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Defining Microbial and Host Pathways Driving Asymptomatic C. difficile Colonization Associated with Aging and High-Sugar Diets

SUMMARY Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated diarrhea, with rising incidence in community settings and a growing burden of asymptomatic colonization. Asymptomatic car- riers, particularly among the elderly and individuals consuming high-sugar diets, represent a critical but underexplored reservoir for transmission and disease progression. This proposal introduces novel, anti- biotic-independent mouse models demonstrating that both dietary sugar and aging independently pro- mote asymptomatic C. difficile colonization. We hypothesize that these factors disrupt colonization re- sistance (CR) through distinct but overlapping microbial, metabolic, and immune pathways. In Aim 1, we will define how traditional and emerging dietary sugars alter the gut environment to permit C. difficile colonization using in vitro bioreactors and in vivo models. Aim 2 will identify age-associated changes in microbiota and mucosal immunity that impair CR, using longitudinal studies and fecal micro- biota transfer. Aim 3 will functionally validate C. difficile genes upregulated during asymptomatic carriage using CRISPR-Cas9 mutants in both sugar- and age-induced models. This integrative, multi-omics approach will uncover the mechanisms enabling asymptomatic colonization and identify microbial and host targets for intervention. The findings will inform microbiome-based strat- egies to prevent CDI in vulnerable populations and shift current paradigms in CDI risk assessment and prevention.

The role of endogenous chimeric mRNA encoded GasderminD fusion proteins in immunity

Project Summary: Programmed inflammatory cell death, or pyroptosis, is a crucial innate defense mechanism that protects hosts against infection and orchestrates subsequent immune responses. Central to this process is Gasdermin D (GSDMD), a protein that forms plasma membrane pores upon activation, enabling the release of pro- inflammatory cytokines such as IL-1β and driving cell lysis. Although GSDMD-mediated pyroptosis has been conventionally understood to be controlled mainly at the post-translational level, through proteolytic cleavage by inflammatory caspases, we have discovered compelling evidence that alternative RNA processing may introduce additional, previously unappreciated complexity in GSDMD regulation. Our laboratories have developed and optimized a highly innovative long-read direct RNA sequencing pipeline, which bypasses conventional cDNA synthesis to avoid artifacts and enables unbiased discovery of native chimeric mRNA (chRNA) in mammalian cells. Using this approach, we have uncovered a remarkably diverse repertoire of chRNA species, including over a thousand unique fusions in murine macrophages and more than two thousand in human inflamed tissues. Among the chRNA found in mice, we identified a chRNA joining the effector domain of GSDMD with a novel C-terminal region encoded by Tmem106a, giving rise to the GSDMD:TMEM106A fusion protein. Functional studies demonstrate that GSDMD:TMEM106A is not only produced in response to inflammatory signals in macrophages but is critical for GSDMD-dependent cytokine release and optimal pyroptosis. Genetic loss of GSDMD:TMEM106A in mice results in reduced cytokine secretion and increased susceptibility to bacterial infection, while in vivo delivery of Gsdmd:Tmem106a mRNA is sufficient for protective immunity. Intriguingly, we have also identified a putative human counterpart, GSDMD:S100A6, which is highly inducible in colon biopsies from patients with inflammatory bowel disease. In this application, we propose a comprehensive exploration of this newly defined class of naturally occurring GSDMD fusion proteins. The specific aims are: (1) to elucidate the subcellular localization, protein-protein interactions, and pore-forming function of GSDMD:TMEM106A during canonical and non-canonical inflammasome activation; (2) to determine the transcriptomic, proteomic, and physiological consequences of GSDMD chRNA expression in vivo during infection, sepsis, and inflammatory disease, and to validate and functionally characterize GSDMD:S100A6 in relevant immune and barrier cell populations. Collectively, this work will establish chimeric splicing as a fundamental source of immunoregulatory protein diversity, redefining the landscape of cell death control in the immune system. By revealing new layers of gasdermin regulation and function, our studies have the potential to identify novel therapeutic strategies for infectious, auto-inflammatory, and immune-mediated diseases.

Causal mechanisms driving germline predisposition to myeloproliferative disorders

SUMMARY/ABSTRACT Although human genetic studies have indicated a significant hereditary predisposition to myeloproliferative neoplasms (MPNs) the underlying mechanisms driving the genetic risk remains unknown. Our large genome wide association study (GWAS) on MPNs identified several non-coding genetic risk loci associated with disease and implicated modulation of hematopoietic stem cell (HSC) self-renewal by the genetic variants. The long-term goal is to utilize our GWAS results to better understand MPN disease initiation and progression and draw out key unknown MPN predisposition genes. The overall objectives in this application are to elucidate the mechanisms by which MPN risk variants promote disease initiation and progression. The central hypothesis is that common genetic variants increase MPN risk by affecting regulatory elements that influence clonal expansion of HSCs carrying MPN driver mutations. The rationale for this project is that the HSC clones with most prevalent driver mutation found in MPN, JAK2V617F show individual specific growth rates and can develop into MPN or remain as clonal hematopoiesis without any consequences indicating that germline genetic factors influence this process. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms by which genetic variation at the GFI1B locus influences MPN predisposition in vivo. 2) To define upstream transcriptional mechanisms disrupted by common genetic variants that predispose to MPN. Under the first aim, a newly generated mouse model will be used to evaluate clonal expansion of JAK2V617F HSCs in the context of a germline Gfi1b enhancer deletion by in vivo competitive transplantation assays. The murine studies will be complemented by an assessment of Gfi1b allele specific clonal expansion in primary human hematopoietic stem and progenitor cells (HSPCs) engineered to carry JAK2V617F mutation. Mechanistically activated mitochondrial respiration will be examined in germline enhancer inactivated JAK2V617F HSPCs in murine models and human patient samples. For the second aim, perturbation of RUNX1 bound cis-regulatory elements by MPN risk variants will be evaluated as a mechanism of clonal expansion in MPN by using lentiviral reporter assays and endogenous CRISPR/Cas9 editing approaches in primary human HSPCs and degron tagged RUNX1 cell lines. A Runx1 haploinsufficiency mouse model will be used to assess global influences of RUNX1 transcriptional network on MPN initiation. Collectively, our proposed studies aim to bridge the gap between inherited genetic variations and the clonal expansion dynamics of MPN stem cells, shedding light on crucial factors influencing disease development. The mouse models proposed in this study provide the in vivo physiological context and functional readouts required to investigate HSC clonal expansion and MPN pathogenesis.

Perturbation of mammary immunoglobulins during maternal antibiotic administration

Project Summary Prescribed in up to 40% of pregnancies, antibiotics represent the most commonly used class of medication during pregnancy. Although this practice is often necessary for maternal health, accumulating evidence suggests that antibiotic exposure may have unintended consequences for the mother-infant dyad. Epidemiologic studies associate maternal antibiotic exposure, especially in the absence of infection, with increased risk of neonatal complications including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), yet the mechanisms driving these associations remain poorly understood. Secretory IgA (sIgA) in milk is an essential component of neonatal mucosal immunity, shaping early gut microbial colonization and providing protection against enteric pathogens. The mechanisms by which maternal physiology regulates the abundance and microbial specificity of these antibodies in milk remain poorly understood. In animal models, the maternal gut–mammary axis governs the generation of milk IgA: IgA-committed lymphocytes from the maternal intestine migrate to the mammary gland during advancing pregnancy via CCL- 28/CCR10 signaling. Our preliminary data suggest that maternal antibiotic exposure disrupts this process leading to a decrease in milk IgA. However, the timing and extent of antibody dysbiosis are undefined; the downstream effects on neonatal intestinal health are unknown; and the underlying mechanisms—whether due to altered microbial stimulation, impaired recruitment of IgA⁺ cells to the mammary gland, or both—remain to be elucidated. Our central hypothesis is that maternal antibiotic exposure reduces pathogen-reactive IgA in milk by impairing gut-to-mammary immune cell trafficking thereby compromising neonatal mucosal immunity and increasing infection susceptibility. We will address this hypothesis through three integrated aims: (1) Determine the magnitude and duration of antibiotic-mediated mammary antibody dysbiosis in women who deliver preterm and at term; (2) Identify microbial targets of mammary antibodies diminished by maternal antibiotic exposure and (3 Determine the role of maternal antibiotics in the disruption of mammary resident IgA+ plasma cells in animal models. This integrative human and animal study will uncover critical mechanisms by which maternal antibiotic use alters the maternal-infant immune axis. The results will provide mechanistic insight into the risks associated with perinatal antibiotic exposure and inform clinical strategies to mitigate risk to neonatal health.

