and neural correlates of memory suppression in subthreshold depression.

Many studies have demonstrated that healthy individuals can intentionally control memory. However, little is known about the behavioral and neural mechanisms of memory control in those with subthreshold depression (SD), a highly prevalent condition associated with severe impairments and a significant social burden. In this study, we used functional magnetic resonance imaging (fMRI) and a generalized form of task-dependent psychophysiological interaction (gPPI) analysis during the think/no-think task to examine the brain mechanism of memory suppression in SD participants. The behavioral results revealed that SD participants were unable to suppress negative memories. Neuroimaging data revealed that the SD group showed greater activation than the healthy control (HC) group in the prefrontal gyrus during memory processing. Moreover, gPPI analysis showed that the SD group had significantly lower right hippocampal functional coupling with the dorsolateral prefrontal cortex during negative memory suppression than the HC group. These results indicated that SD participants recruited more frontal control resources for memory suppression because of executive and prefrontal inhibitory dysfunction. However, the abnormal prefrontal-hippocampal inhibitory pathway resulted in a failure of the memory control process when the stimuli were negative. These findings provide some evidence for understanding why SD individuals have inefficient memory control of negative memories.

The Practice Effect on Time-Based Prospective Memory: The Influences of Ongoing Task Difficulty and Delay.

The practice effect on prospective memory refers to the phenomenon that prospective memory performance can improve with behavior training. Some studies have found that event-based prospective memory (EBPM) can benefit from practice. However, only a few studies have focused on the practice effect on time-based prospective memory (TBPM). In the present study, we planned to explore whether the practice effect on TBPM existed and what its processing mechanism was. In Experiment 1, we tested whether the practice effect existed at all under different background task conditions. The results showed that the practice effect existed only under an easy ongoing task condition. When a 600 ms delay was added after each difficult ongoing task in Experiment 2, we found the same effect as for the easy ongoing task condition in Experiment 1. In addition, the results also suggested that the practice effect was closely related to the improvement in the effectiveness of time monitoring. The present study confirmed the existence of practice effect of TBPM under some conditions of sufficient attention resources and further explored its causes for the first time, which made us have a deeper understanding of the plasticity of TBPM caused by behavior training.

The Effects of Same- and Other-Race Facial Expressions of Pain on Temporal Perception.

Previous studies suggested that threatening stimuli lengthen subjective duration, while facial expressions of pain were found to produce a shortening effect on temporal perception in a recent study. Moreover, individuals' responses to others' pain were influenced by the individuals' relationship to a racial group. However, the effects of same- and other-race pained facial expressions on temporal perception, remain unknown. The aim of this present study was to identify the effect expressions of pain have on temporal perception and to explore whether this effect was modulated by the relationship to a racial group. In a temporal bisection task, Chinese participants were presented with pain or neutral facial expressions displayed by Caucasian (other-race) or Chinese (same-race) models in a 400-1600 ms or 200-800 ms condition. Expressions of pain were rated as more arousing, negative and disagreeable, than neutral facial expressions. These scores were not significantly different between same- and other-race facial expressions. Based on the results of the temporal bisection task, both same- and other-race pained facial expressions lengthened the perceived duration in the 400-1600 ms condition, but only same-race pained facial expressions produced this effect in the 200-800 ms condition. We postulate that the existence of a short-lived effect of pained facial expressions on lengthening temporal perception caused by arousal and attention, occurs at an earlier time point for same-race pained facial expressions than for other-race pained facial expressions.

The influence of phasic alerting on multisensory temporal precision.

The relationship between attention and multisensory integration has attracted the attention of many researchers but remains a topic of debate. As a mechanism that regulates the intensity of attention, little is known regarding whether and how phasic alerting affects multisensory perception. Three experiments and warning cues were employed to investigate the influence of phasic alerting on multisensory temporal processing. Experiments 1 and 2 used a temporal order judgement task and a simultaneity judgement task with audiovisual target stimuli presented at varying stimulus onset asynchronies. Experiment 3 further adopted a dual task to generate a new estimate of participants' performance. Although these tasks differ in terms of the required cognitive mechanisms, decreased just noticeable difference scores in trials with warning cues consistently indicated that participants under phasic alerting had enhanced multisensory temporal precision. The point of subjective simultaneity values differed among the three tasks, suggesting that the influence of phasic alerting on perceptual deviation might be modulated by specific task demands. Experiment 4 adopted a strict method to verify that the mechanisms by which warning cues facilitate multisensory temporal precision are most likely transient general arousal rather than temporal expectancy. There is a close relationship between multisensory integration and some neurodevelopmental disorders. Considering that phasic alerting may heighten attentional capacity, future research could explore the potential medical interventions for the patients with relatively limited attention resources.

