resilience

Investigating the nonlinear complex dynamics of the tuft cell-microbiome cross-talk: the impact of feedback loops on immune regulation, microbial modulation and response to tissue insults

Project Abstract Tuft cells (TCs) are specialized chemosensory epithelial cells that are emerging as critical regulators of intestinal homeostasis. Named over 70 years ago based on their distinct morphology, a defined function for TCs was only elucidated in the last decade. TCs in the small intestine sense succinate from helminths to initiate type 2 immune responses that mediate parasite expulsion. Recently, we discovered a novel physiologic function for TCs in the colon, where their role had been considered minimal. Succinate, a key microbial metabolite, is produced by colonic microbiota as both a precursor to other metabolites and a cross-feeding fuel source for pathogens. TCs respond to succinate by secreting interleukin-25 (IL-25), which activates type 2 cytokine- producing lymphocytes (T2Ls), amplifying TC expansion and reinforcing barrier function. We recently demonstrated that this SPB–TC–IL-25–T2L feedback loop is essential for protection against pathogen-induced colitis. Our preliminary data further suggest that TCs actively promote colonization by succinate-producing bacteria (SPBs), establishing positive feedback on TC-supporting microbes, while other epithelial cells such as goblet cells (GCs) and Paneth cells (PCs) may exert complementary or counterbalancing influences. Supported by new modeling insights, we hypothesize that these epithelial–immune–microbiome interactions form coordinated feedback loops that collectively optimize intestinal resilience. These loops may create a dynamic, multi-stable system that flexibly transitions between homeostatic and hyperplastic states, buffering against microbial fluctuations and pathogenic insults while preventing uncontrolled type 2 inflammation. Using a combination of mathematical modeling and experimental validation, we will develop a multi- layered systems framework to explore how epithelial–immune–microbial feedbacks shape resilience or breakdown in clinically relevant models of colonic infection and inflammation. Our three Aims will (1) develop, calibrate, and validate a mathematical model that integrates TCs, GCs, PCs, SPBs, and SCBs; (2) define the immunological circuits governing epithelial–microbiome equilibrium; and (3) determine how epithelial feedbacks regulate microbial community structure and resilience. In line with NIH’s new initiative to prioritize human-based research, our proposal combines computational modeling, human colonic organoids, and complementary mouse models. Organoid experiments will provide human-relevant data for model calibration, while in vivo studies validate systemic predictions, ensuring both rigor and translational relevance while minimizing reliance on animal models. This work will generate interoperable models that integrate epithelial, microbial, and immune networks, providing predictive insight into intestinal outcomes under homeostatic, infectious, and inflammatory conditions and informing therapeutic strategies for microbiome-targeted interventions.

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.

Overcoming Treatment Resistance by Targeting Polyploid Breast Cancer Cells with AI assisted Single-Cell Analysis

Therapy resistance remains a formidable challenge in breast cancer treatment, with emerging evidence identifying polyploid giant cancer cells (PGCCs) as key drivers. These cells, arising through whole-genome doubling (WGD) events, exhibit enhanced resistance to therapies, contributing to disease relapse. PGCCs are characterized by enlarged cell and nuclear sizes, increased DNA content, and greater resilience compared to non-PGCCs. Their prevalence escalates with disease progression and therapeutic stress, underscoring their critical role in treatment resistance. As such, we hypothesize that inhibiting polyploid cancer cells can effectively reduce therapeutic resistance. Despite this, effective strategies targeting PGCCs are limited, hindered by the lack of high-throughput methods to assess PGCC viability and abundance. Traditional screening assays lack the sensitivity to detect the elimination of small populations of PGCCs, while current detection methods, such as visual inspection and flow cytometry, are not suited for high-throughput compound screening. Our preliminary work has established a high-throughput single-cell morphological analysis pipeline capable of quantifying PGCCs, and we successfully screened 2,726 compounds for their efficacy on PGCCs. Based on the preliminary success, we aim to further improve its robustness and accuracy under diverse staining and imaging conditions, ensuring consistent performance across multiple labs for widespread use in PGCC/WGD studies, with deep learning to accelerate the discovery of therapeutic strategies targeting PGCCs. In addition to empirical screening, our scRNA-Seq analysis of PGCCs has revealed altered gene expression, particularly in genes associated with FOXM1, a transcription factor critical in cell cycle regulation and linked to poor outcomes in various cancers. PGCCs also show altered ferroptosis regulators and elevated reactive oxygen species (ROS), indicating susceptibility to ferroptosis. Here, we propose two independent and complementary aims. Aim 1: We will develop and validate a robust deep learning–based single-cell morphological analysis pipeline for accurate PGCC/non-PGCC discrimination across variable staining, imaging, and lab settings. The model will be benchmarked on independent datasets from external labs and released as open-source, version-controlled software with full documentation to support reproducibility and broad adoption in PGCC/WGD research. Aim 2: Leveraging our screen of 2,726 FDA-approved compounds and mechanistic studies of FOXM1 and ferroptosis, we will prioritize and validate therapies that eradicate PGCCs and reduce treatment resistance. Using patient- derived cells, 3D spheroids, and syngeneic/xenograft models, we will rigorously assess top candidates as monotherapy and in combination with standard-of-care agents. Successful completion of this project will accelerate PGCC/WGD research, advance therapeutic strategies to overcome breast cancer resistance, and especially deliver benefits to patients with high PGCC burden. Given the prevalence of WGD across solid tumors and its induction by standard therapies, our approach holds broad clinical relevance and translational impact.