Factors Driving Wear and Implant Failure in Total Shoulder Arthroplasty

Polyethylene (PE) wear and implant-related failure remain leading causes of revision in total shoulder arthroplasty (TSA), a procedure which now surpasses the growth rate of hip and knee arthroplasty. Both anatomic (aTSA) and reverse (rTSA) TSA outcomes are heavily influenced by complex interactions between rotator cuff function, scapular motion, implant design, and patient-specific loading—factors not adequately captured in current preclinical implant testing standards. Emerging evidence suggests that PE wear progression in TSA is highly dependent on shoulder kinematics, joint loading, implant positioning, and individual patient factors. Nonetheless, data on in vivo motion and load profiles remain sparse, and few tools exist to link these profiles to clinically relevant wear patterns or associated periprosthetic inflammatory tissue responses. Accordingly, the primary objective of this project is to develop validated, patient-specific models that predict PE wear in TSA and identify modifiable surgical, design, and rehabilitation targets to improve implant longevity and restore patient mobility. Additionally, we will establish histopathological hallmarks that indicate TSA failure caused by PE wear debris. Our central hypothesis is that specific shoulder kinematics and joint loading drive distinct PE wear patterns in TSA associated with mechanical failure or inflammatory-mediated osteolysis, depending on implant design and positioning. To achieve the overall objective of this work, shoulder motions and muscle excitations across 25 activities of daily living will be collected at pre-op and post-op (>6 months) in both aTSA and rTSA patients, with long-term follow-up of patient-reported outcomes via validated surveys (5 years). Unsupervised machine learning will categorize patients into movement-based phenotypes, which will then inform a multi-scale modeling framework to estimate in vivo shoulder joint loads and implant wear across the varying movement strategies. Predicted wear patterns will be validated using state-of-the-art preclinical wear simulators. Simultaneously, we will quantify how patient, surgical, and implant factors contribute to wear in retrieved TSA components (>400 samples), correlating imaging-based wear patterns with clinical outcomes, patient-reported function, inflammatory tissue responses, and radiographic indications of loosening. For that purpose, we will establish benchmarks of TSA wear rates and introduce a new histopathological approach augmented by infrared spectroscopic imaging. This work is innovative because we are linking patient-specific movement patterns following TSA with multi-scale computational models to predict PE wear, breaking the current approaches of using generic motions and loads in existing testing standards. This work will produce the first integrated, publicly available database of TSA kinematics, joint loading, and PE wear patterns and rates, along with validated computational tools to inform implant design, surgical planning, rehabilitation strategies, and personalized risk assessment. Ultimately, these advances will improve functional outcomes and long-term success for TSA patients and enable better preclinical testing methods and standards.

Linking Single-Cell Transcriptomic, Morphological, and Temporal Signatures of Vulnerability in Neurodegeneration

Neurodegeneration involves complex cellular phenotypes and molecular changes that vary widely among the cells of the nervous system. Current methodologies permit either detailed molecular profiling (e.g., single-cell transcriptomics) or functional phenotyping (e.g., live imaging of neuronal activity), but not both in the same cells. Thus, it is difficult to directly link a neuron's functional state or fate with its gene expression profile. To address this limitation, we developed an innovative technology, VISTA-FISH (Video Imaging with Spatial- Temporal Analysis by FISH), that couples prospective live-cell imaging with high-resolution spatial transcriptomic profiling of the same cells. This approach enables in situ comparisons of gene expression in neurons that exhibit divergent behaviors or outcomes. Using VISTA-FISH, we will profile iPS-derived human neurons to link single-cell gene expression, morphology, and temporal phenotypes to study molecular pathways driving resilience as well as susceptibility. After exposing neurons carrying TDP43 and C9orf72 mutations to a stimulus inducing TDP43 aggregation, we will jointly record TDP43 localization and neuron activity using live-cell microscopy, then measure single-cell gene expression of the same cells (Aim 1). We will also combine live-cell measurements of TDP43 half-life with CRISPR screening and single-cell gene expression (Aim 2). These rich datasets will enable us to determine transcriptomic changes associated with differences in protein aggregation, protein synthesis, and protein degradation in individual cells, providing an unprecedented molecular perspective on factors responsible for vulnerability and resilience to neurodegeneration.

Hepatotoxicity of Legacy and Replacement PFAS: Role of BRUCE-Mitochondrial Interactions

Epidemiological studies have shown a strong association between exposure to PFAS (Per- and Poly- fluoroalkyl Substances) and liver toxicity. Particularly, legacy C8-PFAS members, PFOS (perfluorooctane sulfonate) and PFOA (perfluorooctanoic acid), are highly toxic, with PFOS estimated to be approximately 10 times more toxic than PFOA in ecotoxicity models. Consequently, PFAS replacements such as GenX and PFBS are marketed as safe alternatives, although growing evidence indicates that these substitutes also exhibit toxic effects. Lab animal model studies have shown hepatotoxic effects of both legacy and replacement PFAS members, characterized by Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form Metabolic dysfunction- associated steatohepatitis (MASH), the two chronic liver diseases affecting an estimated 80-100 million Americans. The broader objective of this project is to understand the underlying mechanisms of PFAS hepatotoxicity in MASLD/MASH. In this context, our initial studies have shown that PFAS exposure of mice downregulates hepatic BRUCE, an autophagy inhibitor, resulting in development of MASLD in WT, and more severe MASLD and even progression to MASH in BRUCE liver-knockdown (BKO) mice. Using primary hepatocytes, we found PFAS-induced BRUCE reduction compromised mitochondrial (mt) functions (respiration, fatty acid oxidation/FAO, and ATP production) and suppressed mitophagy in WT and more so in BKO mice. Pharmacological restoration of mt function in mice prevented PFAS-induced MASLD/MASH. Guided by these compelling preliminary data and scientific premise, we hypothesize that PFAS degradation of BRUCE in hepatocytes induces excessive autophagy (resulting in cytotoxicity) and inhibits mitophagy (resulting in accumulation of damaged mitochondria), leading to release of mtDAMPs to activate inflammation/ fibrosis, thereby facilitating progression from MASLD to MASH. We will test this by three specific aims. Aim 1 (ex vivo) is to determine the human-relevant PFAS doses that modulate BRUCE levels for homeostatic vs cytotoxic autophagy and how BRUCE in turn regulates autophagy. Aim 2 (ex vivo) will investigate BRUCE-driven mitophagy pathway specific to PFAS exposure at human-relevant doses. Aim 3 (ex vivo and in vivo) will involve ex vivo simulation experiments to characterize the role of PFAS-induced, BRUCE-dependent hepatocyte- released mt DAMPs in activation of immune and fibrogenic cells using co-culture assays. Next, we will perform in vivo intervention to validate the role of PFAS-damaged mitochondria in driving MASH progression in mouse models. Furthermore, human relevance of the delineated mechanisms will be ascertained and validated using iPSC-derived human liver organoid system. Impact: This project will advance our understanding of autophagy/mitophagy-centric mechanisms with therapeutic potential in the context of PFAS-induced liver disease MASLD/MASH.

Airway Epithelial Defense Mechanisms in Combating STAT3-Deficiency-Related Lung Infections

Airway Epithelial Defense Mechanisms in Combating STAT3-Deficiency-Related Lung Infections Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes essential for various cellular processes, including survival, proliferation, differentiation, self-renewal, angiogenesis, and immune response. Abnormal and persistent STAT3 activation is detected in diverse human cancers, driving multiple pro- oncogenic functions. Multiple antitumor drug development targets the inhibition of STAT3 to treat various types of cancer. Unfortunately, downregulated STAT3 significantly increases host susceptibility to recurrent infections, especially pneumonia. Additionally, individuals with genetic polymorphisms associated with lower STAT3 expression are more susceptible to severe tuberculosis. Furthermore, patients with autosomal dominant hyper- IgE syndrome (AD-HIES), also known as Job Syndrome, which is caused by de novo STAT3 mutations and substantially decreased STAT3 expression, have a significantly increased susceptibility to bacterial and fungal infections, with high mortality rates and a shortened life span often associated with Pseudomonas aeruginosa infections. Gram-negative bacteria, particularly P. aeruginosa, are opportunistic pathogens that frequently cause hospital-acquired infections. The problems are worsened by the emerging P. aeruginosa with multidrug resistance (MDR), especially in patients with repeated antibiotic treatments, such as Job Syndrome sufferers. Notably, airway epithelial cell-derived proteins play a significant role in the antimicrobial milieu, promoting effective host defense against invading pathogens. One of the most critical STAT3-regulated antimicrobial molecules is bactericidal permeability-increasing protein fold A1 (BPIFA1, also known as SPLUNC1), a multifunctional innate immunity molecule and indispensable host defense protein that is abundantly secreted in the lungs. This application aims to elucidate how STAT3 deficiency impairs host epithelial defense against microbial infections and whether BPIFA1-mediated innate immune responses can sufficiently restore effective antimicrobial protection to prevent pneumonia. The long-term objective is to advance our understanding of the respiratory innate immune response, particularly in relation to epithelial cell-specific antimicrobial defense. We characterized BPIFA1 as an airway lining fluid protein secreted apically in the airway lumen and in primary human airway epithelial cultures. In this study, we hypothesize that mucosal BPIFA1 is an essential antimicrobial protein that plays a critical role in host defense against microbial infections in STAT3-deficiency- associated pneumonia. Our proposed studies will assess innate immunity mechanisms regulating the antimicrobial activity of the airway epithelium in STAT3 deficiency-associated lung infections. By focusing on the crucial epithelial-derived protein product, BPIFA1, our study will provide an alternative treatment for respiratory infections by augmenting native host defense mechanisms in high-risk individuals, including AD-HIES, cancer, and immunocompromised patients.