The Role of Emotion Regulation in Reducing Emotional Distortions of Duration Perception.

Emotional events, especially negative ones, are consistently reported to last longer than neutral events. Previous studies suggested that this distortion of duration perception is linked to arousal and attention bias in response to emotional events. Reappraisal and suppression, arguably the most effective strategies for emotion regulation, have been demonstrated to decrease such arousal and attention bias. The present study investigated whether reappraisal and suppression can reduce emotional distortions of duration perception. Seventy-eight Chinese undergraduates were recruited as paid participants and randomly assigned to nonregulation, reappraisal, and suppression groups. Before they performed a temporal bisection task involving presentation of emotional pictures for different durations, the groups were each given one of three different sets of instructions requiring them to passively perceive, reappraise, or suppress the emotions of the pictures. The results indicated that the distortion of duration perception occurred only in the nonregulation group, suggesting that it can be effectively reduced by reappraisal and suppression.

The effect of phasic alertness on temporal precision.

Many previous studies have found that there is a close relationship between attention and temporal precision. As a mechanism that regulates the intensity of attention, alertness has beneficial influences on perceptual processing. However, little is known regarding whether and how phasic alertness affects temporal precision. Experiment 1 and Experiment 2 used visual and auditory warning cues in a visual temporal order judgment (TOJ) task and a simultaneity judgment (SJ) task to investigate the phasic alerting effect on temporal precision. Participants in the TOJ and SJ tasks were required to make judgments of two successive and synchronous stimuli at various stimulus onset asynchronies (SOAs). Because of dissension regarding the SJ task, Experiment 3 adopted a dual SJ and TOJ task to create a new indicator of participant performance. Although these tasks may differ in the cognitive mechanism they involve, they all produced consistently decreased just noticeable difference (JND) scores and unaltered point of subjective simultaneity (PSS). This suggests that phasic alertness could significantly improve participants' temporal precision (reduced JNDs) of visual perception, without affecting temporal accuracy (unaltered PSS). We then discuss that the alerting effect on temporal sensitivity might be attributed mainly to transient arousal rather than temporal expectancy. Furthermore, the analysis of response ratios at each SOA could distinguish a heightened temporal precision from a reduction of attentional lapses. According to the previous and present studies, phasic alertness might simultaneously benefited the early perceptual processing and late motor execution of responses.

Duration Aftereffect Depends on the Duration of Adaptation.

It has been widely demonstrated that a prolonged adaptation to a relatively long or short stimulus leads to a robust repulsive duration aftereffect. However, little is known about the rapid adaptation to stimulus duration. In this study, we investigated whether the duration aftereffect could also be induced by short-term adaptation to stimuli of both sub- and supra-second durations. To control for the internal reference for duration judgment, participants were adapted to a stimulus of medium duration, and then tested with both longer and shorter stimuli. We found that the duration aftereffect was only observed after long-term adaptation to stimuli of both sub- and supra-second durations, which suggests that the exposure time to the adaptor is a fundamental factor in determining the duration aftereffect. Our findings offer further evidence of the duration aftereffect, which in this study was dissociated from the anchor effect and high-level aftereffects.

Duration adaptation modulates EEG correlates of subsequent temporal encoding.

