New York University

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY: The act of swallowing food and liquid is a basic human function that most people take for granted. Yet, approximately 15% of older adults suffer from impaired swallowing which can lead to malnutrition, frailty and pneumonia. Our previous NIH-funded research has confirmed that age-related decline in the muscles of the pharynx (throat) is associated with negative changes to swallowing mechanics and function, putting older adults at risk for serious health consequences. Given that exercise and nutrition are known powerful stimulators of positive muscular change, we propose to investigate these methods to reverse age-related decline of the pharyngeal swallowing muscles. Specifically, we will test the hypothesis that proactive swallowing exercises (+/- daily protein supplement drinks) will improve the composition, force, and physiology of the pharyngeal muscles. Our study design begins with 12 weeks of no-treatment control, allowing each of our 80-community dwelling older adult participants to serve as their own experimental control. Next, participants will be randomized to complete 12 weeks of pharyngeal exercises (5 days per week) with or without protein drinks. Before and after each phase, our study team will conduct a comprehensive battery of outcome measures to quantify changes to the pharyngeal muscles. Specifically, we will capture pharyngeal muscle composition with magnetic resonance imaging, pharyngeal muscle force with high resolution manometry, and pharyngeal muscle physiology with videofluoroscopy. We expect that proactive swallowing exercises will improve the composition, force, and physiology of the pharyngeal muscles and that these gains will be enhanced in the +protein condition. Finally, we are motivated to identify health-related predictors of treatment success. To that end, we will assess the influence of baseline measures of nutritional status and physical function on treatment success by analyzing biochemical markers extracted from blood samples and by conducting comprehensive analyses of body composition. The global population is rapidly aging and thus many older adults will experience the debilitating impact of impaired swallowing. Therefore, research establishing effective interventions to reverse and/or prevent age-related swallowing muscle decline is timely and important. Building a physiologic reserve in the swallowing muscles can improve the health and quality of life of community-dwelling older adults.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Primary visual cortex (V1) is one of the most studied areas of the cerebral cortex, but we lack a theoretical framework for a comprehensive understanding of V1 neurophysiology. Through the proposed research, we aim to provide one. A class of circuit models, called Oscillatory Recurrent Gated Neural Integrator Circuits (ORGaNICs), simulates many key neurophysiological phenomena. Our goal is to develop a theory for the full range of neurophysiological phenomena in V1, i.e., a single predictive model with biophysically-realistic parameters, and to test that theory with previously published datasets acquired with a wide range of methodologies. Preliminary results demonstrate predictions of the theory commensurate with experimental observations of V1 response dynamics (including onset transients and the stimulus-dependence of gamma oscillations), the dynamics of attentional modulation, experimental evidence for recurrent amplification and inhibitory stabilization, experimental observations about adaptation including tuning changes and decorrelation, noise quenching, the dependence of noise correlations on similarity in orientation preference and attention, and psychophysical contrast discrimination. Aim 1 key contributions: 1) an analytical theory (i.e., closed-form expressions) that makes experimentally- testable predictions about a wide range of phenomena related to the dynamics of V1 activity; 2) closed-form expressions derived from the theory for LFP power spectra; 3) a novel explanation for oscillatory activity in visual cortex. Aim 2 key contributions: 1) an analytical theory of adaptation in V1 that makes experimentally-testable predictions about a wide range of neurophysiological phenomena related to adaptation; 2) the demonstration that adaptation maintains an efficient neural code, subject to finite resources (overall activity in the circuit), despite dynamically changing stimulus statistics. Aim 3 key contributions: 1) an analytical theory that makes experimentally-testable predictions about the variability and covariability of neural responses; 2) experimentally-testable predictions about psychophysical discrimination. The proposed research has the potential to be transformative. We will provide a new set of analytical results and computational tools for characterizing a broad range of neural circuit models, which will have a significant impact on the analysis of experimental data and experimental design, and will make new experimentally- testable predictions for both ORGaNICs and alternative models. We will provide a roadmap for understanding the underlying circuit mechanisms (the cell types, their interconnections and biophysics), and how manipulating those mechanisms may change circuit function to correct disorders of visual perception and attention.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The PI’s goal is to develop an interdisciplinary research program and a foundational algorithmic framework for reliably inferring health states from physiological signals acquired using wearable and portable physiological monitoring devices. Uncovering the health states will unleash an array of applications related to monitoring inflammation, metabolism, fatigue and interoceptive awareness. For instance, it is well known that hormones play an important role in maintaining homeostasis of the body, while cytokines are crucial as mediators of immune response after surgery or infection that disturbs this homeostasis. Adverse external influences such as stress can profoundly alter the hormone or cytokine production in patients, affecting their health and complicating recovery from diseases or surgery. The knowledge of their secretion and modulation in response to major influences such as cardiac surgery, medications, disease, and stress is crucial to the health of patients, more so when more than one of these factors is concurrently present. Thus, there is a compelling but unfulfilled need to quantify hidden health states of inflammation, metabolism, fatigue and interoceptive awareness. The PI’s laboratory seeks to pioneer system-theoretic computational toolsets for understanding the pulsatile signaling underlying the physiological signals (e.g., cytokines, hormones, eye movement) related to different health states and capturing the unobserved temporal dynamics of one’s health states in a biologically plausible manner while considering extensive experimental settings and clinical data. This project will determine the pulsatile physiological signaling from discrete, noisy measurements by performing signal deconvolution to extract the neuronal stimuli underlying their modulation, and will build decoders to quantify internal health states that are indicative of inflammation, metabolism, fatigue and interoceptive awareness using both unlabeled information as well as labels via feedback from patients and clinicians, to help physicians interpret physiological data and inform patient-specific treatment in a holistic manner. The proposed research will use de-identified data both from publicly available datasets and those collected by the PI’s collaborators (e.g., endocrinology, rheumatology, neurosurgery, psychiatry, neuroscience) using wearable or portable devices to perform signal analysis and compare the results against previously published results, known experimental settings, and clinical knowledge to validate the models and provide new insight.