Temporomandibular Joint Disc Replacement: Biomechanical Characterization and Novel Implant Assessment

Project Summary/Abstract Temporomandibular joint (TMJ) disorders inflict approximately 5% to 12% of the population. For advanced disorders of the articular TMJ disc, which typically do not respond to conservative treatments, disc resection is the most common surgical intervention. However, the TMJ disc plays a critical role in distributing mechanical stress and preventing wear to the articular surfaces of the joint. Thus, removing the disc can further disrupt joint homeostasis, driving degeneration and the development of osteoarthritis, which can lead to highly invasive and challenging surgical interventions such as joint reconstructions and total joint replacement. Therefore, there is a critical need for disc replacements that can restore the homeostasis of the joint when disc resection is required. Prior attempts at replacing the disc with alloplastic implants have led to deleterious pathological changes related to wear debris, implant fragmentation, and adverse inflammatory responses. Therefore, it is crucial to consider wear, mechanical strength, and biocompatibility of disc replacement materials in the context of long-term cyclic loading in the TMJ. Accordingly, the objective of this proposal is to create an artificial TMJ disc that replaces the mechanical function of the native disc and prevents subsequent degeneration of the joint. Towards this goal, the proposed research will characterize the mechanical loading environment of the TMJ in order to determine the mechanical criteria of a TMJ disc replacement needed to minimize internal stress in the joint (Specific Aim 1). Further, non-resorbable composite hydrogels will be fabricated using biocompatible materials, refined to exhibit biomimetic properties, and molded into a TMJ disc implant. Rigorous mechanical evaluations will determine material durability and suitability as a TMJ disc replacement (Specific Aim 2). Finally, a large animal study will be utilized to evaluate the safety and efficacy of the developed TMJ disc replacement (Specific Aim 3). Successful completion of the proposed work would represent a paradigm shift in the treatment of TMJ disc disorders that can mitigate further joint degeneration and prevent more invasive and complicated surgeries.

Post-diagnosis changes in body composition and renal cell cancer survival

ABSTRACT Significance. Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and most lethal subtype, and there is great interest in the identification of potentially modifiable prognostic factors. Although weight status seems to be relevant, the relationship between body mass index (BMI) at diagnosis and survival among ccRCC patients indicates that mortality is lowest among those classified as overweight or obese at the time of diagnosis by BMI. This has resulted in confusion in clinical guidance for weight management among ccRCC patients. Recent work involving body composition features (adipose and muscle tissue) has provided some insight, but we do not understand how weight or body composition changes after diagnosis relate to survival, nor how these changes relate to pathological and molecular tumor features— information which is needed to resolve this controversy. Rigorous analytical approaches are further required to accurately address these questions. Innovation. Our study is highly innovative in that 1) we will be the first to leverage a large-scale cohort of ccRCC patients with multiple assessments of weight and body composition from diagnosis onward; 2) we will examine tumor characteristics, including molecular features, as potential drivers of these changes; and 3) we will use a rigorous joint modeling approach to simultaneously model the post-diagnosis trajectories of weight and body composition and their relationships with cancer outcomes in the most statistically sound manner. Our findings will inform clinical management of, and identify modifiable body composition features to improve survival for the growing number of ccRCC patients. Approach. We will use available data from the RESOLVE cohort, an NCI-funded retrospective cohort of 1,239 Stage I-III clear-cell renal cell carcinoma (ccRCC) patients diagnosed between 2000-2020 at Memorial Sloan Kettering Cancer Center. These data include clinical and patient-level factors collected from the medical record, including repeated height and weight assessments, body composition measures from existing computed tomography scans, pathological and molecular tumor characteristics, and overall survival (OS) and disease-free survival (DFS). We will use a joint modeling approach to simultaneously model changes in post-diagnosis body weight (Aim 1) and OS and DFS, as well as post-diagnosis changes in muscle and adipose tissue features (Aim 2) and OS and DFS. Models will include molecular tumor characteristics as predictors of these longitudinal trajectories. Impact. These results will provide crucial insight into the relationship between body composition changes and outcomes among ccRCC patients, and potentially identify tumor-related characteristics driving these associations. These results will resolve apparent paradoxes around the relationship between obesity and ccRCC mortality and identify potential targets for nutrition and physical activity interventions on body composition.

A NOVEL GEMM TO ELUCIDATE THE ROLE OF CHAF1A IN NEUROBLASTOMA DEVELOPMENT

PROJECT SUMMARY: This proposal focuses on the fundamental understanding on how the CHAF1A oncogene drives molecular mechanisms, cellular signaling, and metabolic processes in the oncogenesis of neuroblastoma (NB). NB is an aggressive pediatric cancer, which accounts for 15% of pediatric cancer mortalities. High-risk NB is thought to arise from a small number of recurrent genetic alterations that block the ability of neural crest cells (NCCs) to differentiate. To assess the molecular mechanisms governing NC differentiation, our laboratory has established a definitive role of the epigenetic regulator CHAF1A in blocking NC differentiation and driving NB oncogenesis. In this proposal, we will determine the impact of CHAF1A on NB initiation and progression. To accomplish this goal, we propose to develop a novel CHAF1A-driven genetically-engineered mouse model (GEMM) of NB and test the impact of CHAF1A on NB incidence, histology and metastasis, and the tumor immune microenvironment (TIME). We hypothesize that CHAF1A will increase de novo incidence of NB, reduce mouse survival, and promote a suppressive TIME. By developing a novel GEMM of NB and employing innovative technology (including ATAC-seq, lipidomics, and scRNA-seq), we will: 1- elucidate the role of CHAF1A in NB tumor initiation and progression; and 2- determine the impact of CHAF1A on MYCN-induced oncogenesis. These findings will provide a novel view on the molecular mechanisms driving NB initiation, and will have high clinical implications, informing future differentiation-based interventions for high-risk NBs.

Addressing C-F bonds and amyloid-formation in biological systems

The ingestion, pulmonary inhalation, and dermal infiltration of C-F bond-containing compounds, most commonly found in the form of per- and polyfluoroalkyl organic acids, causes oxidative stress, inflammation, DNA damage, and developmental defects in infants and adults. These chemicals accumulate in the brain, disrupt neurological function and compromise cognitive and locomotory behavior. Yet, we lack a high-resolution road-map of the interactions between C-F bonds and biomolecular assemblies driving the trajectory towards neurodegenerative outcomes. This gap constitutes a significant barrier to advancing measures designed to mitigate C-F chemistry-associated neurotoxicity. Emerging experimental and computational data from our laboratory reveals that perfluorooctanoic acid, perfluorodecanoic acid and perfluorosulfonic acid corrupt biomolecular structures through C-F:side-chain interactions in tested soluble, globular proteins found in milk and tissues (matrices where C-F chemistries have been detected). Furthermore, they impaired the physiological function in these proteins through displacement of physiological ligands or by compromising the binding of co-factors. The neuroblastoma-derived SHSY-5Y cell line insulted with the said C-F moieties displayed altered gene expression corresponding to reactive oxygen species (ROS), protein ubiquitination, inflammation along with compromised cytoskeletal integrity. C-F bond ingestion ablated dopaminergic (DA) neurons in the nematode C. elegans and induced locomotory deficits in a manner mimicking paraquat. Based on these findings, we propose to gather data towards our hypothesis that C-F bond exposure perturbs biomolecular, cellular and organismal assemblies to onset neurodegeneration-linked trajectories. In Aim 1, we will determine whether organic fluoroacids alter mRNA levels in differentiated SHSY-5Y cells and in neuroprotective gut bacteria (Lactobacillus rhamnosus, Bifidobacterium lactis and Lactobacillus acidophilus). We will examine whether the neuroblastoma cell line exposed to C-F chemistry displays readouts designed to inform the onset of neurodegeneration-associated trajectories (including α-synuclein aggregation). In Aim 2, we will further address in a preclinical model whether C-F burden induces protein aggregation (α-synuclein, amyloid β, mHTT), interferes with dopaminergic neuronal assembles and induces locomotory deficits. Completion of the proposed work will complement ongoing experimental biophysical, structural (crystallographic, NMR) and computational (docking, molecular dynamics simulations) mapping of the interactions between these anthropogenic “forever” chemicals and amyloid-forming proteins potentially resulting in a soluble-to-toxic transformation. It will prepare the stage for vertebrate testing. The findings from this relatively understudied area likely exposes interventional targets for C-F chemistry associated neurotoxicity, spurs therapeutic efforts and can also guide the development of more biocompatible alternatives.

