New York University

NIH Research Projects · FY 2025 · 2016-06

PROJECT SUMMARY The human genome is constantly attacked from sources that include environmental pollutants, other exogenous origins that include drug treatment, endogenous reactive oxygen species, and UV light. Among the lesions/adducts are ones derived from polycyclic aromatic compounds, found at toxic waste dumps, superfund sites, in our air, food and water. The resulting DNA lesions cause mutations that lead to cancer. However, not all DNA lesions are equally carcinogenic, as their mutagenic propensities vary: a cascade of processes determines whether they are repaired, or survive for mutagenic or error-free bypass by DNA polymerases. Human nucleotide excision repair (NER) is a key mechanism for removal of many such DNA lesions. The vital importance of NER is demonstrated in the devastating human disorder xeroderma pigmentosum, caused by mutations in NER genes. Notably, some lesions are rapidly repaired, some slowly, and some are resistant and thus particularly genotoxic, a phenomenon that is poorly understood. Likewise, there is a gap in our understanding of the mechanisms underlying DNA lesion bypass by polymerases that can lead to a mutagenic or error-free outcome. The objective of this project is to provide mechanistic insights into the puzzling variability of DNA lesion mutagenicity, focusing on the key steps of lesion recognition for repair and mutagenic bypass, to yield integrated new molecular and dynamic understanding of lesion mutagenic proclivity in unprecedented atomistic detail, using molecular dynamics simulations. Our overall hypothesis is that the structure of the lesion and its base sequence context determine its overall mutagenic propensity. In Aim 1, we will utilize a selected set of DNA lesions/adducts whose structures differ greatly in size and shape, placed in differing sequence contexts, to determine structural, energetic and dynamic characteristics of the lesion-containing DNAs as they bind to Rad4/XPC, the yeast homolog of the human XPC lesion recognition protein. We will reveal how those that bind for productive recognition leading to excision differ from those that fail to do so. In Aim 2 we will determine how the human XPD helicase in TFIIH, that verifies the presence of lesions for NER by stalling, processes lesions of different sizes and shapes, and how XPD mutations that cause human disease inhibit XPD’s function. In Aim 3 we will determine how differing lesion structures in varying nucleosomal positions impose different distortions on the nucleosome and how selected histone acetylations modulate these distortions, to promote or inhibit access for repair. In Aim 4 we investigate endogenous and exogenous DNA peptide crosslink lesions, to determine how selected DNA bypass polymerases process them error-free or mutagenically, in differing DNA sequence contexts. Focusing on the most mutagenic lesions, our work will facilitate identification of appropriate biomarkers for determining risk of developing cancer, advance design of chemotherapy drugs that are less repaired, and yield a predictive tool to identify mutational hotspot sequences induced by different lesions in human tumors.

NIH Research Projects · FY 2025 · 2013-03

Project Summary / Abstract The goal of this research is to discover the cortical computations that determine the response properties of neurons in visual cortical areas V2 and V4, two of the largest visual areas outside the primary visual cortex (V1) in primates. These areas are critical conduits from the primary visual cortex to temporal lobe areas responsible for the recognition and recollection of visually presented objects and scenes. V2 receives a strong direct input from V1, and depends on V1 for its visual responsiveness. We have developed a two-stage model, in which responses are constructed from a suitable combination of V1 afferents, with the design of each stage following a common canonical form. We have characterized the strengths and limitations of this model, and compared it in detail with a related neural net model trained on natural image data. We will now extend and refine our model by giving it additional capabilities, and we will improve the power of our fitting procedures by using data recorded simultaneously from populations of neurons. The next step is to extend understanding to V4, which receives the bulk of its direct input from V2. We are not yet ready to build a principled model of how V4 combines inputs from V2. We believe that V4’s functional circuitry will be similar to that of V2, but in advance of the complete model for V2 we lack a precise account of V4’s inputs. Measurements of V4 responses demonstrate enhanced representation of complex image features, which encourages us to build a model based on both single-neuron and population responses to account for the way it transforms input from V2. To complement the development of the neural model, we will also develop and extend our neural network model that is trained on natural images. A key component of V4’s response is its selectivity for complex forms. Our measurements of selectivity along the image continuum between natural forms and statistically matched textures demonstrated that information about this continuum is captured by relatively late components of the visual response. We will therefore use reverse correlation methods to explore the nature and dynamics of V4 responses to textures, natural images, and suitable image elements. We will also study responses to distorted natural images generated by a diffusion model trained on natural images, which embody an implicit representation of the high dimensional space that those images occupy. This will allow us to explore whether and how neurons in V4 and related areas have a similar implicit representation of the universe of natural images. The outcome of this work will be a new understanding of the functions of V2 and V4. These areas are of interest both because of their potential as a substrate for visual loss and recovery after brain damage, and because they are key parts of the processing chain by which visual signals are transformed to form decisions, guide actions, and create enduring memories of evanescent events.

