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Pierce, J.

Publications and source records attributed to Pierce, J..

15 recordsLinked to original sources

Attentional focus and emotion modulate voice recognition deficits in cerebellar stroke patients

The cerebellum, long regarded as a motor structure, is increasingly recognized for its role in higher-order cognitive and socio-emotional functions. Its contribution to vocal emotion decoding, however, remains insufficiently understood. While prior work has linked the cerebellum to attentional control and predictive coding, direct evidence for its role in modulating prosody recognition under explicit versus implicit attentional demands is lacking. This study investigated how cerebellar stroke--controlled for time since stroke in months, and with an equal number of left- and right-lateralized lesions--alters vocal emotion processing depending on attentional focus. We aimed to disentangle sensory encoding and integration from decisional contributions of the cerebellum by combining behavioral analyses, drift diffusion modeling (DDM), and functional MRI in cerebellar stroke. Fifteen patients with chronic, isolated cerebellar stroke and fifteen matched controls performed two tasks on vocal stimuli expressing anger, happiness, or neutrality. In the explicit task, participants categorized the expressed emotion; in the implicit task, they categorized speaker gender while ignoring emotional tone. Behavioral performance was analyzed using mixed-effects logistic regression and DDM (angle model). Functional MRI analyses included conventional contrasts as well as model-based regressors derived from behavioral and computational parameters. Patients showed lower accuracy than controls, with deficits particularly pronounced in the explicit task. Performance also varied by emotion: gender recognition for angry voices (implicit processing) was relatively preserved, whereas happy and neutral voices were more vulnerable. Contrary to predictions, DDM parameters did not differ between groups. Instead, task effects dominated: implicit processing yielded higher drift rates, larger boundary separation, faster non-decision times, and stronger attentional focus compared to explicit recognition, suggesting that explicit evaluation imposes additional cognitive costs. At the neural level, patients recruited extended networks during explicit processing, including orbitofrontal cortex, amygdala, anterior insula, and cerebellar lobule IX, alongside cerebello-cortical tracts. Implicit processing was associated with more restricted activations, particularly in frontal opercular and cerebellar regions (lobule IX). Model-based analyses further revealed that successful categorization in patients relied on the left inferior frontal gyrus, inferior parietal lobule, and pre-supplementary motor area, although these effects were not significant when controlling for time since stroke. Our findings demonstrate that the cerebellum does not primarily shape decision dynamics but optimizes sensory representations of prosodic cues for downstream evaluation. When predictive tuning is compromised, patients maintain intact decision processes yet rely on compensatory cortical recruitment, particularly during explicit tasks. This pattern supports predictive coding accounts of cerebellar function in socio-emotional communication and highlights the need to consider subtle socio-affective deficits in cerebellar patients.

neuroscience↗

The elusive neural signature of emotion regulation capabilities: evidence from a large-scale consortium

Cognitive reappraisal is a fundamental emotion regulation strategy for mental and physical well-being, but how its neural mechanisms relate to individual differences remains poorly understood. In a consortium effort analyzing 40 fMRI datasets (N=2,175), we examined the relationship between neural activation during reappraisal tasks and three core individual difference indices of reappraisal capabilities: (1) trait questionnaires, (2) task-based affective ratings, and (3) amygdala down-regulation. Strikingly, there was no shared overlap across these three common indices. Only a very weak correlation emerged between amygdala down-regulation and task-based affective ratings. Whole-brain analyses revealed no reliable neural associations with trait questionnaires, and associations with task-based affective ratings fell outside canonical emotion regulation networks (e.g., prefrontal circuitry). Moreover, amygdala down-regulation, often interpreted as a stable individual marker, was confounded by person-specific whole-brain responses -- a limitation extending to fMRI research beyond the emotion regulation domain. These findings challenge the assumption that an individuals prefrontal activity is a valid indicator of their reappraisal capabilities and suggest that common trait, behavioral, and neural measures might capture distinct facets of emotion regulation. More broadly, our results highlight concrete methodological challenges for fMRI research on individual differences, with implications extending beyond emotion regulation to the neuroscience of personality, psychopathology, and general well-being.