Targeting the fibrogenic ECM as an alternative approach to treating IPF

Project Abstract Idiopathic pulmonary fibrosis and, more broadly, progressive pulmonary fibrosis are wound healing disorders whose hallmark is unorganized and unchecked extracellular matrix (ECM) deposition leading to scarring/stiffening of the lung interstitium. A highly complex, multicellular process, the generation of scar itself is primarily a function of activated fibroblasts with contributions from multiple subpopulations and non-fibroblastic cells. Myofibroblasts, the contractile cohort of activated fibroblasts, physically perturb (i.e. stretch) the local ECM microenvironment, which we have recently shown triggers site-specific, stretch-dependent conformational changes within the ECM protein fibronectin. We have previously demonstrated that a specific stretch-induced conformational change in the critical receptor binding domain of fibronectin triggers a cellular “integrin switch”, a stark change in the ECM receptors used by cells to engage fibronectin. This integrin switch is sufficient to drive activation of naïve lung fibroblasts, acquisition of mesenchymal characteristics in alveolar epithelial cells, and pathogenic remodeling of vascular structures. In this proposal we hypothesize that fibronectin displays a stretch- dependent conformational change specifically in regions of active lung fibrogenesis and that this conformational change disrupts homeostatic integrin binding dynamics in fibroblasts, leading to their acquisition of a pro-fibrogenic phenotype and transcriptional program. We address this hypothesis in a systematic way through three proposed aims. The first aim focuses on quantifying the presence and spatial localization of the stretch-induced conformational change within a cohort of lung fibrosis patient tissue samples, determining if it represents a consistent marker of active fibrogenic regions and elucidation of critical microenvironmental signatures that further expand our understanding of the impact of fibronectin's integrin switch in driving disease. In the second aim we will begin to unravel the molecular mechanism explaining how the integrin switch that emerges because of the stretch-induced conformational change drives fibroblast activation and fibrogenic gene programs using both idealized in vitro culture systems as well as ex vivo human disease tissue models. Finally, in the third aim we will explore the therapeutic potential of binding and blocking this specific stretch-induced conformation of fibronectin using a promising new and potential antibody drug in both in vivo and ex vivo models of disease.

Maintaining Plasticity in Neural Networks

Nonstationarity presents a variety of challenges for machine learning systems. One surprising pathology which can arise in nonstationary learning problems is plasticity loss, whereby making progress on new learning objectives becomes more difficult as training progresses. Networks which are unable to adapt in response to changes in their environment experience plateaus or even declines in performance in highly non-stationary domains such as reinforcement learning, where the learner must quickly adapt to new information even after hundreds of millions of optimization steps. The loss of plasticity manifests in a cluster of related empirical phenomena which have been identified by a number of recent works, including the primacy bias, implicit under-parameterization, rank collapse, and capacity loss. While this phenomenon is widely observed, it is still not fully understood. This talk will present exciting recent results which shed light on the mechanisms driving the loss of plasticity in a variety of learning problems and survey methods to maintain network plasticity in non-stationary tasks, with a particular focus on deep reinforcement learning.

Cellular and genetic mechanisms of cerebral cortex folding

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding, both of which emerge during development. Over the last few years, work from my lab has shown that specific cellular and genetic mechanisms play central roles in cortex folding, particularly linked to neural stem and progenitor cells. Key mechanisms include high rates of neurogenesis, high abundance of basal Radial Glia Cells (bRGCs), and neuron migration, all of which are intertwined during development. We have also shown that primary cortical folds follow highly stereotyped patterns, defined by a spatial-temporal protomap of gene expression within germinal layers of the developing cortex. I will present recent findings from my laboratory revealing novel cellular and genetic mechanisms that regulate cortex expansion and folding. We have uncovered the contribution of epigenetic regulation to the establishment of the cortex folding protomap, modulating the expression levels of key transcription factors that control progenitor cell proliferation and cortex folding. At the single cell level, we have identified an unprecedented diversity of cortical progenitor cell classes in the ferret and human embryonic cortex. These are differentially enriched in gyrus versus sulcus regions and establish parallel cell lineages, not observed in mouse. Our findings show that genetic and epigenetic mechanisms in gyrencephalic species diversify cortical progenitor cell types and implement parallel cell linages, driving the expansion of neurogenesis and patterning cerebral cortex folds.

Gut/Body interactions in health and disease

The adult intestine is a major barrier epithelium and coordinator of multi-organ functions. Stem cells constantly repair the intestinal epithelium by adjusting their proliferation and differentiation to tissue intrinsic as well as micro- and macro-environmental signals. How these signals integrate to control intestinal and whole-body homeostasis is largely unknown. Addressing this gap in knowledge is central to an improved understanding of intestinal pathophysiology and its systemic consequences. Combining Drosophila and mammalian model systems my laboratory has discovered fundamental mechanisms driving intestinal regeneration and tumourigenesis and outlined complex inter-organ signaling regulating health and disease. During my talk, I will discuss inter-related areas of research from my lab, including:1- Interactions between the intestine and its microenvironment influencing intestinal regeneration and tumourigenesis. 2- Long-range signals from the intestine impacting whole-body in health and disease.

The melanopsin mosaic: exploring the diversity of non-image forming retinal ganglion cells

In this talk, I will focus on recent work that has uncovered the diversity of intrinsically photosensitive retinal ganglion cells (ipRGCs). These are a unique type of retinal ganglion cell that contains the photopigment melanopsin. ipRGCs are the retinal neurons responsible for driving non-imaging forming behaviors and reflexes, such as circadian entrainment and pupil constriction, amongst many others. My lab has recently focused on uncovering the diversity of ipRGCs, their distribution throughout the mammalian retina, and their axon projections in the brain.

Identification of dendritic cell-T cell interactions driving immune responses to food

Programmed axon death: from animal models into human disease

Programmed axon death is a widespread and completely preventable mechanism in injury and disease. Mouse and Drosophila studies define a molecular pathway involving activation of SARM1 NA Dase and its prevention by NAD synthesising enzyme NMNAT2 . Loss of axonal NMNAT2 causes its substrate, NMN , to accumulate and activate SARM1 , driving loss of NAD and changes in ATP , ROS and calcium. Animal models caused by genetic mutation, toxins, viruses or metabolic defects can be alleviated by blocking programmed axon death, for example models of CMT1B , chemotherapy-induced peripheral neuropathy (CIPN), rabies and diabetic peripheral neuropathy (DPN). The perinatal lethality of NMNAT2 null mice is completely rescued, restoring a normal, healthy lifespan. Animal models lack the genetic and environmental diversity present in human populations and this is problematic for modelling gene-environment combinations, for example in CIPN and DPN , and identifying rare, pathogenic mutations. Instead, by testing human gene variants in WGS datasets for loss- and gain-of-function, we identified enrichment of rare SARM1 gain-of-function variants in sporadic ALS , despite previous negative findings in SOD1 transgenic mice. We have shown in mice that heterozygous SARM1 loss-of-function is protective from a range of axonal stresses and that naturally-occurring SARM1 loss-of-function alleles are present in human populations. This enables new approaches to identify disorders where blocking SARM1 may be therapeutically useful, and the existence of two dominant negative human variants in healthy adults is some of the best evidence available that drugs blocking SARM1 are likely to be safe. Further loss- and gain-of-function variants in SARM1 and NMNAT2 are being identified and used to extend and strengthen the evidence of association with neurological disorders. We aim to identify diseases, and specific patients, in whom SARM1 -blocking drugs are most likely to be effective.