NIH Research Projects · FY 2025 · 2011-09

PROJECT SUMMARY Stochastic switches are a broad class of genetic mechanisms that enable single cells to switch certain genes on and off randomly, without responding to their environment. Such switches are prevalent in pathogenic bacteria, where they are often involved in generating diverse surface protein repertoires across the bacterial population, which enables a subset of cells to avoid detection by the immune system. In general, stochastic switches provide a strategy for survival in fluctuating environments, by maintaining subpopulations of cells in pre-adapted states that are prepared for future, possibly unpredictable, environmental stresses. In particular, these strategies are known to be important in antibiotic persistence, a non-genetic, reversible, physiological state with enhanced tolerance for antibiotics that occurs in a subpopulation of bacterial cells. This grant applies novel microfluidic devices that enable single cell observations persister cell lineages, with transcriptomics, and bioinformatics to study three major facets of stochastic switching. We use microscopy and synthetic biology to understand why bacterial aggregation, a behavior that enhances survival under antimicrobial treatment, is regulated by stochastic switching, and how to reverse aggregate states using small molecule inhibitors of key genetic pathways. We use a novel custom microfluidics setup that enables single- cell lineage tracking on hundreds of thousands of cells to observe antibiotic persister states that could not previously be observed, and apply transcriptomics to reveal molecular mechanisms of persistence. We use a new population genetic approach to modeling bacterial recombination, which can be flexibly applied to infer recombination parameters from large-scale genomic and metagenomic sequencing datasets. We apply this method to study how stochastic switching is influenced by recombination in the context of the human gut microbiome. The proposed research will substantially advance understanding of the role of stochastic switches, aggregation, and recombination in bacterial adaptation. Through its emphasis on precise quantification using powerful single cell microfluidics and microscopy, the research will yield new avenues to address antibiotic persistence of bacteria, to perturb bacterial aggregated states, and to understand how the human gut environment selects for and maintains antibiotic resistance and surface antigen genes.