neuroscience↗

IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2

Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1{beta}-driven NF-{kappa}B transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.

immunology↗

Differential Engagement of Associative-Limbic and Sensorimotor Regions of the Cerebellum and Basal Ganglia in Explicit vs. Implicit Emotional Processing

Emotional prosody processing involves a widespread network of brain regions, but the specific roles of the cerebellum and basal ganglia in explicit and implicit tasks are not well known or understood. This study investigated how the cerebellum and basal ganglia contribute to explicit (emotion categorization) and implicit (gender categorization) processing of emotional prosody, namely when attention is directly versus implicitly oriented towards the emotion of the voice stimuli, respectively. Twenty-eight healthy French-speaking participants (average age: 65 years old) underwent high-resolution functional MRI while performing explicit and implicit vocal emotion processing tasks. Neuroimaging results revealed--and replicated--that both tasks recruited a widespread network, including the superior temporal cortex, inferior frontal cortex, primary motor and somatosensory cortices, basal ganglia, and cerebellum. The explicit task elicited stronger activations in the basal ganglia (caudate nucleus, putamen) and cerebellar regions (Crus I/II, lobules VI, VIIb, and X), consistent with higher cognitive control demands. In contrast, the implicit task was associated with activations in cerebellar lobules IV-V, VI, VIII, and IX, along with the thalamus. Regression-based functional connectivity analyses further demonstrated stronger connectivity between the right cerebellar lobule IX and the putamen, as well as the cerebellar vermis (XII), particularly during implicit processing. These findings highlight the distinct contributions of the cerebellum and basal ganglia to emotional prosody processing, with explicit tasks engaging associative and cognitive control networks, while implicit tasks rely more on sensorimotor and automatic neural processing mechanisms.

neuroscience↗

Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans

Differences in naive alcohol sensitivity among individuals are a strong predictor of later-life alcohol use disorders (AUD). However, the genetic bases of alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode Caenorhabditis elegans. We performed a genome-wide association study and identified five quantitative trait loci (QTL) that underlie natural variation in alcohol sensitivity. We validated that a variant in the conserved ubiquitin-like domain of a C. elegans ortholog of protein kinase D, dkf-2, likely underlies the chromosome V QTL. Furthermore, lower alcohol sensitivity, i.e. resistance to intoxication, was conferred by dkf-2 loss-of-function mutations. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD. Article summaryWe investigated the genetic basis of differences in alcohol sensitivity, a key predictor of alcohol use disorder. We measured alcohol-induced behavioral changes in over 150 genetically diverse nematode strains. Using a genome-wide association study, which links genetic differences to traits, we identified five genomic regions associated with alcohol sensitivity. We then showed that variation in a gene encoding protein kinase D influences resistance to intoxication. These findings identify a conserved molecular pathway that affects alcohol sensitivity and highlight a potential target for intervention. They show how natural genetic variation can reveal mechanisms underlying complex, human-relevant traits.

genetics↗

Non-apoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans

While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the mechanistic role of BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health. Significance statementBH3-only proteins were known for their function in inducing cell death. Their presence in healthy adult neurons, however, suggests additional roles. Our study focused on the BH3-only protein EGL-1 in the nematode Caenorhabditis elegans, where its apoptotic role was discovered. We reveal a new role in cell-autonomously promoting exopher production - a process where neurons extrude large vesicles containing potentially harmful cell contents. EGL-1 appears to promote this by regulating mitochondrial dynamics. We also report that low levels of EGL-1 benefit neuronal health and function. These findings expand our understanding of BH3-only proteins, mitochondrial dynamics, and exopher production in neurons and provide insights for neurodegenerative diseases.