Cortical seizure mechanisms: insights from calcium, glutamate and GABA imaging

Focal neocortical epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood, but is likely to relate to the intermittent collapse of feed-forward GABAergic inhibition. Inhibition could fail through multiple mechanisms, including (i) an attenuation or even reversal of the driving force for chloride in postsynaptic neurons because of intense activation of GABAA receptors, (ii) an elevation of potassium secondary to chloride influx leading to depolarization of neurons, or (iii) insufficient GABA release from interneurons. I shall describe the results of experiments using fluorescence imaging of calcium, glutamate or GABA in awake rodent models of neocortical epileptiform activity. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagatedcentrifugally. GABA transients lasted longer than glutamate transients and were maximal ~1.5 mm from the focus. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing runaway recruitment of excitatory neurons as a fundamental mechanism underlying the escape of seizures from local inhibitory restraint.

Driving human visual cortex, visually and electrically

The development of circuit-based therapeutics to treat neurological and neuropsychiatric diseases require detailed localization and understanding of electrophysiological signals in the human brain. Electrodes can record and stimulate circuits in many ways, and we often rely on non-invasive imaging methods to predict the location to implant electrodes. However, electrophysiological and imaging signals measure the underlying tissue in a fundamentally different manner. To integrate multimodal data and benefit from these complementary measurements, I will describe an approach that considers how different measurements integrate signals across the underlying tissue. I will show how this approach helps relate fMRI and intracranial EEG measurements and provides new insights into how electrical stimulation influences human brain networks.

Linking GWAS to pharmacological treatments for psychiatric disorders

Genome-wide association studies (GWAS) have identified multiple disease-associated genetic variations across different psychiatric disorders raising the question of how these genetic variants relate to the corresponding pharmacological treatments. In this talk, I will outline our work investigating whether functional information from a range of open bioinformatics datasets such as protein interaction network (PPI), brain eQTL, and gene expression pattern across the brain can uncover the relationship between GWAS-identified genetic variation and the genes targeted by current drugs for psychiatric disorders. Focusing on four psychiatric disorders---ADHD, bipolar disorder, schizophrenia, and major depressive disorder---we assess relationships between the gene targets of drug treatments and GWAS hits and show that while incorporating information derived from functional bioinformatics data, such as the PPI network and spatial gene expression, can reveal links for bipolar disorder, the overall correspondence between treatment targets and GWAS-implicated genes in psychiatric disorders rarely exceeds null expectations. This relatively low degree of correspondence across modalities suggests that the genetic mechanisms driving the risk for psychiatric disorders may be distinct from the pathophysiological mechanisms used for targeting symptom manifestations through pharmacological treatments and that novel approaches for understanding and treating psychiatric disorders may be required.

Neural Representations of Social Homeostasis

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviors ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviors. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behavior.

A transcriptomic axis predicts state modulation of cortical interneurons

Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes, but it is not known whether these subtypes have correspondingly diverse activity patterns in the living brain. We show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, but that this diversity is organized by a single factor: position along their main axis of transcriptomic variation. We combined in vivo 2-photon calcium imaging of mouse V1 with a novel transcriptomic method to identify mRNAs for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 Subclasses, 11 Types, and 35 Subtypes using previously-defined transcriptomic clusters. Responses to visual stimuli differed significantly only across Subclasses, suppressing cells in the Sncg Subclass while driving cells in the other Subclasses. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory Subtypes that fired more in resting, oscillatory brain states have less axon in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro and express more inhibitory cholinergic receptors. Subtypes firing more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 Subtypes shape state-dependent cortical processing.

Neural circuits for novel choices and for choice speed and accuracy changes in macaques

While most experimental tasks aim at isolating simple cognitive processes to study their neural bases, naturalistic behaviour is often complex and multidimensional. I will present two studies revealing previously uncharacterised neural circuits for decision-making in macaques. This was possible thanks to innovative experimental tasks eliciting sophisticated behaviour, bridging the human and non-human primate research traditions. Firstly, I will describe a specialised medial frontal circuit for novel choice in macaques. Traditionally, monkeys receive extensive training before neural data can be acquired, while a hallmark of human cognition is the ability to act in novel situations. I will show how this medial frontal circuit can combine the values of multiple attributes for each available novel item on-the-fly to enable efficient novel choices. This integration process is associated with a hexagonal symmetry pattern in the BOLD response, consistent with a grid-like representation of the space of all available options. We prove the causal role played by this circuit by showing that focussed transcranial ultrasound neuromodulation impairs optimal choice based on attribute integration and forces the subjects to default to a simpler heuristic decision strategy. Secondly, I will present an ongoing project addressing the neural mechanisms driving behaviour shifts during an evidence accumulation task that requires subjects to trade speed for accuracy. While perceptual decision-making in general has been thoroughly studied, both cognitively and neurally, the reasons why speed and/or accuracy are adjusted, and the associated neural mechanisms, have received little attention. We describe two orthogonal dimensions in which behaviour can vary (traditional speed-accuracy trade-off and efficiency) and we uncover independent neural circuits concerned with changes in strategy and fluctuations in the engagement level. The former involves the frontopolar cortex, while the latter is associated with the insula and a network of subcortical structures including the habenula.

Did you see that hazard? Scanning and detection deficits of drivers with hemianopia

Mechanisms of Axon Growth and Regeneration

Almost everybody that has seen neurons under a microscope for the first time is fascinated by their beauty and their complex shape. Early on during development, however, there are hardly any signs of their future complexity, but the neurons look round and simple. How do neurons develop their sophisticated structure? How do they initially generate domains that later have distinct function within neuronal circuits, such as the axon? And, can a better understanding of the underlying developmental mechanisms help us in pathological conditions, such as a spinal cord injury, to induce axons to regenerate? Here, I will talk about the cytoskeleton as a driving force for neuronal polarization. We will then explore how cytoskeletal changes help to reactivate the growth program of injured CNS axons to elicit axon regeneration after a spinal cord injury. Finally, we will discuss whether axon growth and synapse formation may be processes in neurons that might exclude each other. Following this developmental hypothesis, it will help us to generate a novel perspective on regeneration failure in the adult CNS, and how we can overcome this failure to induce axon regeneration. Thus, this talk will describe how we can exploit developmental mechanisms to induce axon regeneration after a spinal cord injury.

The wonders and complexities of brain microstructure: Enabling biomedical engineering studies combining imaging and models

Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue as in Convection-Enhanced Delivery procedures. This study reports the first systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fiber, namely: the corpus callosum, the fornix and the corona radiata. Ovine samples from three different subjects have been imaged using scanning electron microscope combined with focused ion beam milling. Particular focus has been given to the axons. For each tract, a 3D reconstruction of relatively large volumes (including a significant number of axons) has been performed. Namely, outer axonal ellipticity, outer axonal cross-sectional area and its relative perimeter have been measured. This study [1] provides useful insight into the fibrous organization of the tissue that can be described as composite material presenting elliptical tortuous tubular fibers, leading to a workflow to enable accurate simulations of drug delivery which include well-resolved microstructural features.  As a demonstration of the use of these imaging and reconstruction techniques, our research analyses the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of the electron microscopy images. Considering that the white matter structure is mainly composed of elongated and parallel axons we computed the permeability along the parallel and perpendicular directions using computational fluid dynamics [2]. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio about 2 in both the white matter structures analysed, thus demonstrating their anisotropic behaviour. This is in line with the experimental results obtained using perfusion of brain matter [3]. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that also the white matter heterogeneity should be considered when modelling drug transport in the brain. Our findings, that demonstrate and quantify the anisotropic and heterogeneous character of the white matter, represent a fundamental contribution not only for drug delivery modelling but also for shedding light on the interstitial transport mechanisms in the extracellular space. These and many other discoveries will be discussed during the talk." "1. https://www.researchsquare.com/article/rs-686577/v1, 2. https://www.pnas.org/content/118/36/e2105328118, 3. https://ieeexplore.ieee.org/abstract/document/9198110

Neural Population Dynamics for Skilled Motor Control

The ability to reach, grasp, and manipulate objects is a remarkable expression of motor skill, and the loss of this ability in injury, stroke, or disease can be devastating. These behaviors are controlled by the coordinated activity of tens of millions of neurons distributed across many CNS regions, including the primary motor cortex. While many studies have characterized the activity of single cortical neurons during reaching, the principles governing the dynamics of large, distributed neural populations remain largely unknown. Recent work in primates has suggested that during the execution of reaching, motor cortex may autonomously generate the neural pattern controlling the movement, much like the spinal central pattern generator for locomotion. In this seminar, I will describe recent work that tests this hypothesis using large-scale neural recording, high-resolution behavioral measurements, dynamical systems approaches to data analysis, and optogenetic perturbations in mice. We find, by contrast, that motor cortex requires strong, continuous, and time-varying thalamic input to generate the neural pattern driving reaching. In a second line of work, we demonstrate that the cortico-cerebellar loop is not critical for driving the arm towards the target, but instead fine-tunes movement parameters to enable precise and accurate behavior. Finally, I will describe my future plans to apply these experimental and analytical approaches to the adaptive control of locomotion in complex environments.