NIH Research Projects · FY 2026 · 2009-09

Project Summary The remarkable regenerative potential of the liver in young mammals is due to the ability of quiescent hepatocytes to nimbly respond to mitogenic signals. This relies on a well-coordinated gene regulatory program, which we propose is embedded in the hepatic epigenome. The epigenome serves dual roles in regulating gene expression and in protecting cells from the threat of transposable elements (TEs), which if unleashed can cause DNA damage and genomic instability. A complex combination of epigenetic marks organizes the genome into regions (i.e. chromatin states) which dictate which regions stay open and which stay closed. Closed chromatin states encompass silenced genes and most TEs. Open chromatin states contain actively transcribed genes as well as genes held in a poised configuration in anticipation of signals that alter their expression to change cellular function or identity. We discovered that genes that promote liver regeneration are poised in quiescent livers, with repressive (H3K27me3) and activating (H3K4me3) marks. Since H3K27me3 was lost on these genes during regeneration, we conclude this is a key element of the epigenetic code that confers regenerative potential to young livers. We uncovered a surprising flexibility in this code through studying the epigenetic regulator, UHRF1, which is essential for maintaining DNA methylation during DNA replication. We found that Uhrf1 loss in hepatocytes (Uhrf1HepKO) resulted in global DNA hypomethylation, but did not activate TEs. We attributed this to epigenetic compensation by H3K27me3, which became enriched on hypomethylated TEs and depleted from promoters in Uhrf1HepKO mice, with a concomitant premature activation of pro-regenerative genes and accelerated liver regeneration in these mice. Our central hypothesis is that the youthful epigenetic code permits transcription factor access to pro-regenerative genes while restricting access to TEs, and that this code is rewritten during aging, resulting in TE activation and regenerative decline. We further hypothesize that UHRF1 and H3K27me3 are key elements of this code. To test this, we will identify the molecular mechanisms of epigenetic compensation in young Uhrf1HepKO livers and will examine the role of H3K27me3 in pro- regenerative genes regulation in wild type livers (Aim 1). By Integrating epigenomic and transcriptomic profiling of aged mouse and human livers compared to chromatin states in young livers, we will establish how aging repatterns the hepatic epigenome to repress pro-regenerative genes and activate TEs (Aim 2). In Aim 3, we explore whether depleting H3K27me3 can rejuvenate the liver. Together, the outcomes of this work will uncover how the dual roles of the epigenome – gene regulation and suppression of transposon threat – are integrated in regulating liver regeneration in young mice and will provide a foundation to manipulate the epigenome to augment regenerative potential in the elderly and those suffering from liver failure.

NIH Research Projects · FY 2025 · 2007-02

Mechanisms of neural patterning and the generation of neural diversity in the brain. We have shown that neural diversity in the optic lobe of Drosophila is generated by three mechanisms: Each neural stem cell (neuroblast; NB) expresses sequentially a series of temporal transcription factors (tTF) and divides to produce an intermediate precursor that divides once more to generate a NotchON and a NotchOFF neuron. The neuroepithelium that generates NBs is patterned by spatial TFs (sTFs) and by signaling molecules. Different regions of the neuroepithelium generate NBs that undergo the same tTF series but produce different neurons due to spatial patterning of the neuroepithelium of origin. We offer to continue our investigations into the development of the medulla and address whether stochastic factors complement the deterministic and intrinsic programs that generate diversity (Aim 1) and investigate how many different spatial regions comprise the NE and how this spatial patterning controls the stoichiometry of neurons (Aim 2). There are many more than 800 NBs to produce neurons populating the 800 medulla columns that process visual information from the 800 unit-eyes in the fly retina. We will test whether an excess number of the same neurons is produced from all the NBs and culled later by apoptosis, or whether the temporal series progresses independently of cell cycle: In the latter case, the lack of coordination between the progression of the temporal series and cell cycle introduces a stochastic component that would allow flexibility in the identity (and number) of the neurons produced by each NB. The role of stochastic patterning of neural stem cells has been demonstrated in mammals but is very poorly understood. The repetitive structure and precise genetic manipulations in the fly optic lobe make this system ideal to address these questions: Aim 1: Progression of the temporal series and cell cycle: The many NBs (at least twice as many as columns) suggest that neurons are produced in excess and culled, or that each NB only produces stochastically a subset of the neurons. Aim 1.1: Do NBs produce excess numbers of neurons and those that do not find a partner are later culled by cell death? Aim 1.2: Is the progression of temporal windows coordinated with cell cycle? Aim 1.3: Are all temporal windows used to generate all the neurons that a given NB could produce? Aim 1.4: What is the temporal window of origin of the ~100 medulla neurons? Aim 1.5: Does the length of temporal windows determine the number of neurons produced at each temporal window? Aim 1.6: Does the speed of transition of temporal windows rely on regulation of RNA stability and/or translation status? Aim 2: Spatial patterning and epigenetic memory: How do NBs from different spatial domains undergo the same temporal series but produce different neurons in different stoichiometry? Aim 2.1: How does Dpp signaling generate at least three subdomains within one of the spatial domains? Aim 2.2: Define new spatial sub-domains using scRNAseq of neuroepithelial cells Aim 2.3: Is the spatial identity of neuroepithelial cells transmitted to NBs and neurons by epigenetic memory? Aim 2.4: Use scRNAseq to identify the neurons produced by each spatial domain. Aim 2.5: How does the integration of spatio-temporal patterning and Notch signaling control neuronal features?