NIH Research Projects · FY 2026 · 2023-09

Project Summary Chronic psychosocial stress is a major risk factor for functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Notably, there is high co-morbidity between IBS and stress-related psychiatric disorders such as major depressive disorder (MDD), with IBS and MDD representing two of the most prevalent and debilitating illnesses worldwide. Potentially underlying this co-morbidity is the recent finding that chronic stress elicits low-grade inflammation, which has been associated with both IBS and MDD. Moreover, increasing evidence suggests that the gut-brain axis, or connections between the central and enteric nervous systems, contributes to the etiology of IBS. However, the mechanisms through which an emotional state such as chronic stress influences gut pathophysiology, including inflammation, remain poorly understood. In preliminary experiments using the chronic social defeat stress (CSDS) model in mice, we find that intestinal inflammation and barrier permeability become elevated following CSDS in both male and female mice, and these phenomena correlate with depression-like behaviors such as social avoidance. In this project, I will investigate how psychosocial stress causes this gut pathophysiology. Using retrograde viral tracing strategies from the gut to the brain, and whole-brain imaging, I have generated a list of candidate stress-activated brain regions that directly innervate the gut. In the first aim of this proposal, I will use integrated neuroscience and immunology techniques, such as chemogenetics and flow cytometry, to determine if activation of these brain regions can trigger gut inflammation and barrier permeability. Moreover, I aim to identify subsets of enteric neurons in the intestine that receive signals from the brain during stress to propagate IBS-like symptoms. In the second aim, I will then assess how inflammatory signals in the gut are conveyed to the brain to influence stress-relevant behaviors. As the brain can detect the inflammatory state of peripheral tissues through sensory afferent nerves, I will first identify which stress-responsive brain regions receive input from gut. I will then use fiber photometry to evaluate how gut inflammation modulates neuronal activity in these brain regions and its consequences on behavior. In parallel, I will investigate if a compromised intestinal barrier allows bacterial toxin translocation from the gut lumen into circulation to promote systemic inflammation and depression-like behaviors. Collectively, this project aims to define bi-directional stress-activated gut-brain circuits that contribute to IBS- and MDD-related symptoms.

NIH Research Projects · FY 2025 · 2023-08

Nursing home staff shortages are well known to be an important factor impacting both the quality of care that nursing home residents receive, their health outcomes, and healthcare worker outcomes. Staffing shortages are compounded by limited financial resources in nursing homes during public health emergencies, especially for smaller nursing homes. These staffing shortages disproportionately impact nursing home residents living with Alzheimer’s disease and related dementias (ADRD) as they require more time from staff compared to care for residents who do not have ADRD. As the number of Americans living with ADRD increases, the need for fully staffed nursing homes that can provide quality care for older adults living with ADRD is now more important than ever. During public health emergencies, direct funding to nursing homes has been proposed as an expedient way to prevent staffing losses and maintain safety standards for residents. One federal policy mechanism utilized by nursing homes in 2020 and 2021 was the Paycheck Protection Program (PPP). The PPP loan program offers a unique natural experiment by which to evaluate the effectiveness and efficacy of a program that directly funds small businesses and in the case of this project, nursing homes, to maintain safe staffing levels during public health emergencies. While PPP loans were effective overall at keeping workers on the payroll across all US small businesses, it is unclear if the effects of the program worked as well for nursing homes in socioeconomically deprived neighborhoods which prior work from our team showed have lower staffing rates. Using robust econometric methods and an exploratory sequential mixed methods approach, the proposed project will assess the effectiveness and equity of PPP funding by 1) examining changes in staffing patterns and resident outcomes among nursing homes that received the PPP loans compared to nursing homes that did not and evaluating whether changes in staffing patterns and outcomes were equitable for those with ADRD living in the most socioeconomically deprived facilities; 2) qualitatively exploring facility strategies, tools, and social contexts that promoted resilience to declines in staffing and ADRD resident outcomes after receipt of PPP, and 3) quantitatively assessing the extent to which resilience strategies, cultures, and behaviors identified in Aim 2 are reflected in administrative actions about staffing and care for residents with ADRD, and how actions differed by neighborhood context. The overall goal is to develop a framework by which to guide future nursing home responses to public health emergencies that will improve staff patterns and subsequent ADRD outcomes in the most socioeconomically deprived/lowest-resourced neighborhoods.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract Large knowledge gaps remain regarding strategies to promote the adoption of hydroxyurea (HU), particularly in sub-Saharan African countries including Nigeria, where more than 75% of annual sickle cell anemia births occur. The vast majority of people with SCD in Africa do not receive evidenced-based health care (e.g., newborn screening, health education, prophylaxis for infection, optimal nutrition and hydration, blood transfusion, transcranial Doppler screening, and HU therapy), despite its effectiveness in reducing SCD-related adverse outcomes and mortality. The use of HU in SSA is <1% among SCD patients. Our preliminary findings indicate that provider-level barriers are significant and must be addressed to improve HU adoption. To address HU adoption we will use the NIH-funded study (e.g., Realizing Effectiveness Across Continents with Hydroxyurea (REACH) Clinical Trial (NCT01966731)) that developed an evidence-informed, clinical, practical, and easy-to- follow algorithm to 1) Screen patients for sickle cell disease (SCD), 2) Initiate HU treatment, and 3) Maintain HU dosage over time (SIM) for the improved management of SCD as our intervention. The Nigerian government released guidelines supporting the SIM intervention for HU adoption for improved SCD management, and HU is on the list of essential medicines for Nigeria. Our implementation strategy for improving SCD management in Nigeria uses a practical and replicable evidence-based task-sharing strategy, TAsk-Strengthening Strategy for Hemoglobinopathies (TASSH), adopted from our TAsk-Strengthening Strategy for Hypertension control (TASSH) trials in Ghana and Nigeria containing the essential components of i) Training healthcare workers/providers to be more patient-centered in clinical consultations, ii) Clinical reminders, and iii) Practice facilitation (TCP) known as (TASSH TCP) for SCD management. Using a sequential exploratory mixed-methods study design, we will conduct this study using the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework in four sequential phases to assess the effectiveness of SIM adoption by providers in the context of the TASSH TCP implementation strategy in Nigeria.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT Child sexual abuse (CSA) is a global public health problem affecting 1 in 5 girls and 1 in 12 boys before age 18. Parents are uniquely positioned to protect children from CSA, yet parents have largely been ignored in CSA primary prevention efforts and the few that do exist have not demonstrated a significant effect on protective behaviors. Parent education (PE) programs provide parents with foundational skills related to child development, parent-child communication, and safety. These foundational skills can be logically extended into didactics relevant to CSA prevention: healthy sexual development, strategies for parents to communicate with their children and others about sexual topics and sexual behaviors, and creating physical and online environments safe from potential exploitation and recognizing grooming behaviors. Our team developed Smart Parents – Safe and Healthy Kids (Smart Parents) as a single session, skills-based, parent-focused CSA prevention module that adds these key CSA-specific prevention concepts to PE program curricula. Leveraging the PE foundational skills, Smart Parents provides parents with CSA-prevention knowledge to increase their CSA-related attitudes and perceived norms as well as the opportunity to practice protective behavioral skills. A recent cluster randomized clinical trial demonstrated preliminary to be effective in raising parents' awareness and increasing their intention to use of CSA protective behaviors when added to Parents as Teachers (PAT), an evidence-based PE program supported by most state child welfare systems. The proposed study seeks to expand the empirical evidence for the effectiveness of Smart Parents and to explore the implementation factors that might promote or hinder adoption, fidelity, and scalability, the proposed study uses a type 2 hybrid effectiveness-implementation design. We will conduct a stepped wedge-cluster randomized trial (N = 400) To determine effectiveness (Aim1) of Smart Parents when added to PAT (PAT+Smart Parents) on CSA-related awareness and intention to use CSA protective behaviors compared to parents receiving PAT treatment as usual (PAT-TAU. We will follow-up participating parents in both conditions at 12- and 24-months to determine retention of awareness (i.e., knowledge and attitudes) and actual use of protective behaviors (Aim 2). To describe factors that hold promise for future dissemination and implementation efforts (Aim 3), we will: assess parent, provider, and organizational-level moderators of Smart Parents effectiveness; conduct a cost analysis; and conduct structured interviews with Smart Parents providers (N = 100) and focus groups with key PE stakeholders (N = 25) to identify factors that may impact future dissemination and implementation. By leveraging the foundational skills taught in existing PE used by state-supported family service providers across the US—and supported through federal policy such as the Family First Prevention Services Act—the integration of Smart Parents into PE programs is not only efficient and cost-effective, but constitutes a sustainable model of system-wide, real-world, community-based implementation of primary CSA prevention.