Spatial Mapping to Detail the Role of Biomolecules in Governing Biofilm Organization and Resiliency to Stress in Pseudomonas aeruginosa Biofilms

PROJECT SUMMARY The bacterium Pseudomonas aeruginosa is a leading cause of hospital acquired infections, exhibiting substantial antibiotic tolerance due to growth in biofilms. Our previous work shows how biofilm fitness is increased by alkyl quinolones (AQs), a class of molecules produced by the Pseudomonas Quinolone Signal (PQS) pathway of Pseudomonas aeruginosa. AQs form aggregates that spatially limit regions of cell death and reduce overall cell death in biofilms. Spatial studies build on ”what” molecules are doing by revealing when, where, and with whom they are found. Others have shown that AQs transiently bind amyloids and our preliminary results find that amyloid localization is shifted in the absence of AQs. However, the spatial relationships of these molecules have not been investigated. Our research combines multiple spatial analytical techniques, such as fluorescence microscopy, polarized light microscopy, confocal Raman microscopy to assemble detailed maps of AQ and amyloid localization during biofilm development. Using transgenic strains we will also determine amyloid distribution as a function of AQ abundance. This work will build on previous findings that AQ concentrations are able to shift locally in response to stress. We hypothesize that this can impact the localization of amyloids and allow biofilms to respond locally to stress, shielding the greater biofilm from damage. We will map biomolecular distribution of entire colony biofilms in response to stress to determine if local responses have the ability to shield more distal regions of the biofilm. The capacity of spatial biomolecular organization to increase bacterial resilience and infection virulence is an understudied area that has the potential to bring to light to novel targets for therapeutics to fight biofilm infections.

Decoding stress vulnerability

Although stress can be considered as an ongoing process that helps an organism to cope with present and future challenges, when it is too intense or uncontrollable, it can lead to adverse consequences for physical and mental health. Social stress specifically, is a highly prevalent traumatic experience, present in multiple contexts, such as war, bullying and interpersonal violence, and it has been linked with increased risk for major depression and anxiety disorders. Nevertheless, not all individuals exposed to strong stressful events develop psychopathology, with the mechanisms of resilience and vulnerability being still under investigation. During this talk, I will identify key gaps in our knowledge about stress vulnerability and I will present our recent data from our contextual fear learning protocol based on social defeat stress in mice.

Rejuvenating the Alzheimer’s brain: Challenges & Opportunities

Unlocking the Secrets of Microglia in Neurodegenerative diseases: Mechanisms of resilience to AD pathologies

How Intermittent Bioenergetic Challenges Enhance Brain and Body Health

Humans and other animals evolved in habitats fraught with a range of environmental challenges to their bodies and brains. Accordingly, cells and organ systems possess adaptive stress-responsive signaling pathways that enable them to not only withstand environmental challenges, but also to prepare for future challenges and function more efficiently. These phylogenetically conserved processes are the foundation of the hormesis principle in which repeated exposures to low to moderate amounts of an environmental challenge improve cellular and organismal fitness. Here I describe cellular and molecular mechanisms by which cells in the brain and body respond to intermittent fasting and exercise in ways that enhance performance and counteract aging and disease processes. Switching back and forth between adaptive stress response (during fasting and exercise) and growth and plasticity (eating, resting, sleeping) modes enhances the performance and resilience of various organ systems. While pharmacological interventions that engage a particular hormetic mechanism are being developed, it seems unlikely that any will prove superior to fasting and exercise.