NIH Research Projects · FY 2026 · 2002-07

Project Summary Memories are essential for survival and contribute to numerous brain functions. The storage of long-term memories takes time: newly formed memories are initially labile, but over time stabilize and strengthen through a process known as memory consolidation. Defects in this process underlie many devastating conditions associated with cognitive impairment, including neurodevelopmental disorders and neurodegenerative diseases. Therefore, elucidating the molecular mechanisms underlying memory consolidation and strengthening is key to understanding how memories function and ultimately developing novel, effective therapies to treat cognitive impairments. Over 25 years of work in this field, our group has identified fundamental molecular mechanisms of memory consolidation in the rat and mouse hippocampus, a brain region critical for episodic and spatial memories. Among those mechanisms, the gene encoding insulin-like growth factor 2 (IGF-2 or IGF-II) emerged as a key target of the evolutionarily conserved CREB-C/EBP pathway. IGF-2 is necessary for memory consolidation and also strengthens memory. In fact, administering recombinant IGF-2 at the time of learning or memory retrieval significantly enhances and prolongs memory retention by preventing memory decay. These memory-enhancing effects are mediated selectively via a high- affinity receptor for IGF-2, known as IGF-2 receptor (IGF-2R). Another ligand of this receptor, mannose-6- phosphate (M6P), exerts similar effects, indicating that memory enhancement derives from IGF-2R activation, which itself is necessary for memory consolidation. In mouse models, both IGF-2 and M6P can reverse most core deficits of autism spectrum disorder and Angelman syndrome, as well as major problems associated with neurodegenerative diseases including Alzheimer’s and Huntington’s disease; these effects are mediated via IGF-2R. Despite these remarkable effects in both healthy and pathophysiological states, relatively little is known about the biology of the IGF-2/IGF-2R system in the brain. Based on strong preliminary data, in the proposed research we aim to significantly advance the cellular and molecular characterization of the IGF- 2/IGF-2R system. By employing state-of-the-art molecular techniques, including RNAscope, regulated mouse genetics, biochemistry, immunohistochemistry, proteomics, transmission electron microscopy, ribosomal profiling, RNA-seq, and hippocampus-dependent behavioral tasks in mice, we will accomplish the following Aims: 1) Determine which hippocampal cell types express and regulate IGF-2 and IGF-2R under basal conditions and during memory consolidation; 2) Identify the hippocampal cell types that require IGF-2 and/or IGF-2R to form long-term memory; and 3) Elucidate the mechanisms of action of IGF-2R in memory consolidation. The outcomes of the proposed studies will significantly advance our understanding of the roles of IGF-2 and IGF-2R in memory consolidation and enhancement.

NIH Research Projects · FY 2025 · 2000-04

Project Abstract Twenty-four investigators from the University’s Faculty of Arts and Science and School of Medicine request support for their vision research through continuation of a Core Grant. They are bound together by their research interests in the biological and behavioral bases of eye disease, vision, and visually guided behavior. The proposed Core will comprise four modules, each of which will benefit research in the research areas represented by program faculty: a Functional Imaging Module, a Design and Fabrication Module, a Neuroanatomy Module, and a Translational Reseach Module.