neuroscience↗

Suppressing mortality and curbing cellular damage by targeting VHL

Mortality rate increases with age and can accelerate upon extrinsic or intrinsic damage to individuals. Identifying factors and mechanisms that curb population mortality rate has wide-ranging implications. Here, we show that targeting the VHL-1 (Von Hippel- Lindau) protein suppresses C. elegans mortality caused by distinct factors, including elevated reactive oxygen species, temperature, and APOE4, the genetic variant that confers high risks of neurodegeneration in Alzheimers diseases and all-cause mortality in humans. These mortality factors are of different physical-chemical nature, yet result in similar cellular dysfunction and damage that are suppressed by deleting VHL-1. Stabilized HIF-1 (hypoxia inducible factor), a transcription factor normally targeted for degradation by VHL-1, recapitulates the protective effects of deleting VHL-1. HIF-1 orchestrates a genetic program that defends against mitochondrial abnormalities, excess oxidative stress, cellular proteostasis dysregulation, and endo-lysosomal rupture, key events that lead to mortality. Genetic Vhl inhibition also alleviates cerebral vascular injury and synaptic lesions in APOE4 mice, supporting an evolutionarily conserved mechanism. Collectively, we identify the VHL-HIF axis as a potent modifier of APOE4 and mortality and propose that targeting VHL-HIF in non-proliferative animal tissues may suppress tissue injuries and mortality by broadly curbing cellular damage.

physiology↗

Hexafluoro slows retinal degeneration and improves visual function in zebrafish models of Usher syndrome 1F

Usher syndrome is the leading genetic cause of deafblindness, affecting hundreds of thousands of people worldwide. The deafness can be addressed with hearing aids or cochlear implants, but there is currently no treatment for the vision loss, which is due to progressive degeneration of retinal photoreceptors. Studies in animal models of Usher syndrome have shown that photoreceptor degeneration is exacerbated by exposure to bright light, and other studies have shown that light-induced photostress reduces mitochondrial function. We previously synthesized hexafluoro and showed that it is a potent Sirt3 activator that promotes mitochondrial respiration. Here we examined the efficacy of hexafluoro as a potential therapeutic for treatment of vison loss in a zebrafish model of Usher syndrome type 1F, which exhibits early and severe vision defects along with vestibular dysfunction as seen in Usher type 1 pathology. We find that hexafluoro improves visual function, reduces photoreceptor degeneration, and protects the retina against exposure to bright light in this USH1F model.

neuroscience↗

Exploiting Embryonic Niche Conditions to Grow Wilms Tumor Blastema in Culture

Wilms Tumor (WT), or nephroblastoma, is the most common pediatric kidney cancer. Most WTs display a "favorable" triphasic histology, in which the tumor is comprised of blastemal, stromal, and epithelial cell types. Blastemal predominance after neoadjuvant chemotherapy or diffuse anaplasia ("unfavorable" histology; 5-8%) portend a worse prognosis. Blastema likely provide the putative cancer stem cells (CSCs), which retain molecular and histologic features characteristic of nephron progenitor cells (NPCs), within WTs. NPCs arise in the metanephric mesenchyme (MM) and populate the cap mesenchyme (CM) in the developing kidney. WT blastemal cells, like NPCs, similarly express markers, SIX2 and CITED1. Tumor xenotransplantation is currently the only dependable method to propagate tumor tissue for research or therapeutic screening, since efforts to culture tumors in vitro as monolayers have invariably failed. Therefore, a critical need exists to propagate WT stem cells rapidly and efficiently for high-throughput, real-time drug screening. Previously, our lab developed niche conditions that support the propagation of murine NPCs in culture. By applying similar conditions to WTs, we have successfully expanded and passaged WT cells from five distinct untreated patient tumors and maintained key NPC "stemness" markers, SIX2, NCAM and YAP1, and CSC marker ALDH1. These findings suggest that our culture conditions sustain the WT blastemal population, as previously shown for normal NPCs. As a result, we have developed new WT cell lines and a multi-passage in vitro model for studying the blastemal lineage/CSCs in WTs. Furthermore, this system supports growth of heterogeneous WT cells, upon which potential drug therapies could be tested for efficacy and resistance.