From the guts to the brain through adaptive immunity in the prevention of Alzheimer’ disease

Dr. Pasinetti is the Saunders Family Chair and Professor of Neurology at Icahn School of medicine at Mount Sinai, New York. His studies allowed him to develop novel therapeutic approaches through investigation of preventable risk factors including mood disorders in the promotion of resilience against neurodegenerative disorder. In his presentation Dr. Pasinetti will discuss novel concepts about the gut-brain axis in mechanisms associated to peripheral adaptive immunity as therapeutic targets to mitigate the onset and the progression of Alzheimer’s disease and other form of dementia.

The Picower Institute Spring 2023 Symposium "Environmental and Social Determinants of Child Mental Health

Studies show that abuse, neglect or trauma during childhood can lead to lifelong struggles including with mental health. Fortunately research also indicates that solutions and interventions at various stages of life can be developed to help. But even among people who remain resilient or do not experience acute stresses, a lack of opportunity early in life due to poverty or systemic racism can still constrain their ability to realize their full potential. In what ways are health and other outcomes affected by early life difficulty? What can individuals and institutions do to enhance opportunity?" "This daylong event will feature talks by neuroscientists, policy experts, physicians, educators and activists as they discuss how our experiences and biology work together to affect how our minds develop and what can be accomplished in helping people overcome early disadvantages.

Early life adversity, inflammation, and depression-onset: Results from the Teen Resilience Project

My research focuses broadly on the lifelong health disparities associated with experiences of adversity early in life. In this talk I will present the results of our recently completed Teen Resilience Project, a prospective and longitudinal study of first onset depression during adolescence. First, I will present the results on whether and how inflammatory processes may be shaped by early life adversity. Second, I will present data on the role of stress-induced inflammation in reward-related psychological processes. Finally, I will discuss the biobehavioral predictors of first-onset depression in this sample.

Biopsychosocial pathways in dementia inequalities

In the United States, racial/ethnic inequalities in Alzheimer's disease and related dementias persist even after controlling for socioeconomic factors and physical health. These persistent and unexplained disparities suggest: (1) there are unrecognized dementia risk factors that are socially patterned and/or (2) known dementia risk factors exhibit differential impact across social groups. Pursuing these research directions with data from multiple longitudinal studies of brain and cognitive aging has revealed several challenges to the study of late-life health inequalities, highlighted evidence for both risk and resilience within marginalized communities, and inspired new data collection efforts to advance the field.

Growing Up in Academia with Onur Güntürkün

There are stories of resilience, passion, braveness and determination and the one of Onur Güntürkün. He has managed to beat the odds in so many ways, from moving countries, surviving the polio, establishing a new field against the advice of a senior professor and much more, all the while keeping a positive spirit, an endless curiosity and the braveness to keep going despite adversities. Join me on Monday, February 28, 2022, 6 p.m. (CET) for a Growing Up in Academia with Onur Güntürkün.

NMC4 Short Talk: Resilience through diversity: Loss of neuronal heterogeneity in epileptogenic human tissue impairs network resilience to sudden changes in synchrony

A myriad of pathological changes associated with epilepsy, including the loss of specific cell types, improper expression of individual ion channels, and synaptic sprouting, can be recast as decreases in cell and circuit heterogeneity. In recent experimental work, we demonstrated that biophysical diversity is a key characteristic of human cortical pyramidal cells, and past theoretical work has shown that neuronal heterogeneity improves a neural circuit’s ability to encode information. Viewed alongside the fact that seizure is an information-poor brain state, these findings motivate the hypothesis that epileptogenesis can be recontextualized as a process where reduction in cellular heterogeneity renders neural circuits less resilient to seizure onset. By comparing whole-cell patch clamp recordings from layer 5 (L5) human cortical pyramidal neurons from epileptogenic and non-epileptogenic tissue, we present the first direct experimental evidence that a significant reduction in neural heterogeneity accompanies epilepsy. We directly implement experimentally-obtained heterogeneity levels in cortical excitatory-inhibitory (E-I) stochastic spiking network models. Low heterogeneity networks display unique dynamics typified by a sudden transition into a hyper-active and synchronous state paralleling ictogenesis. Mean-field analysis reveals a distinct mathematical structure in these networks distinguished by multi-stability. Furthermore, the mathematically characterized linearizing effect of heterogeneity on input-output response functions explains the counter-intuitive experimentally observed reduction in single-cell excitability in epileptogenic neurons. This joint experimental, computational, and mathematical study showcases that decreased neuronal heterogeneity exists in epileptogenic human cortical tissue, that this difference yields dynamical changes in neural networks paralleling ictogenesis, and that there is a fundamental explanation for these dynamics based in mathematically characterized effects of heterogeneity. These interdisciplinary results provide convincing evidence that biophysical diversity imbues neural circuits with resilience to seizure and a new lens through which to view epilepsy, the most common serious neurological disorder in the world, that could reveal new targets for clinical treatment.