NIH Research Projects · FY 2026 · 2023-08

Project Summary Heteroatom units, such as C(sp3)–OH and C(sp3)–NH2, are prevalent motifs in many pharmaceutically relevant drugs and natural products. Methods to incorporate these important functional groups at the expense of C–H bonds rely on the use of non-commercial heteroatom transfer agents, precious transition metals, and/or costly engineered enzymes. Also, these methods often require harsh exogenous oxidants to promote the C–heteroatom bonding event, which greatly limits substrate scope. In this proposal, we highlight the employment of economical nitroarenes as versatile reagents that can serve as the C(sp3)–H bond activator and the oxygen atom source for the C–H hydroxylation of aliphatic systems under benign visible-light irradiation. Notably, the heteroatom transfer event occurs anaerobically, thereby allowing for significant expansion of substrate scope compared to previous state-of-the-art methods. Asymmetric C–H hydroxylation protocols can be achieved with the use of recyclable photoexcited nitroarene atropisomers, leading to a sustainable approach for the late-stage installation of chiral alcohol groups. The development of a universal platform for C–H heteroatom incorporation of aliphatic systems can be engendered under this reaction paradigm via a formal polar crossover event and coupling with nucleophiles. The merger of chiral H-bond donor catalysts or chiral phosphoric acid catalysts to this approach can enable a general platform for asymmetric heteroatom incorporation directly from C–H bonds without the need for a leaving group, which is an underdeveloped area in synthesis. For C–N bond formation, chemoselective transfer of the nitrogen atom from the nitroarene moiety to aliphatic systems can be achieved under photoirradiation empowering facile formation of imines directly from methylene units. In-situ hydrogenation of the formed imine products generates amines formally from C–H bonds; thus, resulting in a C–H amination event from the multi-fold reactivity of photoexcited nitroarenes. The synthetic utility of the proposed protocols illustrates that late-stage C–H heteroatom incorporation events promoted by photoexcited nitroarenes can provide a cost-effective means for the synthesis of complex molecular scaffolds. Overall, novel C–H heteroatom events can be achieved in a mild, general, and sustainable manner by exploiting the multifunctional role of photoinduced nitroarenes. It is anticipated that photoexcited nitroarenes will serve as useful tools for the anaerobic heteroatom incorporation of organic molecules.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Eukaryotic cells sequester critical biochemical reactions into discrete membranous compartments, whereby membrane dynamics driven by protein catalysts facilitate differentiation, communication, and spatial organization of intracellular compartments. Within a cell, mitochondria are mainly organized into highly interconnected networks, whose diverse functions are dependent on their complex structure and organization. In humans, OPA1 and MICOS are essential biomolecular machines that control not only the morphology of the mitochondrial reticulum, but also the efficiency of many key mitochondrial processes, including oxidative phosphorylation, metabolism, apoptosis, and mtDNA maintenance. The GTPase OPA1 is crucial for mitochondrial IM fusion and regulating cristae dynamics, whereas the multi-component MICOS complex plays a dual role by shaping IM cristae junctions and forming contact sites with the outer membrane. Characterizing how mitochondrial dynamics are realized and regulated will be essential to deciphering the link between mitochondrial morphology and function. Moreover, molecular abnormalities in mitochondrial dynamics result in aberrant mitochondrial structure, impaired bioenergetics, severely reduced respiratory capacity, mtDNA instability, increased sensitivity to apoptosis, and development of a wide variety of disease conditions, including neurodegenerative disorders, diverse cancers, obesity, and cardiovascular diseases. Yet, the molecular mechanisms that alter mitochondrial morphology and function remain incompletely understood. Here, using a combination of cellular and structural analyses, we aim to develop a molecular understanding of mitochondrial dynamics that govern key physiological processes in cells. We propose to determine the molecular mechanism of mitochondrial morphogenesis by exploring the assembly mechanism of OPA1 and its interactions with the mitochondrial lipid cardiolipin (Aim 1). We further propose to characterize the molecular details of multi-component MICOS complex and protein dynamics that facilitate cristae formation and maintain the characteristic architecture of mitochondria (Aim 2). Structural and functional studies of mitochondrial protein machines will provide a platform to identify the basis of pathologies linked to human disease and age-related illness. Understanding the precise molecular mechanisms of mitochondrial dynamics will increase the probability of success in developing new therapeutic interventions.