NIH Research Projects · FY 2025 · 1999-09

Project Summary The establishment of neuronal connectivity requires axons to select the proper neurons to form synapses with, which can be achieved through guidance signals or through activity-dependent processes. We still have a poor understanding of the mechanisms and molecules that direct neuronal specific connectivity pattern. The Drosophila color vision circuit offers a powerful paradigm to study synaptic specificity because of the availability of a connectome, a deep knowledge of its development, and powerful genetic tools to manipulate the circuit. In the fly retina, color photoreceptors R7 and R8 are stochastically specified, whereas their neuronal medulla targets are produced through a highly deterministic program. We will study how this propagation is achieved. Activity-dependent neural patterning is another powerful mean to coordinate different brain regions. Neuronal activity can occur at early developmental stages, prior to sensory input and the onset of synaptogenesis in the form of calcium waves whose significance has not yet been fully elucidated. We will study how early waves of activity that we observe at a very specific time point during fly retinal development are generated and what role they play. Aim 1. How do stochastically determined photoreceptor subtypes find their targets in the optic lobes? Aim 1.1. Synaptic specificity downstream of color photoreceptors: We will identify medulla neurons specific to subsets of photoreceptors and will identify the factors involved in the recognition by their input neurons. Aim 1.2. Establishment of synaptic specificity downstream of R7 color photoreceptors: We will study how a family of cell adhesion molecules allows matching between R7 cells and their Dm8 targets in the brain Aim 1.3. How does information from p and yR7 propagate downstream of Dm8: Once a medulla cell has made contacts with its cognate photoreceptor, it must itself transmits this information to its downstream partners. We will investigate how these choices are propagated down the visual pathway. Aim 1.4. Apoptotic pathway regulating the culling of unconnected neurons: Target neurons that are not connected die. We will study how specific adhesion molecules regulate this death and the molecular pathways involved. Aim 2. Mechanisms and functions of waves of spontaneous activity in the retina Aim 2.1. Description and cellular substrates of retinal calcium waves: We will analyze which cells are involved in calcium waves and whether these waves propagate to downstream medulla regions. Aim 2.2. Molecular mechanisms of retinal calcium waves: We will study how ER calcium stores and gap junction proteins are required to generate and propagate the waves. Aim 2.3. Determine the developmental role of retinal calcium waves: By disrupting the calcium waves, we will study what role they play in patterning the retina, and/or medulla neurons that are targets of photoreceptors.

NIH Research Projects · FY 2025 · 1999-09

PROJECT SUMMARY We investigate an important function of the vestibular system, and its multisensory properties, in spatial navigation, specifically head direction (HD) cells. HD cells encode directional heading like a compass and these properties are generated through a ring attractor network that is defined by orienting landmarks and updated using self-motion velocity cues. The goal of this renewal application is to establish the principles and circuits linking vestibular signals to HD cells in the anterior thalamus, through three aims. In the first two aims we will thoroughly test theory-driven hypotheses about the self-motion signal that updates the ring attractor. We will disentangle two contributions to HD tuning strength: self-motion velocity input, and brain state, which we hypothesize exerts a tonic modulatory role on the intrinsic properties of the attractor itself. We will show that passive rotations are as effective in updating the HD attractor as active foraging, and will test model-driven hypotheses about their multisensory properties. In Aim 3 we will genetically and optogenetically manipulate large or discrete regions of the cerebellum while monitoring the activity of HD cells in anterodorsal and laterodorsal thalamus. The hypothesized role of multisensory cerebellar signals is 2-fold: to help maintain internal models about 1) rotation velocity, and 2) gravity. The former updates the firing and the latter defines the 3D tuning of HD cells. Collectively, these experiments will provide a long-overdue, thorough and quantitative understanding of the multisensory properties of one of the most important components of the spatial navigation circuit. Our strength is an interdisciplinary approach based on a quantitative understanding of both multisensory and computational neuroscience, which promises novel insights into the organization of the spatial properties of HD cells and their links with the vestibular system.