Mature retina is resilient to partial photoreceptor loss

I will discuss recent findings from our lab about the effects of partial photoreceptor loss on the retinal circuit’s structure and function. I will relate this work to the question of whether the visual system can distinguish between changes in light level and photoreceptor number.

The Picower Institute Spring 2021 Symposium: Early Life Stress & Mental Health

Though studies show that abuse, neglect or trauma during childhood can lead to lifelong lifelong struggles including in mental health, research also indicates that solutions and interventions at various stages of life can be developed to help. And while many people manage to remain resilient, a lack of opportunity early in life, including because of poverty and systemic racism, can constrain their ability to realize their full potential. In what ways are health and other outcomes affected? How can systems instead restore opportunity? "The Picower Institute for Learning and Memory's biennial spring symposium, 'Early Life Stress & Mental Health,' will examine these issues. The daylong event will feature talks by neuroscientists, policy experts, physicians, educators and activists as they discuss how our experiences and biology work together to affect how our minds develop and what can be accomplished in helping people overcome early disadvantages.

The Impact of Racism-related Stress on Neurobiological Systems in Black Americans”

Black Americans experience diverse racism-related stressors throughout the lifespan. Disproportionately high trauma exposure, economic disadvantage, explicit racism and inequitable treatment are stressors faced by many Black Americans. These experiences have a cumulative negative impact on psychological and physical health. However, little is understood about how experiences of racism, such as discrimination, can mediate health outcomes via their effects on neurobiology. I will present clinical, behavioral, physiological and neurobiological data from Black American participants in the Grady Trauma Project, a longstanding study of trauma conducted in inner-city Atlanta. These data will be discussed in the context of both risk and resilience/adaptation perspectives. Finally, recommendations for future clinical neuroscience research and targets for intervention in marginalized populations will be discussed.

Advancing Communication Science to Address Tobacco-Related Health Disparities

Tobacco use is the leading cause of preventable deaths and illnesses in the United States and globally. Sexual, racial, ethnic minorities, young adults, and populations from rural areas and lower socioeconomic positions are disproportionately impacted by the health harms of tobacco use and exposure to secondhand smoke. In this talk, Andy Tan, Associate Professor at the Annenberg School for Communication, will provide an overview of integrating communication science to address inequalities in health information exposure, message processing, and behavioral effects associated with pro- and anti-tobacco communications among vulnerable populations. He will present findings from recent work including examining inequities in tobacco advertising exposure among young adult sexual minorities, experiences of smoking risk and protective factors among transgender and gender expansive adults, and development of a culturally responsive communication intervention to increase resilience against tobacco marketing influences and reduce smoking among young adult LGB women.

Social deprivation, coping and drugs: a bad cocktail in the COVID-19 era: evidence from preclinical studies

The factors that underlie an individual’s vulnerability to switch from controlled, recreational drug use to addiction are not well understood. I will discuss the evidence in rats that in individuals housed in enriched conditions, the experience of drugs in the relative social and sensory impoverishment of the drug taking context, and the associated change in behavioural traits of resilience to addiction, exacerbate the vulnerability to develop compulsive drug intake. I will further discuss the importance of the acquisition of alcohol drinking as a mechanism to cope with distress as a factor of exacerbated vulnerability to develop compulsive alcohol intake. Together these results demonstrate that experiential factors in the drug taking context, which can be substantially driven by social isolation, shape the vulnerability to addiction.

Logical Neural Networks

The work to be presented in this talk proposes a novel framework seamlessly providing key properties of both neural nets (learning) and symbolic logic (knowledge and reasoning). Every neuron has a meaning as a component of a formula in a weighted real-valued logic, yielding a highly interpretable disentangled representation. Inference is omnidirectional rather than focused on predefined target variables, and corresponds to logical reasoning, including classical first-order logic theorem proving as a special case. The model is end-to-end differentiable, and learning minimizes a novel loss function capturing logical contradiction, yielding resilience to inconsistent knowledge. It also enables the open-world assumption by maintaining bounds on truth values which can have probabilistic semantics, yielding resilience to incomplete knowledge.

Differential Resilience of Neurons and Networks with Similar Behavior to Perturbation

Both computational and experimental results in single neurons and small networks demonstrate that very similar network function can result from quite disparate sets of neuronal and network parameters. Using the crustacean stomatogastric nervous system, we study the influence of these differences in underlying structure on differential resilience of individuals to a variety of environmental perturbations, including changes in temperature, pH, potassium concentration and neuromodulation. We show that neurons with many different kinds of ion channels can smoothly move through different mechanisms in generating their activity patterns, thus extending their dynamic range.