NIH Research Projects · FY 2024 · 2023-07

Project Summary Many of the sounds that animals hear are created by their own actions and being able to correctly differentiate these sounds is critical to a range of behaviors. An influential idea is that the brain uses sensory-motor predictions to anticipate sounds generated by movement, and identifying the circuit mechanisms that learn and implement these predictions is critical to our understanding of cortical function in health and disease. Since predictive computations involve the interaction of sensory and non-sensory signals, identifying underlying circuit mechanisms will require understanding how distributed but interconnected brain regions work together. While the thalamus is often perceived as a simple conduit of sensory information, the second-order thalamus is tightly linked with both the sensory and motor cortex, positioning it to play a key role in integrating sensory and non- sensory information. This proposal will test the hypothesis that the auditory second-order thalamus shapes predictive processing throughout the auditory cortex. First, I will use a transgenic mouse line that specifically labels second-order thalamic neurons to map the precise functional connections of the second-order auditory thalamus (Aim 1, K99). Next, I will develop an acoustic augmented reality home cage environment where mice can rapidly learn multiple predictive behaviors. I will perform wireless recordings while freely moving mice make multiple sound-generating movements to determine the sensory, movement, and prediction information encoded in the second-order auditory thalamus (Aim 2, K99). Finally, I will perform simultaneous multi-area recordings and targeted neural interventions in the thalamus and cortex of behaving mice to determine how predictive computations are carried out across the thalamocortical circuit (Aim 3, R00). With the guidance of my mentorship team, I have developed a training plan at New York University that will provide me the technological skills needed to complete these aims and make important discoveries about how distributed circuits integrate sensory and non-sensory information during predictive processing. The proposed training plan will also provide me with the conceptual framework and professional skills to achieve my long-term career goal: to investigate how distributed circuits work together mechanistically to enable context-dependent auditory processing in health and disease as an independent scientist.