NIH Research Projects · FY 2024 · 1999-09

Visual information detected by the retina is sent for further processing to deeper layers of the visual centers that feed into specialized behavior circuits. Much is known about how visual centers and local circuits function, but we do not understand how the many cell types that compose them are generated and how these circuits assemble and are coordinated between brain regions. We study the simplified, yet highly performing visual system of Drosophila for which we have obtained a deep understanding of neural diversity, mechanisms that also apply to mammalian neurogenesis. In a separately funded grant, we have generated a very large dataset where we have identified through single cell mRNA sequencing the individual transcriptome of most (169 neural types) neurons and glia in the four optic lobe ganglia, lamina, medulla, lobula and lobula plate, through six development stages starting when the neurons are first generated. This represents a huge resource that will allow us to identify the molecular pathways involved in the processes studied here. In the current proposal, we will define how the circuits formed by optic lobe neurons are assembled and how development of the different optic lobe neuropils is synchronized: Aim 1. Retinotopic projection of photoreceptors to the lamina and medulla. We will define the role of the lamina in the establishment of retinotopy in the medulla and what guides photoreceptors and lamina neurons to their retinotopic location. We will then identify the molecular guidance pathways involved in pathfinding in lamina and medulla, and determine the potential role of pioneer neurons that might guide retinotopy of the other neurons. Aim 2 Timing of differentiation and layer formation in the medulla neuropil. Medulla neurons are born from the same neural progenitors in a sequential order, a fundamental mechanism of 'temporal patterning'. We will test the model that temporal patterning allows medulla neurons to progressively innervate each layer of the lobula and of the medulla and we will define the molecular mechanisms synchronizing birth order and layer formation. Aim 3: Development of output neurons from the lobula: Visual features and optic glomeruli. Signals from the medulla are conveyed to the lobula and are then passed on to Lobula Columnar Neurons (LCNs) that connect to 'optic glomeruli' that control behavior. We will study how ~20 subtypes of LCNs connect to different layers of the lobula and to specific glomeruli in the central brain and will define the molecular mechanisms of their specific targeting. Aim 4. Building the broad-field motion pathway. Motion is computed by neurons that compare the outputs of upstream neurons in a specific orientation. We will investigate the developmental programs that instruct the dendrite orientation of the first orientation-selective neurons (T4 and T5) and how they each project to one of the 4 layers of the lobula plate that each detects motion in one of 4 cardinal directions. This study will provide fundamental insights into the coordination of various elements of a simple and amenable visual system. Our findings will not only provide novel fundamental concepts for the development of circuits for sensory processing, but will also contribute general concepts applicable to circuit formation in vertebrates.

NIH Research Projects · FY 2026 · 1998-04

Biomedical advances in HIV prevention and care, principally pre-exposure prophylaxis (PrEP) and treatment as prevention, led to optimistic predictions and plans to bring HIV under control by 2020. However, in the US, more than a dozen HIV outbreaks among people who inject drugs (PWID) since the sentinel HIV outbreak in Indiana PWID in 2014, suggest there are threats to maintaining effective control. In NYC, 64% of PWUD living with HIV are viremic, and mortality rates in HIV-positive PWID are twice as high as other people living with HIV. PrEP uptake among PWUD is very low (0-3% in the US), even in the midst of outbreaks when it is needed most. After a decade of declines, new HIV diagnoses in US PWID have been increasing 4% per year since 2012. Thus, our Center for Drug Use and HIV Research has chosen the theme, “Reinvigorating HIV prevention and care for people who use drugs: Accelerating progress and sustaining gains in the midst of societal disruption.” To achieve this, we will lead the field and support our investigators to: 1) understand how largescale societal changes may undermine HIV prevention and treatment for PWUD, 2) gain knowledge and skills to carry out studies that address the specific needs of PWUD at elevated risk of HIV infection, morbidity and mortality, and 3) engage with community members to improve the relevance and impact of the knowledge generated. We are committed to supporting new and early stage investigators (new/ESI) to achieve their potential as productive and successful scientists. We will achieve these aims through four Cores – an Administrative Core, the Pilot Projects and Mentoring Core, and two Research Support Cores – the Infectious Disease Epidemiology and Social-Behavioral Theory Core, and the Transdisciplinary Research Methods Core. These Cores support our research base and affiliated investigators to conduct cutting-edge science and enhance synergy across investigators from multiple disciplines, thereby leading to contributions to the field that are beyond what the individual projects could have achieved. Our theme and aims build upon many years of research experience and collaboration, broad methodological and theoretical expertise and innovation, and engagement with community and public health partners locally, regionally and nationally.