Learning from unexpected events in the neocortical microcircuit

Predictive learning hypotheses posit that the neocortex learns a hierarchical model of the structure of features in the environment. Under these hypotheses, expected or predictable features are differentiated from unexpected ones by comparing bottom-up and top-down streams of data, with unexpected features then driving changes in the representation of incoming stimuli. This is supported by numerous studies in early sensory cortices showing that pyramidal neurons respond particularly strongly to unexpected stimulus events. However, it remains unknown how their responses govern subsequent changes in stimulus representations, and thus, govern learning. Here, I present results from our study of layer 2/3 and layer 5 pyramidal neurons imaged in primary visual cortex of awake, behaving mice using two-photon calcium microscopy at both the somatic and distal apical planes. Our data reveals that individual neurons and distal apical dendrites show distinct, but predictable changes in unexpected event responses when tracked over several days. Considering existing evidence that bottom-up information is primarily targeted to somata, with distal apical dendrites receiving the bulk of top-down inputs, our findings corroborate hypothesized complementary roles for these two neuronal compartments in hierarchical computing. Altogether, our work provides novel evidence that the neocortex indeed instantiates a predictive hierarchical model in which unexpected events drive learning.

Analogical encodings and recodings

This talk will focus on the idea that the kind of similarity driving analogical retrieval is determined by the kind of features encoded regarding the source and the target cue situations. Emphasis will be put on educational perspectives in order to show the influence of world semantics on learners’ problem representations and solving strategies, as well as the difficulties arising from semantic incongruence between representations and strategies. Special attention will be given to the recoding of semantically incongruent representations, a crucial step that learners struggle with, in order to illustrate a promising path for going beyond informal strategies.

Digitization as a driving force for collaboration in neuroscience

Many of the collaborations we encounter in our scientific careers are centered on a common idea that can be associated with certain resources, such as a dataset, an algorithm, or a model. All partners in a collaboration need to develop a common understanding of these resources, and need to be able to access them in a simple and unambiguous manner in order to avoid incorrect conclusions especially in highly cross-disciplinary contexts. While digital computers have entered to assist scientific workflows in experiment and simulation for many decades, the high degree of heterogeneity in the field had led to a scattered landscape of highly customized, lab-internal solutions to organizing and managing the resources on a project-by-project basis. Only with the availability of modern technologies such as the semantic web, platforms for collaborative coding or the development of data standards overarching different disciplines, we have tools at our disposal to make resources increasingly more accessible, understandable, and usable. However, without overarching standardization efforts and adaptation of such technologies to the workflows and needs of individual researchers, their adoption by the neuroscience community will be impeded. From the perspective of computational neuroscience, which is inherently dependent on leveraging data and methods across the field of neuroscience for inspiration and validation, I will outline my view on past and present developments towards a more rigorous use of digital resources and how they improved collaboration, and introduce emerging initiatives to support this process in the future (e.g., EBRAINS http://ebrains.eu, NFDI-Neuro http://www.nfdi-neuro.de).

Contrasting neuronal circuits driving reactive and cognitive fear

The last decade in the field of neuroscience has been marked by intense debate on the meaning of the term fear. Whereas some have argued that fear (as well as other emotions) relies on cognitive capacities that are unique to humans, others view it as a negative state constructed from essential building blocks. This latter definition posits that fear states are associated with varying readouts that one could consider to be parallel processes or serial events tied to a specific hierarchy. Within this framework, innate defensive behaviors are considered to be common displays of fear states that lie under the control of hard-wired brain circuits. As a general rule, these defensive behaviors can be classified as either reactive or cognitive based on a thread imminence continuum. However, while evidence of the neuronal circuits that lead to these divergent behavioral strategies has accrued over the last decades, most literature has considered these responses in isolation. As a result, important misconceptions have arisen regarding how fear circuits are distributed in the brain and the contribution of specific nodes within these circuits to defensive behaviors. To mitigate the status quo, I will conduct a systematic comparison of brain circuits driving the expression of freezing and active avoidance behavior, which I will use as well-studied proxies of reactive and cognitive fear, respectively. In addition, I propose that by integrating associative information with interoceptive and exteroceptive signals the central nucleus of the amygdala plays a crucial role in biasing the selection of defensive behaviors.

Evolution of vision - The regular route and shortcuts

Eyes abound in the animal kingdom. Some are large as basketballs and others are just fractions of a millimetre. Eyes also come in many different types, such as the compound eyes of insects, the mirror eyes of scallopsor our own camera-like eyes. Common to all animal eyes is that they serve the same fundamental role of collecting external information for guidingthe animal’s behaviour. But behaviours vary tremendously across the animal kingdom, and it turns outthis is the key to understand how eyes evolved. The lecture will take a tour from the first animals that could only sense the presence of light, to those that saw the first crude image of the world and finally to animals that use acute vision for interacting with otheranimals. Amazingly, all these stages of eye evolution still exist in animals living today, and this is how we can unravel the evolution of behaviours that has been the driving force behind eye evolution

Advances in Computational Psychiatry: Understanding (cognitive) control as a network process

The human brain is a complex organ characterized by heterogeneous patterns of interconnections. Non-invasive imaging techniques now allow for these patterns to be carefully and comprehensively mapped in individual humans, paving the way for a better understanding of how wiring supports cognitive processes. While a large body of work now focuses on descriptive statistics to characterize these wiring patterns, a critical open question lies in how the organization of these networks constrains the potential repertoire of brain dynamics. In this talk, I will describe an approach for understanding how perturbations to brain dynamics propagate through complex wiring patterns, driving the brain into new states of activity. Drawing on a range of disciplinary tools – from graph theory to network control theory and optimization – I will identify control points in brain networks and characterize trajectories of brain activity states following perturbation to those points. Finally, I will describe how these computational tools and approaches can be used to better understand the brain's intrinsic control mechanisms and their alterations in psychiatric conditions.

Dr Lindsay reads from "Models of the Mind : How Physics, Engineering and Mathematics Shaped Our Understanding of the Brain" 📖

Though the term has many definitions, computational neuroscience is mainly about applying mathematics to the study of the brain. The brain—a jumble of all different kinds of neurons interconnected in countless ways that somehow produce consciousness—has been described as “the most complex object in the known universe”. Physicists for centuries have turned to mathematics to properly explain some of the most seemingly simple processes in the universe—how objects fall, how water flows, how the planets move. Equations have proved crucial in these endeavors because they capture relationships and make precise predictions possible. How could we expect to understand the most complex object in the universe without turning to mathematics? — The answer is we can’t, and that is why I wrote this book. While I’ve been studying and working in the field for over a decade, most people I encounter have no idea what “computational neuroscience” is or that it even exists. Yet a desire to understand how the brain works is a common and very human interest. I wrote this book to let people in on the ways in which the brain will ultimately be understood: through mathematical and computational theories. — At the same time, I know that both mathematics and brain science are on their own intimidating topics to the average reader and may seem downright prohibitory when put together. That is why I’ve avoided (many) equations in the book and focused instead on the driving reasons why scientists have turned to mathematical modeling, what these models have taught us about the brain, and how some surprising interactions between biologists, physicists, mathematicians, and engineers over centuries have laid the groundwork for the future of neuroscience. — Each chapter of Models of the Mind covers a separate topic in neuroscience, starting from individual neurons themselves and building up to the different populations of neurons and brain regions that support memory, vision, movement and more. These chapters document the history of how mathematics has woven its way into biology and the exciting advances this collaboration has in store.

How Brain Circuits Function in Health and Disease: Understanding Brain-wide Current Flow

Dr. Rajan and her lab design neural network models based on experimental data, and reverse-engineer them to figure out how brain circuits function in health and disease. They recently developed a powerful framework for tracing neural paths across multiple brain regions— called Current-Based Decomposition (CURBD). This new approach enables the computation of excitatory and inhibitory input currents that drive a given neuron, aiding in the discovery of how entire populations of neurons behave across multiple interacting brain regions. Dr. Rajan’s team has applied this method to studying the neural underpinnings of behavior. As an example, when CURBD was applied to data gathered from an animal model often used to study depression- and anxiety-like behaviors (i.e., learned helplessness) the underlying biology driving adaptive and maladaptive behaviors in the face of stress was revealed. With this framework Dr. Rajan's team probes for mechanisms at work across brain regions that support both healthy and disease states-- as well as identify key divergences from multiple different nervous systems, including zebrafish, mice, non-human primates, and humans.