NIH Research Projects · FY 2025 · 2023-07

Project Summary Development of the nervous system requires the generation of diverse neuronal types that subsequently drastically alter their shape and physiology to form vast interconnected networks. Each process requires precise gene regulation. Technological innovations have drastically increased the scale at which we can distinguish neuronal identities or stages based on transcriptomics or epigenetics. However, principles guiding post-transcriptional control of gene expression, which is essential for neural development and homeostasis, by regulatory factors including RNA-binding proteins (RBP) and miRNAs has not been defined at a similar systematic level. As numerous neurodegenerative disorders have been linked to impaired RBP-RNA interactions, and there is a huge need for improved cell type engineering strategies for therapeutics, insight into this process is critically important. I propose to use the Drosophila visual system as a model to study post- transcriptional regulation during specification and wiring of an entire neural sensory system. Specifically, this proposal focuses on the regulation of mRNA translational repression, which is a conserved feature of both neuronal fate diversification and differentiation in vertebrate and invertebrates. A single-cell transcriptomic atlas of the developing visual system, or optic lobe, was recently described which defines the transcriptome of each neuronal type in the optic lobe throughout development. Consistent with results from other model systems, many genes associated with terminal neuronal function were detected at transcripts in the immature neurons well before they are functionally required, and the corresponding protein was absent for two selected genes studied. I aim to define the scope of translational regulation in this system by first performing whole-tissue and select cell-specific ribosome profiling of the optic lobe over development, and determine the upstream control of this process using a combination of bioinformatics and genetics (Aim 1). Next I will tease apart the molecular and cellular mechanism by which two genes associated with different neuron signaling pathways are repressed at the translational level to assess how their expression is coordinated (Aim 2). Finally, I will adapt a single-cell translation profiling technique, scRibo-STAMP, in the Drosophila visual system to profile translation of all optic lobe neurons during specification and wiring. Combined with machine-learning based analysis, I will predict RBP/miRNA-RNA target interactions to gain fundamental insight into how RNA regulatory networks are shaped (Aim 3). Together this study will provide significant insights into the role of translational regulation during formation of the nervous system relevant to both human development and health.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Speaking multiple languages is the norm for the majority of the population of the world. However, research on the neural bases of multilingualism has not been commensurate with the demographic relevance of this population. In no small part, this has been due to the traditionally lower socioeconomic or immigrant status of multilingual individuals. Consequently, there is a lack of fundamental knowledge about the organization and interaction between languages in the bilingual brain. This lack of knowledge has appalling implications for planning behavioral and surgical treatments for bilingual individuals with neurological disorders: it is currently unclear which cortical tissue needs to be spared, and how much and how often each language should be targeted to maximize recovered language function after brain damage in bilingual individuals. Thus, there is a critical need to obtain a better understanding of how multilingual individuals’ languages are organized and how they interact at different levels of representation to inform the development of strategies that maximize potential language recovery after brain damage in a demographic group that will be the majority of the US population by 2040. The proposed project will address this gap in knowledge by combining the study of aphasic and healthy Spanish- English bilingual individuals in behavioral and fMRI tasks to create a symbiosis where theory and praxis mutually inform each other. Specifically, the project will investigate the typology of deficits in post-stroke aphasic bilinguals at the lexical level (i.e., single-word level; Aim 1A), and at the morphosyntactic level (i.e., how words are combined into meaningful phrasal/sentential structures; Aim 1B) through the analysis of a spontaneous speech corpus. The validity of the conclusions derived from these analyses will be tested and confirmed with tailored behavioral experiments (Aim 1C). Aim 2 will target the neural bases of these processes through a combination of voxel-based lesion-symptom mapping in post-stroke aphasic bilinguals (Aim 2A) and fMRI analysis of healthy bilingual individuals (Aim 2B). Critically, by combining the study of a large speech corpus, targeted experimental paradigms, and neuroimaging research, the proposed project holds the potential to obtain a comprehensive characterization of bilingual individuals’ language organization across linguistic levels. This information will constitute the first step to subsequently develop theoretically informed language recovery strategies, and protocols tailored to the needs and characteristics of brain damaged bilingual individuals. Thus, the successful accomplishment of the projects laid out in this proposal will establish the basis to develop strategies that maximize potential language recovery after brain damage in a demographic group that will soon be the majority of the US population. This award will also provide the candidate, who has a strong background in cognitive neuroscience and electrophysiological methods, with critical training in patient testing and neuroimaging methods, to promote a successful transition to an independent research career.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Dental fear affects over 53 million American adults. According to the U.S. Surgeon General, it leads to “needless pain and suffering, causing devastating complications to an individual's wellbeing, with financial and social costs that significantly diminish quality of life and burden American society.” Standard treatment — compassionate but ultimately counterproductive — includes anti-anxiety medication or more substantial anes- thesia, which (a) does nothing to reduce subsequent anxiety or avoidance, (b) leads to continued dental prob- lems, and (c) perpetuates the cycle of fear—>avoidance—>dental problems. Alternatively, cognitive-behavioral treatments (CBT) for dental fear have been developed, subjected to dozens of high-quality trials, and found to be efficacious. However, CBT has, almost exclusively, been offered only in a few specialty clinics worldwide as- sociated with universities and there is no disseminable model for integrating CBT into the workflow of dental practices. To fill this gap, we have created a stepped-care approach to dental fear treatment that can be implemented in private practice dental offices throughout the U.S. and is eminently scalable. Stepped-care in- volves starting with the least intensive option and progressing to more intensive options only when necessary. At the low end is a self-administered intervention: (a) a smartphone “app” that can be used privately in waiting rooms by an unlimited number of patients combined with (b) a paper-and-pencil “Pre-Game Plan” in which the patient records — to be reviewed with the dental staff prior to dental services — (1) pre-treatment fear levels, (2) the factor generating the most anxiety, (3) a stop-signal the patient will use to alert the dentist,(4) things the dental team can do to maximize this patient's comfort, and (5) a self-generated anxiety management plan. If patients are not in the “low fear” zone following their dental procedures, they may receive 1-hour (if still in moderate zone) or 2-hours (if still in severe zone) of dental fear CBT in their dentists' offices conducted by a collaborating mental health provider. In the first phase of this study, we will pilot test the approach with fearful patients (N»35,700) at two University dental centers. In the second phase, we will test the it in private dental practices (n = 100 volunteers from a pool of 10,000 practicing dentists in the metropolitan areas of Philadel- phia and New York [and the corridor between them] who graduated from dental school from either New York University or the University of Pennsylvania). The aims are to study factors influencing patients' and dentists' willingness to try stepped-care, to test the efficacy of the approach, to test the dosing of CBT interventions de- pending on patients' fear levels, and to test whether the way in which we believe CBT works (i.e., by helping patients disconfirm their beliefs regarding feared outcomes) is truly the active ingredient. Finally, we will develop dissemination materials for dentists and mental health providers on “How to Effectively Treat Dental Fear with a Stepped-Care Approach.”

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Environmental Neuroscience for All uses a combination of online and in-person tools and an open science approach to support high school students in carrying out their own original research projects focusing on environmental neuroscience, a fast-growing field of research at the intersection of behavioral science and more ‘traditional’ STEM fields that recognizes the critical role of human brain and behavioral science in better understanding the impact that the environment has on humans, and the impact that humans have on our environment. How is our brain health and wellbeing affected by our environment? Can we improve how we interact with our environment by deepening our understanding of how the human brain is wired? Together with scientists and their teachers and communities, students will explore these and other questions about the multi- directional relationship between the human brain, human behavior, and our environment. We will build on the technology, content, and network of schools and community partners created through our SEPA project BrainWaves and our community science platform MindHive. We will develop curriculum materials and tools grounded in open science practices, which represent a shift away from narrower, more traditional views of the “scientific method,” toward a collaborative and iterative approach to science inquiry. We will also build out an online platform with tools that support collaborative study ideation, peer feedback, data collection and engagement, and communication. Students will learn how to formulate research questions and translate them into testable hypotheses; design, review, and revise environmental neuroscience studies; and collect, analyze, and communicate research findings. Together, the curriculum materials and web-based platform will support authentic community science research spearheaded by teens in a network of environmental neuroscientists, community organizations, and student peers - both locally and nationwide, and both in-person and online. In sum, Environmental Neuroscience for All will connect learners and their communities across the nation; and in doing so create pathways toward more transparent and accessible environmental science. As such, the project will not only help further integrate human brain and behavioral science, an increasingly relevant STEM field, into preK-12 science curricula, but will also educate a new generation of scientists in open science principles, building the foundations for a STEM workforce that approaches environmental challenges as a collective, interdisciplinary effort.