NIH Research Projects · FY 2025 · 1994-09

It is difficult to underestimate the potential public health significance of the pandemic for generating new outbreaks of HIV among PWID. While public health scale implementation of “combined prevention and care for HIV” among PWID has led to dramatic reductions in HIV transmission in many high-income countries, multiple outbreaks of HIV have also occurred, e.g., in the US, Western and Eastern Europe, and Israel. While there were distinct features of each outbreak, a number of common features were noted across the outbreaks, including: 1) community economic dislocations, 2) inadequate or interrupted HIV prevention services, 3) local introduction of new injectable drugs, and 4) homeless PWID as a very high-risk group. The pandemic and its associated lockdown/control measures appear to be re-creating the very conditions that generated HIV outbreaks among PWID in the pre-pandemic era. Additionally, the pandemic has been associated with a large increase in the use of fentanyl, which increases the potential for HIV risk behavior and the risk of drug overdose. We propose to examine HIV risk behaviors among PWID during and after the pandemic to understand the potential effect of pandemic-related disruptions in NYC, a location that has experienced the world’s largest local HIV epidemic among PWID, through three specific aims: Assess short term (within 3 years) impact of the pandemic on HIV risk among PWID in NYC, including potential increases in critical bio-behavioral risks (composite risk for HIV transmission and composite multi-person risk for HIV acquisition).20,21 Compare trends in fatal and non-fatal overdoses in New York City to identify possible factors related to recent trends in fatal overdoses. Identify organizational and individual behavioral factors, focusing on fentanyl use, that may be associated with low HIV incidence and overdose prevention among PWID in New York City. Multiple methods will be used to achieve these aims, including continuous RDS surveys, with follow-up of PWID of particular interest, and in-depth qualitative interviews. We will contribute data to local, national and international studies of the effects of the pandemic on HIV risk, HIV outbreaks among PWID, and drug overdose.

NIH Research Projects · FY 2025 · 1993-01

Project Summary/Abstract This is a competing renewal application for funds to support pre- and postdoctoral training in visual neuroscience at New York University in the Center for Neural Science (CNS) and the Cognition and Perception Program in the Department of Psychology (CP). We seek to renew training support for 4 predoctoral and 1 postdoctoral fellows. This level of support is justified by the need for the training program to provide for the training of a diverse yet coherent group of trainees. With the help of previous NEI support, the Visual Neuroscience Training Program has become a leading center for research training and has launched and shaped the careers of many who have made important contributions to the field. The 18 faculty of the training program seek to understand the visual system from a variety of disciplinary perspectives, but all share a consistent focus on understanding visual function. The quality, experience, breadth, and productivity of the training faculty has in the past and will in the future provide a fertile intellectual environment in which young scientists can thrive. Four newly recruited faculty have invigorated the program and made it even better, and have broadened its reach into the general area of visual disorders. There is ample instruction through courses and especially through mentoring in the research labs of CNS and CP that helps bring trainees to the frontiers of vision research. Many active researchers supported by NEI and other agencies provide direction, leadership, and support for students once they emerge as more independent senior scholars. Extensive shared facilities, including MRI scanners, an MEG and a TMS facility operated solely for research in the two participating departments, facilitate collaborations among faculty and trainees. The students who join the CNS and CP doctoral programs are of outstanding quality and a high proportion have historically gone on to successful and in some cases stellar careers in visual neuroscience.