New Strategies and Approaches to Tackle and Understand Neurological Disorder

Broadly, the Mauro Costa-Mattioli laboratory (The MCM Lab) encompasses two complementary lines of research. The first one, more traditional but very important, aims at unraveling the molecular mechanisms underlying memory formation (e.g., using state-of-the-art molecular and cell-specific genetic approaches). Learning and memory disorders can strike the brain during development (e.g., Autism Spectrum Disorders and Down Syndrome), as well as during adulthood (e.g., Alzheimer’s disease). We are interested in understanding the specific circuits and molecular pathways that are primarily targeted in these disorders and how they can be restored. To tackle these questions, we use a multidisciplinary, convergent and cross-species approach that combines mouse and fly genetics, molecular biology, electrophysiology, stem cell biology, optogenetics and behavioral techniques. The second line of research, more recent and relatively unexplored, is focused on understanding how gut microbes control CNS driven-behavior and brain function. Our recent discoveries, that microbes in the gut could modulate brain function and behavior in a very powerful way, have added a whole new dimension to the classic view of how complex behaviors are controlled. The unexpected findings have opened new avenues of study for us and are currently driving my lab to answer a host of new and very interesting questions: - What are the gut microbes (and metabolites) that regulate CNS-driven behaviors? Would it be possible to develop an unbiased screening method to identify specific microbes that regulate different behaviors? - If this is the case, can we identify how members of the gut microbiome (and their metabolites) mechanistically influence brain function? - What is the communication channel between the gut microbiota and the brain? Do different gut microbes use different ways to interact with the brain? - Could disruption of the gut microbial ecology cause neurodevelopmental dysfunction? If so, what is the impact of disruption in young and adult animals? - More importantly, could specific restoration of selected bacterial strains (new generation probiotics) represent a novel therapeutic approach for the targeted treatment of neurodevelopmental disorders? - Finally, can we develop microbiota-directed therapeutic foods to repair brain dysfunction in a variety of neurological disorders?

The pharmacology of consciousness

My research uses a range of methods to better understand how the brain’s natural chemicals control complex behaviours, thoughts and perceptions. I also have a particular fascination about the factors that determine the contents of an individual’s conscious experience. In this talk I will present work that sits at the intersection of these two research areas looking at the role of different neurotransmitter systems in driving changes in conscious state. Specifically, I will discuss a series of studies using ambiguous stimuli to explore the neuropharmacological processes that underly alternations in perceptual awareness. By comparing different methods and neurotransmitter systems including: serotonin (psychedelics), noradrenaline (pupillometry) and Glutamate/GABA (Magnetic Resonance Spectroscopy MRS) we can start to tease apart the distinct role that different neurotransmitter systems play in coordinating conscious experience across time.

Brainstorms Festival

The Brainstorms Festival is the No1 online neuroscience and AI event for scientists, businesses, investors and startups. Join and listen to talks from leading scientists, take part in interactive discussions, and network with the people driving neurotech and AI innovation globally. The festival provides a digital playground for visionaries with dozens of medical innovations, panel discussions, workshops, a hackathon, and a neuroethics panel discussion which is crucial topic for neurodiversity and disability rights. Register now and be part of our amazing crowd!

Translational upregulation of STXBP1 by non-coding RNAs as an innovative treatment for STXBP1 encephalopathy

Developmental and epileptic encephalopathies (DEEs) are a broad spectrum of genetic epilepsies associated with impaired neurological development as a direct consequence of a genetic mutation, in addition to the effect of the frequent epileptic activity on brain. Compelling genetic studies indicate that heterozygous de novo mutations represent the most common underlying genetic mechanism, in accordance with the sporadic presentation of DEE. De novo mutations may exert a loss-of-function (LOF) on the protein by decrementing expression level and/or activity, leading to functional haploinsufficiency. These diseases share several features: severe and frequent refractory seizures, diffusely abnormal background activity on EEG, intellectual disability often profound, and severe consequences on global development. One of major causes of early onset DEE are de novo heterozygous mutations in syntaxin-binding-protein-1 gene STXBP1, which encodes a membrane trafficking protein playing critical role in vesicular docking and fusion. LOF STXBP1 mutations lead to a failure of neurotransmitter secretion from synaptic vesicles. Core clinical features of STXBP1 encephalopathy include early-onset epilepsy with hypsarrhythmic EEG, or burst-suppression pattern, or multifocal epileptiform activity. Seizures are often resistant to standard treatments and patients typically show intellectual disability, mostly severe to profound. Additional neurologic features may include autistic traits, movement disorders (dyskinesia, dystonia, tremor), axial hypotonia, and ataxia, indicating a broader neurologic impairment. Patients with severe neuro-cognitive features but without epilepsy have been reported. Recently, a new class of natural and synthetic non-coding RNAs have been identified, enabling upregulation of protein translation in a gene-specific way (SINEUPs), without any increase in mRNA of the target gene. SINEUPs are translational activators composed by a Binding Domain (BD) that overlaps, in antisense orientation, to the sense protein-coding mRNA, and determines target selection; and an Effector Domain (ED), that is essential for protein synthesis up regulation. SINEUPs have been shown to restore the physiological expression of a protein in case of haploinsufficiency, without driving excessive overexpression out of the physiological range. This technology brings many advantages, as it mainly acts on endogenous target mRNAs produced in situ by the wild-type allele; this action is limited to mRNA under physiological regulation, therefore no off-site effects can be expected in cells and tissues that do not express the target transcript; by acting only on a posttranscriptional level, SINEUPs do not trigger hereditable genome editing. After bioinformatic analysis of the promoter region of interest, we designed SINEUPs with 3 different BD for STXBP1. Human neurons from iPSCs were treated and STXBP1 levels showed a 1.5-fold increase compared to the Negative control. RNA levels of STXBP1 after the administration of SINEUPs remained stable as expected. These preliminary results proved the SINEUPs potential to specifically increase the protein levels without impacting on the genome. This is an extremely flexible approach to target many developmental and epileptic encephalopathies caused by haploinsufficiency, and therefore to address these diseases in a more tailored and radical way.

HCN2: a key ion channel driving pain, migraine and tinnitus

Safety in numbers: how animals use motion of others as threat or safety cues

Our work concerns the general problem of adaptive behaviour in response to predatory threats, and of the neural mechanisms underlying a choice between strategies. When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behaviour in rodents, but how contextual information is integrated to guide this choice is still far from understood. The social environment is a potent contextual modulator of defensive behaviours of animals in a group. Indeed, anti-predation strategies are believed to be a major driving force for the evolution of sociality. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices accompanied by lasting changes in the fly’s internal state, reflected in altered cardiac activity. In this talk, I will discuss our work on how flies process contextual cues, focusing on the social environment, to guide their behavioural response to a threat. We have identified a social safety cue, resumption of activity, and visual projection neurons involved in processing this cue. Given the knowledge regarding sensory detection of looming threats and descending neuron involved in the expression of freezing, we are now in a unique position to understand how information about a threat is integrated with cues from the social environment to guide the choice of whether to freeze.

Sensory modalities driving social behavior via the central oxytocin system

Modulation of C. elegans behavior by gut microbes

We are interested in understanding how microbes impact the behavior of host animals. Animal nervous systems likely evolved in environments richly surrounded by microbes, yet the impact of bacteria on nervous system function has been relatively under-studied. A challenge has been to identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. To accomplish these goals, we use an animal host — the roundworm C. elegans, which feeds on bacteria — in combination with its natural gut microbiome to identify inter-organismal signals driving host-microbe interactions and decision-making. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. Using this system, we discovered that commensal bacterial metabolites directly modulate nervous system function of their host. Beneficial gut microbes of the genus Providencia produce the neuromodulator tyramine in the C. elegans intestine. Using a combination of behavioral analysis, neurogenetics, metabolomics and bacterial genetics we established that bacterially produced tyramine is converted to octopamine in C. elegans, which acts directly in sensory neurons to reduce odor aversion and increase sensory preference for Providencia. We think that this type of sensory modulation may increase association of C. elegans with these microbes, increasing availability of this nutrient-rich food source for the worm and its progeny, while facilitating dispersal of the bacteria.