NIH Research Projects · FY 2025 · 2023-06

Project Summary: Animals perform goal-directed behaviors in complex environments, without the need for extensive experience, by harnessing an internal model of the world. These internal models, or cognitive maps, are central to model-based decision making. Importantly, understanding the neural circuitry of model-based decisions holds promise for improving treatments of neuropsychiatric disorders in which decision-making goes awry. An outstanding question in reinforcement learning (RL) is how cognitive maps are learned from experience, and what neural substrates support them. The orbitofrontal cortex (OFC) has been implicated in representing cognitive maps, and this project proposes to characterize the emergence of a cognitive map in rodent OFC during a value-based decision making task. This project asks three core questions: 1) How does a model-based RL agent learn a cognitive map using purely model-free RL methods? Here recent advances in meta-RL in state-of- the-art recurrent neural network (RNN) models will be trained with model-free RL, in which the emergence of a cognitive map can be fully characterized. 2) How does the OFC represent cognitive maps? Here partially trained rats will be implanted with Neuropixels probes, and neural recordings will capture emerging representations of cognitive maps in population-level OFC activity as rats learn the task structure. 3) Can poor learning of cognitive maps be bolstered with structured behavioral training? An attractive therapeutic approach for improving decision making strategies is through behavioral training alone, and here an RNN model of rodents will be used to characterize modes of poor learning and develop prescriptive training, and will then be employed in rats to uniquely addresses specific learning deficits. This proposed project employs both experimental and computational techniques as part a comprehensive career development plan toward becoming an independent investigator. Specific experimental training for electrophysi- ological recordings from behaving animals complements computational training on modeling neural activity with deep neural networks. The career development plan also includes structured opportunities for collaborating with experimentalists. It incorporates a breadth of science communication experiences through research conferences and public talks within the local training institution. Importantly, the career development plan incorporates targeted preparation for independent investigator applications, including chalk-talk opportunities, workshops to develop unique research questions, and exposure to the faculty search process. The Constantinople, Savin, and Glim- cher labs at New York University’s Center for Neural Science are a training environment uniquely positioned to deliver this interdisciplinary training: their cutting-edge research into decision-making, animal behavior, reinforce- ment learning, and systems neuroscience make it an ideal institution and set of labs to develop a health-related career studying decision-making strategies in neuroscience.

NIH Research Projects · FY 2026 · 2023-06

Project Summary Our long-term goal is to develop new chemical reactions for the synthesis of compounds that could be used as medicines. We will build upon our expertise in the synthesis of cyclic peroxides, a family of natural products that exhibit a broad range of biological activities, suggesting their application to the treatment of malaria, cancer, and viral and bacterial infections. During the proposed funding period, we will investigate our hypothesis that initiation of ferroptosis is a general property of cyclic peroxides, and we will optimize the potency and metabolic stability of FINO2, a cyclic peroxide we developed that initiates cell death by a new mechanism. The target of FINO2 is unknown so we will study the mechanism by which cyclic peroxides like FINO2 initiate programmed cell death, in collaboration with Professor Brent Stockwell (Columbia University). We will also develop new methods for the synthesis of the cyclic peroxide structural motif found in many naturally occurring peroxides. We will also investigate the synthesis of aromatic peroxides, a structural class whose synthesis and reactivity have not been addressed. In the proposed funding period, we will also extend our investigations of mechanisms of acetal substitution reactions, which are important methods in natural product synthesis and carbohydrate chemistry. Using systematic studies of model systems, we can identify the factors that contribute to the stability and reactivity of oxocarbenium ions, which are intermediates involved in many of the reactions of carbohydrates, including enzymatic reactions. We will determine how the carboxyl group in sugars such as sialic acids influence the stereoselectivity of reactions involving these sugars. We will demonstrate remote neighboring-group participation as a means of controlling stereoselectivity in cyclic and acyclic compounds. The proposed research is innovative because it addresses structural types and reactive intermediates that have received little attention in the literature. The proposed research is significant because it will lead to new pathways for making biologically active compounds and will provide deeper mechanistic understanding of chemical and biological processes. These studies are relevant to human health because they could result in drugs that kill cells by unique pathways, leading to new treatments for various diseases. Furthermore, the mechanistic understanding of intermediates involved in reactions of carbohydrates could lead to new ways of designing enzyme inhibitors.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT With rates of mental health service utilization as low as 40%, racial and ethnic minority young adults with serious mental illnesses (SMI) are at high risk for disengaging from mental health services. They experience greater unmet need and increased risk for long-term health disparities, poverty, incarceration, and early mortality. Disparities in treatment engagement are often driven by the lack of services that take into account the unique developmental needs and relevant cultural factors that impact young adults’ on-going participation in treatment. The PI’s preliminary findings among racial and ethnic minority young adults indicate that they desired greater knowledge, appreciation, and support of their cultural identities from mental health providers. However, there are few evidence-based treatment engagement programs for young adults with SMI, and none that explicitly target both the developmental and cultural preferences of those who are racial and ethnic minorities. This Career Development Award proposes a comprehensive path towards becoming an independent clinician investigator adapting and optimizing evidence-based interventions to target cultural determinants of health and reduce mental health disparities among adolescents and young adults. This proposal uses the participatory ADAPT-IT framework to partner with racial and ethnic minority young adults with SMI (n=15), providers (n=9), and expert mentors to adapt a brief, evidence-based young adult treatment engagement intervention to include three new person-centered, cultural identity-focused components. The adapted intervention will then be evaluated in a mixed-methods pilot optimization trial for feasibility, acceptability, and preliminary impact on treatment engagement at an urban, publicly-funded, adult psychiatric rehabilitation program. The pilot comprises the preparation stage of the multiphase optimization strategy (MOST), during which young adults (n=80) will be assigned to one of eight conditions to test new components in an efficient factorial experiment. In-depth interviews administered post-intervention will contextualize and clarify findings. To further her long-term career goal of becoming an independent clinician investigator focused on improving mental health services for underserved youth during the transition to adulthood, the PI will pursue training in the following four areas: (1) developing empirically-driven engagement interventions for older adolescents and young adults, (2) adapting interventions to be culturally relevant to underserved, minoritized populations, (3) using MOST, and (4) grant writing. The product of this study will be an R01 of a large-scale optimization trial powered to test intervention components for efficacy and change in targeted mechanisms of treatment engagement. Overall, this award will ensure the PI’s successful transition to an independent investigator with an established program of research focused on intervention development, adaptation, and optimization for addressing mental health disparities in minoritized adolescents and young adults.