Differential Resilience of Neurons and Networks with Similar Behavior to Perturbation. (Simultaneous translation to Spanish)

Both computational and experimental results in single neurons and small networks demonstrate that very similar network function can result from quite disparate sets of neuronal and network parameters. Using the crustacean stomatogastric nervous system, we study the influence of these differences in underlying structure on differential resilience of individuals to a variety of environmental perturbations, including changes in temperature, pH, potassium concentration and neuromodulation. We show that neurons with many different kinds of ion channels can smoothly move through different mechanisms in generating their activity patterns, thus extending their dynamic range. The talk will be simultaneously translated to spanish by the interpreter Liliana Viera, MSc. Los resultados tanto computacionales como experimentales en neuronas individuales y redes pequeñas demuestran que funcionamientos de redes muy similares pueden pueden resultar de conjuntos bastante dispares de parámetros neuronales y de las redes. Utilizando el sistema nervioso estomatogástrico de los crustáceos, estudiamos la influencia de estas diferencias en la estructura subyacente en la resistencia diferencial de los individuos a una variedad de perturbaciones ambientales, incluidos los cambios de temperatura, pH, concentración de potasio y neuromodulación. Mostramos que neuronas con muchos tipos diferentes de canales iónicos pueden moverse suavemente a través de diferentes mecanismos para generar sus patrones de actividad, extendiendo así su rango dinámico. La conferencia será traducida simultáneamente al español por la intérprete Liliana Viera MSc.

Stress and the developing brain - molecular mechanisms of risk and resilience

Adult Neurogenesis, Enriched Environments, and the Neurobiology of Early Life-style Dependent Resilience

Resilience to sensory uncertainty in the primary visual cortex

COSYNE 2023

Anxiety levels after vicarious social defeat stress are associated with vulnerability and resilience to cocaine-induced conditioned place preference in female mice

Behavioural Markers of Resilience and Susceptibility in a Neurodevelopmental Two-Hit Model of Schizophrenia

Behavioural and neuropathological characterization of a rat model of resilience in the field of Alzheimer’s Disease

Does physical exercise offer resilience in a social defeat stress mouse model?

Fear circuit-based neurobehavioral signatures and transcriptional networks promoting resilience to chronic social stress

Functional protection in J20/VLW mice: a model of cognitive resilience to Alzheimer’s disease

GABAergic modulation of cortical excitability and resilience to seizures

High Resilience of Cerebellum Across the Life-Span: Imaging Genomics Leads for identifying and validating Neuroprotective Drug Discovery

Hypothalamic pacemaking mechanism that drives acclimation-induced heat resilience

Oxidative balance alterations in the rat ventral hippocampus are associated to the vulnerability and resilience to stress-induced anhedonia

Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress

The role of locus coeruleus-noradrenergic system in resilience following child abuse

The role of Rev-ERBα circadian clock gene in stress resilience and development of depression-like behaviour

Stress resilience in SCA3: study of depression and cognitive comorbidities in a mouse model

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

The VPAC2 Receptor Mediates Resilience to Stress in Female, but Not Male Mice

Beta-caryophyllene (BCP) and stress resilience: Behavioral and molecular insights in depression-related disorders

FENS Forum 2024

Central role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to anxiety

FENS Forum 2024

Effects of early handling and sex on cognitive resilience in APP/PS1 mice

FENS Forum 2024

Home tobacco smoke exposure and family resilience scores among U.S. children

FENS Forum 2024

The epicenter of trauma resilience?

FENS Forum 2024

Increased intestinal permeability and unexpected resilience to DSS colitis-induced sickness behaviour in the Neuroligin-3R451C mouse model of autism

FENS Forum 2024

LOU/c/Jall rat as a resilience model in the context of sporadic Alzheimer’s disease induced by streptozotocin

FENS Forum 2024

A maternal diet enriched with African walnuts confers neurodevelopmental resilience to MnCl2-induced neurotoxic cascades in rats

FENS Forum 2024

Metabolic neural constraints provide resilience to noise in feed-forward networks

FENS Forum 2024

Modeling pain sensitivity in healthy individuals: The influence of emotional traits and resilience

FENS Forum 2024

Resilience to changes in hippocampal excitatory synapses contribute to cognitively healthy Tg2576 mice

FENS Forum 2024

Unraveling the interplay between psychological resilience, intrinsic functional connectivity and processing speed in healthy ageing

FENS Forum 2024

Unveiling molecular signatures in resilience following child abuse: Noradrenergic cells transcriptomics in human post-mortem tissues

FENS Forum 2024