NIH Research Projects · FY 2025 · 1992-09

This is a competing renewal application for funds to support pre- and postdoctoral training in Integrative Neuroscience at the Center for Neural Science at New York University. This proposal aims to continue and enhance a successful implementation of our training program focused on four interrelated core areas of investigation: learning, memory, development and plasticity. The proposed training program includes a partnership with the Graduate Program in Neuroscience and Physiology at the NYU School of Medicine. We seek to renew our support at the level of 5 predoctoral and 2 postdoctoral fellows. This number of trainees requested is based primarily on the importance of fostering a cohesive training group of a sufficient size to support trainee development across levels, from pre to post-doctoral and from cellular-molecular to systems and cognitive approaches, across program divisions, and between translational and basic research. This represents an increase of one trainee, with a clinical/translational focus. Our proposed training program will provide a central focus for pre and postdoctoral training in areas of neuroscience critical to advancing knowledge of development and degeneration of the nervous system, neural disease processes, and disorders of memory and mental health. Our trainees will have the opportunity to be a part of a cohort of world class scientists engaged in cutting-edge research related to learning, memory, development and plasticity. We have compiled a group of 26 training faculty that will provide an integrative, collaborative training experience that crosses traditional disciplinary boundaries, spans levels of analysis, and levels of training. The trainees, predoctoral fellows in the third year or higher and postdoctoral fellows in the early years post-PhD, will have access to a special seminar series, individualized mentoring, opportunities to develop translational thinking, and workshops to promote balanced professional and academic skills important for future success. In this renewal, we have added a specific postdoctoral training component. We expect our trainees to remain in the program for 1-2 years, at which time we expect that they will have obtained independent funding or transitioned to another research support mechanism. In either case, they will have a continuing, high-level of support from the program. We seek to build a steadily growing cohort of scientists with shared goals and interests, that will advance the goals of NIMH for research into the neural mechanisms of development, disorders and mental disease.

NIH Research Projects · FY 2025 · 1989-08

Project Summary To optimally estimate properties of the environment, one should use all available sensory and prior infor- mation. Sensory input arises from multiple sensory modalities, and is uncertain due to physical and neural noise. An ideal observer must combine all cues, taking into account cue reliability and considering alternative causes for discrepancies between cues such as inferring that they derive from different objects (i.e., separate causes) or that one or both sense modalities are miscalibrated. Human behavior is often consistent with “opti- mal” cue integration defined as maximizing combined-cue reliability. Can observers access internal estimates of reliability for confidence judgments to inform subsequent behavior? What computations does the brain use to solve these problems and how do they unfold over time? We tackle these questions by combining computational theory and behavioral experiments to elucidate the dynamics and time course of multisensory cue integration. The standard framework for understanding sensory integration incorporates five key components: (1) reliability-based cue weighting, (2) integration of prior infor- mation, (3) causal inference, (4) cross-modal recalibration and (5) confidence in the sensory estimates. Past work on multisensory cue integration has primarily dealt with situations that are static, but the world is dynamic and ever-changing, many activities (locomotion, driving, sports, etc.) depend critically on combining information over time and on temporal estimates, and sensory cue integration unfolds over time. In Aim 1, we will develop and test models of multisensory temporal perception, both for relative timing and perception of duration as well as understanding how spatial and temporal correlation jointly contribute to causal inference. In Aim 2 we look at sensory-motor integration from a similar perspective: the planning and execution of movement also involves multisensory integration prior to, during, and after a movement, both for movement itself and for judgments about movement success. Finally, in Aim 3 we look at the use of multiple visual and other sensory cues for perception of heading and object motion from optic flow and other cues. We will study whether the five compo- nents of multisensory integration help us to better understand the analysis of optic flow over time, and integrat- ing optic flow with natural self-motion in a virtual environment, for the estimation of heading and detection of moving objects. These studies will shed light on the dynamic processes used to combine sensory information to form a co- herent percept, the unfolding of sensory integration as perceptual decisions are made, and how our senses guide us in an ever-changing world. A better understanding of the dynamics of these processes will inform fu- ture studies on the neural implementation of these computations. These experiments on healthy humans will provide a starting point for understanding multisensory perception in individuals in which these systems are compromised by conditions that impact sensory input (e.g., amblyopia, macular degeneration, stroke).

Other NSERC · FY 2024

Effective Field Theories, Solitons Monopoles and Instantons, Classical Field Theory, Yang-Mills Theory, Nonperturbative effects in QFT

Other NSERC · FY 2024

Neuroscience, Physiology, Behavior, Plasticity, Noradrenaline, Neuromodulation, Electrophysiology, Auditory, Cortex, Neural Circuits

Other NSERC · FY 2024

computer vision, machine learning, representation learning, unsupervised learning, self-supervised learning

Other NSERC · FY 2024

machine learning, deep learning, generative artificial intelligence, few-shot learning, generative modeling, synthetic data, representation learning, computer vision