NIH Research Projects · FY 2025 · 2023-05

PROJCT SUMMARY/ABSTRACT Inconsistent findings regarding whether and how E-cigarette (EC) use influences subsequent tobacco use behaviors complicate evidence-based tobacco regulation. Among youth, EC use is associated with greater risk of transitioning to combustible cigarette (CC) smoking, but estimated effect sizes of EC exposure vary substantially across studies. Among adults who currently smoke CCs, ECs show potential to help quit CC smoking in some studies but not in others. These inconsistent findings may be due in part to a preponderance of observational studies, use of small size cross-sectional data, and inadequate control for covariates, Further, despite considerable heterogeneity in the size of estimated EC exposure effects, whether specific characteristics modify the EC exposure effects has been largely ignored in literature. Understanding how ECs influence subsequent CC smoking, particularly among vulnerable subgroups (e.g., age, gender), and their intersectionality, will help inform regulatory activities that address tobacco-related health disparities. Lastly, it is unclear whether estimated EC exposure effects from a certain population subgroup or at a certain time can be generalized to different subgroups or times. Generalizable EC exposure effects could provide critical evidence for tobacco regulators. To address these knowledge gaps, this study aims to use causal machine learning methods to determine the influence of ECs on subsequent CC smoking, in overall US youth and adult populations and in vulnerable subgroups, and to explore methods for estimating generalizable EC exposure effects. A secondary analysis of the longitudinal Population Assessment of Tobacco and Health study will be conducted to address the following specific aims. Aim 1: Determine average exposure effects of EC use on subsequent CC smoking in youth and adults. Aim 2: Determine heterogeneous EC exposure effects among vulnerable subgroups (age, gender, poverty, race/ethnicity). Aim 3: Evaluate the performance of causal machine learning methods to generalize EC exposure effects using both simulated and PATH Study data. To successfully accomplish these aims and develop into an independent methodologist in tobacco regulator science (TRS), I will obtain training in the following areas: 1) TRS theories and measures, especially health disparities in TRS; 2) Causal inference methods for evaluating exposure effects; and 3) Machine learning skills for high-dimensional data analysis. During the award period, I will be supported in my research and training goals by my institution and interdisciplinary mentoring team, which consists of experts in the fields of TRS, causal inference, machine learning, and health disparities. The K01 research and training experience will result in an R01 with the overarching goal of extending causal machine learning methods for generalization to address more complex real-world questions. In the long term, I will bring TRS, machine learning methods, and causal inference together to address pressing issues in TRS. This effort will put causal machine learning methods in the hands of tobacco researchers and facilitate the use of complex data to inform FDA regulations.

NIH Research Projects · FY 2026 · 2023-04

How memory is stored in the brain is unknown. The dominant synaptic plasticity and memory (SPM) hypothesis asserts that memory is stored by functional modifications induced by learning at a subset of the synapses of the neurons that are activated to encode the learning experience. This predicts permanent memory erasure is caused by post-learning inhibition of a molecular synaptic plasticity maintenence mechanism that is necessary for persistent storage of the long-term memory. Indeed, erasure of a variety of memories has been demonstrated by intracranial ZIP administration. ZIP inhibits the kinase activity of atypical PKCs, PKMζ and PKCι/λ, both of which can be persistently upregulated following memory acquisition. PKMζ is both necessary and sufficient for wildtype late-LTP maintenance, and when the PKMζ gene Prkcz is deleted, PKCι/λ compensates for the loss of PKMζ, becoming necessary for maintaining late-LTP. Intracranial aPKC manipulations erase a variety of long-term memories, but not all, providing crucial support for the foundational SPM hypothesis. However, because the manipulations act generally, affecting cells that may not participate in the memory storage, it is crucial to selectively depotentiate synapses in a memory-associated subset of cells to critically test the SPM hypothesis. Indeed, others have used the fact that memory formation requires protein synthesis to challenge the SPM hypothesis. They demonstrated that post-learning optogenetic stimulation of a context-fear memory-activated subset of hippocampal neurons is sufficient to express the memory, even after an amnesia-producing block of protein synthesis. However, these studies did not critically test the SPM hypothesis because neither hippocampus function, nor the most common N-Methyl-D-Aspartate receptor (NMDAR)- and aPKC-dependent form of LTP in the hippocampus are necessary for context-fear memory, amongst other experimental issues. We propose to critically test the SPM hypothesis using 1) a long-term active place avoidance memory that is sufficient to induce persistent hippocampal synaptic potentiation, and depends on hippocampus PKMζ, both for at least 30 days; 2) optogenetic activation of neurons that is sufficient to express the avoidance memory; and 3) aPKC manipulations that are genetically targeted to the memory-associated subset of cells. We will optogenetically activate a “sufficient-for-memory” subset of the hippocampal neurons that are allocated to encode and recall a specific place memory, after erasing the memory and associated synaptic plasticity by aPKC manipulation of the same cells. We will evaluate if after erasure, optogenetic activation of the memory-associated cells expresses the spatial information in neural discharge and the conditioned avoidance behavior that express the memory. If the optogenetic activation causes memory expression, the SPM hypothesis will require modification, at least as far as it it concerns aPKC-dependent synaptic plasticity and active place avoidance memory.