Abstraction and Analogy in Natural and Artificial Intelligence

Learning by analogy is a powerful tool children’s developmental repertoire, as well as in educational contexts such as mathematics, where the key knowledge base involves building flexible schemas. However, noticing and learning from analogies develops over time and is cognitively resource intensive. I review studies that provide insight into the relationship between mechanisms driving children’s developing analogy skills, highlighting environmental inputs (parent talk and prior experiences priming attention to relations) and neuro-cognitive factors (Executive Functions and brain injury). I then note implications for mathematics learning, reviewing experimental findings that show analogy can improve learning, but also that both individual differences in EFs and environmental factors that reduce available EFs such as performance pressure can predict student learning.

The cellular phase of Alzheimer’s Disease: from genes to cells

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggregation or Aβ oligomer formation could not be convincingly demonstrated until now. Indeed, many questions (e.g. what causes Aβ toxicity, what is the relation between Aβ and Tau pathology, what causes neuronal death, why is amyloid deposition not correlated with dementia etc…) were already raised when the amyloid hypothesis was conceived 25 years ago. These questions remain in essence unanswered. It seems that the old paradigm is not tenable: the amyloid cascade is too linear, too neurocentric, and does not take into account the long time lag between the biochemical phase i.e. the appearance of amyloid plaques and neuronal tangles and the ultimate clinical phase, i.e. the manifestation of dementia. The pathways linking these two phases must be complex and tortuous. We have called this the cellular phase of AD (De Strooper and Karran, 2016) to suggest that a long period of action and reaction involving neurons, neuronal circuitry but also microglia, astroglia, oligodendrocytes, and the vasculature underlies the disease. In fact it is this long disease process that should be studied in the coming years. While microglia are part of this process, they should not be considered as the only component of the cellular phase. We expect that further clinical investigations and novel tools will allow to diagnose the effects of the cellular changes in the brain and provide clinical signs for this so called preclinical or prodromal AD. Furthermore the better understanding of this phase will lead to completely novel drug targets and treatments and will lead to an era where patients will receive an appropriate therapy according to their clinical stage. In this view anti-amyloid therapy is probably only effective and useful in the very early stage of the disease and AD does no longer equal to dementia. We will discuss in our talk how single cell technology and transplantation of human iPS cells into mouse brain allow to start to map in a systematic way the cellular phase of Alzheimer’s Disease.

Fast and deep neuromorphic learning with time-to-first-spike coding

Engineered pattern-recognition systems strive for short time-to-solution and low energy-to-solution characteristics. This represents one of the main driving forces behind the development of neuromorphic devices. For both them and their biological archetypes, this corresponds to using as few spikes as early as possible. The concept of few and early spikes is used as the founding principle in the time-to-first-spike coding scheme. Within this framework, we have developed a spike-timing-based learning algorithm, which we used to train neuronal networks on the mixed-signal neuromorphic platform BrainScaleS-2. We derive, from first principles, error-backpropagation-based learning in networks of leaky integrate-and-fire (LIF) neurons relying only on spike times, for specific configurations of neuronal and synaptic time constants. We explicitly examine applicability to neuromorphic substrates by studying the effects of reduced weight precision and range, as well as of parameter noise. We demonstrate the feasibility of our approach on continuous and discrete data spaces, both in software simulations and on BrainScaleS-2. This narrows the gap between previous models of first-spike-time learning and biological neuronal dynamics and paves the way for fast and energy-efficient neuromorphic applications.

Synthesizing Machine Intelligence in Neuromorphic Computers with Differentiable Programming

The potential of machine learning and deep learning to advance artificial intelligence is driving a quest to build dedicated computers, such as neuromorphic hardware that emulate the biological processes of the brain. While the hardware technologies already exist, their application to real-world tasks is hindered by the lack of suitable programming methods. Advances at the interface of neural computation and machine learning showed that key aspects of deep learning models and tools can be transferred to biologically plausible neural circuits. Building on these advances, I will show that differentiable programming can address many challenges of programming spiking neural networks for solving real-world tasks, and help devise novel continual and local learning algorithms. In turn, these new algorithms pave the road towards systematically synthesizing machine intelligence in neuromorphic hardware without detailed knowledge of the hardware circuits.

Interneuron desynchronization and breakdown of long-term place cell stability in temporal lobe epilepsy

Temporal lobe epilepsy is associated with memory deficits but the circuit mechanisms underlying these cognitive disabilities are not understood. We used electrophysiological recordings, open-source wire-free miniaturized microscopy and computational modeling to probe these deficits in a model of temporal lobe epilepsy. We find desynchronization of dentate gyrus interneurons with CA1 interneurons during theta oscillations and a loss of precision and stability of place fields. We also find that emergence of place cell dysfunction is delayed, providing a potential temporal window for treatments. Computation modeling shows that desynchronization rather than interneuron cell loss can drive place cell dysfunction. Future studies will uncover cell types driving these changes and transcriptional changes that may be driving dysfunction.

Neural Circuit Mechanisms of Emotional and Social Processing

How does our brain rapidly determine if something is good or bad? How do we know our place within a social group? How do we know how to behave appropriately in dynamic environments with ever-changing conditions? The Tye Lab is interested in understanding how neural circuits important for driving positive and negative motivational valence (seeking pleasure or avoiding punishment) are anatomically, genetically and functionally arranged. We study the neural mechanisms that underlie a wide range of behaviours ranging from learned to innate, including social, feeding, reward-seeking and anxiety-related behaviours. We have also become interested in “social homeostasis” -- how our brains establish a preferred set-point for social contact, and how this maintains stability within a social group. How are these circuits interconnected with one another, and how are competing mechanisms orchestrated on a neural population level? We employ optogenetic, electrophysiological, electrochemical, pharmacological and imaging approaches to probe these circuits during behaviour.

Recurrent network models of adaptive and maladaptive learning

During periods of persistent and inescapable stress, animals can switch from active to passive coping strategies to manage effort-expenditure. Such normally adaptive behavioural state transitions can become maladaptive in disorders such as depression. We developed a new class of multi-region recurrent neural network (RNN) models to infer brain-wide interactions driving such maladaptive behaviour. The models were trained to match experimental data across two levels simultaneously: brain-wide neural dynamics from 10-40,000 neurons and the realtime behaviour of the fish. Analysis of the trained RNN models revealed a specific change in inter-area connectivity between the habenula (Hb) and raphe nucleus during the transition into passivity. We then characterized the multi-region neural dynamics underlying this transition. Using the interaction weights derived from the RNN models, we calculated the input currents from different brain regions to each Hb neuron. We then computed neural manifolds spanning these input currents across all Hb neurons to define subspaces within the Hb activity that captured communication with each other brain region independently. At the onset of stress, there was an immediate response within the Hb/raphe subspace alone. However, RNN models identified no early or fast-timescale change in the strengths of interactions between these regions. As the animal lapsed into passivity, the responses within the Hb/raphe subspace decreased, accompanied by a concomitant change in the interactions between the raphe and Hb inferred from the RNN weights. This innovative combination of network modeling and neural dynamics analysis points to dual mechanisms with distinct timescales driving the behavioural state transition: early response to stress is mediated by reshaping the neural dynamics within a preserved network architecture, while long-term state changes correspond to altered connectivity between neural ensembles in distinct brain regions.

Age Effects on Eye Blink-Related Neural Activity and Functional Connectivity in Driving

Bernstein Conference 2024

Unsupervised sparse deconvolutional learning of features driving neural activity

COSYNE 2022

Unsupervised sparse deconvolutional learning of features driving neural activity

COSYNE 2022

An adaptive state-space control framework for driving decision variables

COSYNE 2025

Behavioural strategies and brain-wide neural circuits driving postural control in larval zebrafish

Cell-type specific chromatin profiling of human MDD disease signature identifies novel epigenetic mechanisms of astrocyte plasticity driving bidirectional stress response

Descending neuron population activity driving limb-dependent behaviors

Development of a sound processor driving optical cochlear implant for behavioural experiments in animals

Microglial response is a pathogenic driving mechanism in the Ndufs4 KO mouse model of Leigh syndrome

Driving effect of distal surround stimuli on primary visual cortex firing rates

FENS Forum 2024

Evidence for central-pattern-generator circuits driving the REM-NREM sleep cycle

FENS Forum 2024

Eyeblink patterns in simulated sports driving: The impact of driving performance, eyeblink rate, and individual factors

FENS Forum 2024

Functional architecture of dopamine neurons driving fear extinction learning

FENS Forum 2024

Functional stimulation system for rehabilitation of gait and driving neural plasticity after spinal cord injury

FENS Forum 2024

Neural dynamics of mood-influenced driving using fMRI: Connectivity patterns and speed variations

FENS Forum 2024

Time is of the essence: Exploring excitation/inhibition imbalance driving distinct functional network phenotypes in ASD

FENS Forum 2024