cancer biology↗

Transgenerational effects of alcohol on intoxication sensitivity in Caenorhabditis elegans

Alcohol abuse and dependence have a substantial heritable component. Although the genome has been considered the sole vehicle of heritable phenotypes, recent studies suggest that drug or alcohol exposure may induce alterations in gene expression that are transmitted across generations. Still, the transgenerational impact of alcohol use (and abuse) remains largely unexplored in part because multigenerational studies using rodent models present challenges for time, sample size, and genetic heterogeneity. Here, we took advantage of the extremely short generation time, large broods, and clonal form of reproduction of the nematode Caenorhabditis elegans. We developed a model of preconception parental alcohol exposure to test alterations in behavioral responses to acute alcohol treatment (intoxication) in subsequent F1, F2 and F3 generations. We found that a chronic alcohol-treatment paradigm in the parental generation resulted in alcohol-naive F3 progeny displaying moderate resistance to intoxication. To compare the treatment duration and timing on this transgenerational effect, we repeated the study using an intermittent treatment paradigm. We found that intermittent treatment resulted in alcohol-naive F3 progeny displaying moderate hypersensitivity to intoxication. Further study of this phenomena using this new C. elegans model may yield mechanistic insights into how transgenerational effects may occur in other animals.

genetics↗

Basal ganglia and cerebellar contributions to vocal emotion processing: a high resolution fMRI study

Until recently, brain networks underlying emotional voice prosody decoding and processing were focused on modulations in primary and secondary auditory, ventral frontal and prefrontal cortices, and the amygdala. Growing interest for a specific role of the basal ganglia and cerebellum was recently brought into the spotlight. In the present study, we aimed at characterizing the role of such subcortical brain regions in vocal emotion processing, at the level of both brain activation and functional and effective connectivity, using high resolution functional magnetic resonance imaging. Variance explained by low-level acoustic parameters (fundamental frequency, voice energy) was also modelled. Wholebrain data revealed expected contributions of the temporal and frontal cortices, basal ganglia and cerebellum to vocal emotion processing, while functional connectivity analyses highlighted correlations between basal ganglia and cerebellum, especially for angry voices. Seed-to-seed and seed-to-voxel effective connectivity revealed direct connections within the basal ganglia especially between the putamen and external globus pallidus and between the subthalamic nucleus and the cerebellum. Our results speak in favour of crucial contributions of the basal ganglia, especially the putamen, external globus pallidus and subthalamic nucleus, and several cerebellar lobules and nuclei for an efficient decoding of and response to vocal emotions.

neuroscience↗

Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron

Neuronal activity often leads to alterations in gene expression and cellular architecture. The nematode Caenorhabditis elegans, owing to its compact translucent nervous system, is a powerful system in which to study conserved aspects of the development and plasticity of neuronal morphology. Here we focus on one sensory neuron in the worm, termed URX, which senses oxygen and signals tonically proportional to environmental oxygen. Previous studies have reported that URX has variable branched endings at its dendritic sensory tip. By controlling oxygen levels and analyzing mutants, we found that these branched endings grow over time as a consequence of neuronal activity. Furthermore, we observed that the branches contain microtubules, but do not appear to harbor the guanylyl cyclase GCY-35, a central component of the oxygen sensory transduction pathway. Interestingly, we found that although URX dendritic tips grow branches in response to long-term activity, the degree of branch elaboration does not correlate with oxygen sensitivity at the cellular or the behavioral level. Given the strengths of C. elegans as a model organism, URX may serve as a potent system for uncovering genes and mechanisms involved in activity-dependent morphological changes in neurons.

neuroscience↗

KRAB Zinc Finger Proteins coordinate across evolutionary time scales to battle retroelements