Repetitive exposure to relatively long or short sensory events has been shown to shorten or lengthen the perceived duration of a subsequent event. However, the neural basis of this phenomenon, called duration adaptation, remains unclear. In this study, we used electroencephalography (EEG) to investigate whether duration adaptation could modulate the subsequent temporal encoding represented by the contingent negative variation (CNV). Participants were asked to reproduce the duration of a test stimulus after adapting duration (Experiment 1) or after anchor duration (Experiment 2). We found that both adapting duration and anchor duration affected the reproduction duration of a subsequently presented test stimulus. The simultaneously recorded event-related potentials (ERPs) revealed that test stimuli evoked clearly identifiable N1, P2 and CNV components in the fronto-central scalp. Further analyses showed that the CNV amplitude was modulated by duration adaptation: adaptation to shorter duration (200ms) increased whereas adaptation to longer duration (800ms) decreased the CNV amplitude. These findings suggest that the neural correlates of temporal encoding represented by the CNV amplitude reflect the duration aftereffect. Additionally, the duration adaptation effect observed on the P2 component also suggests an early expectancy effect on subsequent encoding processes. Finally, no effect of anchor duration was observed on the CNV amplitude, which implies that different mechanisms underlie the duration aftereffect and the anchor effect.

Pre-stimulus beta and gamma oscillatory power predicts perceived audiovisual simultaneity.

Pre-stimulus oscillation activity in the brain continuously fluctuates, but it is correlated with subsequent behavioral and perceptual performance. Here, using fast Fourier transformation of pre-stimulus electroencephalograms, we explored how oscillatory power modulates the subsequent discrimination of perceived simultaneity from non-simultaneity in the audiovisual domain. We found that the over-scalp high beta (20-28Hz), parieto-occipital low beta (14-20Hz), and high gamma oscillations (55-80Hz) were significantly stronger before audition-then-vision sequence when they were judged as simultaneous rather than non-simultaneous. In contrast, a broad range of oscillations, mainly the beta and gamma bands over a great part of the scalp were significantly weaker before vision-then-audition sequences when they were judged as simultaneous versus non-simultaneous. Moreover, for auditory-leading sequence, pre-stimulus beta and gamma oscillatory power successfully predicted subjects' reports of simultaneity on a trial-by-trial basis, with stronger activity resulting in more simultaneous judgments. These results indicate that ongoing fluctuations of beta and gamma oscillations can modulate subsequent perceived audiovisual simultaneity, but with an opposing pattern for auditory- and visual-leading sequences.

Abnormal brain activation during directed forgetting of negative memory in depressed patients.

The frequent occurrence of uncontrollable negative thoughts and memories is a troubling aspect of depression. Thus, knowledge on the mechanism underlying intentional forgetting of these thoughts and memories is crucial to develop an effective emotion regulation strategy for depressed individuals. Behavioral studies have demonstrated that depressed participants cannot intentionally forget negative memories. However, the neural mechanism underlying this process remains unclear. In this study, participants completed the directed forgetting task in which they were instructed to remember or forget neutral or negative words. Standard univariate analysis based on the General Linear Model showed that the depressed participants have higher activation in the inferior frontal gyrus (IFG), superior frontal gyrus (SFG), superior parietal gyrus (SPG), and inferior temporal gyrus (ITG) than the healthy individuals. The results indicated that depressed participants recruited more frontal and parietal inhibitory control resources to inhibit the TBF items, but the attempt still failed because of negative bias. We also used the Support Vector Machine to perform multivariate pattern classification based on the brain activation during directed forgetting. The pattern of brain activity in directed forgetting of negative words allowed correct group classification with an overall accuracy of 75% (P=0.012). The brain regions which are critical for this discrimination showed abnormal activation when depressed participants were attempting to forget negative words. These results indicated that the abnormal neural circuitry when depressed individuals tried to forget the negative words might provide neurobiological markers for depression.

Visual duration aftereffect is position invariant.

Adaptation to relatively long or short sensory events leads to a negative aftereffect, such that the durations of the subsequent events within a certain range appear to be contracted or expanded. The distortion in perceived duration is presumed to arise from the adaptation of duration detectors. Here, we focus on the positional sensitivity of those visual duration detectors by exploring whether the duration aftereffect may be constrained by the visual location of stimuli. We adopted two different paradigms, one that tests for transfer across visual hemifields, and the other that tests for simultaneous selectivity between visual hemifields. By employing these experimental designs, we show that the duration aftereffect strongly transfers across visual hemifields and is not contingent on them. The lack of position specificity suggests that duration detectors in the visual system may operate at a relatively later stage of sensory processing.