KRAB Zinc Finger Proteins (KZNFs) are the largest and fastest evolving family of human transcription factors1,2. The evolution of this protein family is closely linked to the tempo of retrotransposable element (RTE) invasions, with specific KZNF family members demonstrated to transcriptionally repress specific families of RTEs3,4. The competing selective pressures between RTEs and the KZNFs results in evolutionary arms races whereby KZNFs evolve to recognize RTEs, while RTEs evolve to escape KZNF recognition5. Evolutionary analyses of the primate-specific RTE family L1PA and two of its KZNF binders, ZNF93 and ZNF649, reveal specific nucleotide and amino changes consistent with an arms race scenario. Our results suggest a model whereby ZNF649 and ZNF93 worked together to target independent motifs within the L1PA RTE lineage. L1PA elements eventually escaped the concerted action of this KZNF \"team\" over [~]30 million years through two distinct mechanisms: a slow accumulation of point mutations in the ZNF649 binding site and a rapid, massive deletion of the entire ZNF93 binding site.

evolutionary biology↗

Temporal and spatial factors that influence magnetotaxis in C. elegans

Many animals can orient using the earths magnetic field. In a recent study, we performed three distinct behavioral assays providing evidence that the nematode Caenorhabditis elegans orients to earth-strength magnetic fields (Vidal-Gadea et al., 2015). In addition to these behavioral assays, we found that magnetic orientation in C. elegans depends on the AFD sensory neurons and conducted subsequent physiological experiments showing that AFD neurons respond to earth-strength magnetic fields. A new behavioral study by Landler et al. (2017) suggested that C. elegans does not orient to magnetic fields and raises issues that cast doubt on our study. Here we reanalyze Lander et al.s data to show how they appear to have missed observing positive results, and we highlight differences in experimental methods and interpretations that may explain our different results and conclusions. Moreover, we present new data from our labs together with replication by an independent lab to show how temporal and spatial factors influence the unique spatiotemporal trajectory that worms make during magnetotaxis. Together, these findings provide guidance on how to achieve robust magnetotaxis and reinforce our original finding that C. elegans is a suitable model system to study magnetoreception.

neuroscience↗

Systematic Characterization Of Human 21st Chromosome Orthologs In Caenorhabditis elegans

Individuals with Down syndrome have neurological and muscle impairments due to an additional copy of the human 21st chromosome (HSA21). Only a few of ~200 HSA21 genes encoding protein have been linked to specific Down syndrome phenotypes, while the remainder are understudied. To identify poorly characterized HSA21 genes required for nervous system function, we studied behavioral phenotypes caused by loss-of-function mutations in conserved HSA21 orthologs in the nematode Caenorhabditis elegans. We identified ten HSA21 orthologs that are required for neuromuscular behaviors: cle-1 (COL18A1), cysl-2 (CBS), dnsn-1 (DONSON), eva-1 (EVA1C), mtq-2 (N6ATM1), ncam-1 (NCAM2), pad-2 (POFUT2), pdxk-1 (PDXK), rnt-1 (RUNX1), and unc-26 (SYNJ1). We also found that three of these genes are required for normal release of the neurotransmitter acetylcholine. This includes a known synaptic gene unc-26 (SYNJ1), as well as uncharacterized genes pdxk-1 (PDXK) and mtq-2 (N6ATM1). As the first systematic functional analysis of HSA21 orthologs, this study may serve as a platform to understand genes that underlie phenotypes associated with Down syndrome.\n\nARTICLE SUMMARYDown syndrome causes neurological and muscle dysfunction due to an extra 21st chromosome. This chromosome has over 200 genes, most of which are understudied. To address this, we studied whether reducing function of these gene equivalents in the worm C. elegans caused neuronal or muscle defects. We identified ten genes conserved between human and worm that mediate function of behaviors. Among these, we show the uncharacterized genes mtq-2 and pdxk-1 are important for synaptic transmission and are exclusively expressed in nervous system. Our analysis may reveal functions of poorly studied genes that affect nervous system function in Down syndrome.

neuroscience↗