NIH Research Projects · FY 2026 · 2023-04

Effective HIV treatment has increased long-term survival among people living with HIV (PWH). However, deaths related to non-communicable diseases (NCDs) are rising in the U.S. and globally, threatening progress in reducing HIV-related mortality. Despite evidence-based interventions to prevent and treat NCDs, implementation into HIV clinical workflows has lagged. Vietnam is a global leader in integrating HIV and NCD services and recently reorganized its health care system to respond to the shift from infectious diseases to chronic comorbidities. This creates a “living laboratory” for implementation science (IS) research not readily available in the U.S., where HIV care remains fragmented. Our proposed D43 research training program offers a unique scientific opportunity to leverage Vietnam’s investment in health system redesign to study integrated models of care for PWH that will inform HIV care innovation in the U.S. The program will equip trainees with critical IS skills through coursework, mentoring, and experiential learning in high-volume integrated clinical settings and further provide U.S. and Vietnamese researchers opportunities to evaluate the scalability of integrated delivery models under real-world rigorous conditions. Lessons generated from this research will augment existing U.S. resources by providing proof-of-concept for low-cost, high-impact care for PWH in the U.S. Although conducted abroad, the program is designed to directly benefit the American public. The crossnational collaboration will identify innovations in implementation and practice improvement relevant to both countries. Findings from trainee research will inform affordable integrated care models applicable to underserved U.S. settings, including rural communities. Finally, successful curriculum components will also be adapted into existing U.S. implementation science training programs, strengthening the domestic workforce’s capacity to confront the rapidly growing HIV-NCD epidemic. By advancing strategies to prevent and manage comorbidities among PWH, this project will directly help sustain the long-term effectiveness of U.S. HIV programs and protect gains in life expectancy. Our aims are to: 1) Leverage Vietnam’s clinical research platform to provide an applied research training program that equips trainees with research skills and generates data that informs strategies for integrating HIV and NCD care; 2) Engage in robust cross-national scientific exchange to disseminate innovative integrated care models and implementation strategies relevant to both the U.S. and Vietnam; and 3) Strengthen U.S. implementation science capacity by identifying effective training and program components that can be adapted into existing U.S.-based training programs to reverse the growing burden of NCD-related diseases among PWH.

NIH Research Projects · FY 2026 · 2023-03

Project Summary: Proper mineralization of dental enamel protects against bacterial attack that causes tooth decay (caries). The ameloblasts cells are responsible for producing and secreting an abundance of proteins (laying a foundation for enamel growth) as well as engaging in active mineral transport (calcifying the enamel). These functions are stage dependent with amelogenesis being divided into the secretory (protein synthesis) and maturation stage (mineralization). However, the mechanisms providing metabolic support for these processes and how mitochondrial dysfunction might alter them is poorly understood. Mitochondria are organelles within the cells that convert nutrients into energy via the production of ATP, and deficiency in mitochondrial function results in human diseases. Mitochondria play an important role in enamel as evidenced by defects in mitochondrial DNA causing abnormal enamel development. Therefore, the goal in this competing renewal proposal is to investigate the interplay between mitochondrial function and enamel formation during environmental insults and determine whether this is altered in patients with genetic disorders that effect mitochondrial function. We will specifically address this in the context of Down syndrome (DS), or Trisomy 21, and during dental fluorosis, a process in which exposure to excess of fluoride during development weakens tooth enamel. DS patients present with enamel defects including hypocalcification and hypoplasia, both caused by developmental defects in enamel formation. Mitochondrial dysfunction is widely reported in DS. The overarching hypothesis of this proposal is that altered mitochondrial function in DS ameloblasts alters enamel crystal formation and impacts sensitivity to fluorosis. In strong support, our preliminary data show that Dp- 16 mice (an established mouse model of DS) have mechanically weak and morphologically abnormal enamel. Moreover, overexpression of RCAN1 (a gene associated with DS pathophysiology that is expressed in ameloblasts) in enamel cell lines, significantly impaired mitochondrial function. We have also reported that fluoride exposure of enamel cells significantly affected the biosynthesis of the proteins of the electron transport chain (ETC) responsible for maintaining ATP production, but not in other cells tested, suggesting unique sensitivity of enamel cells to fluoride, possibly associated with higher ROS levels. In the proposed studies we will use DS mouse models (Dp16 mice, Rcan1-KO mice, Dp16 x Rcan1-KO mice) to address the role of mitochondria in the ameloblasts of these mice. We will also use recently developed reporter mice expressing fluorescently labelled secretory and maturation stage ameloblasts to induce fluoride and investigate mitochondrial defects using single cell RNASeq and bulk RNAseq to compare ameloblasts with other tissues. To address if ameloblasts of DS models are more sensitive to fluoride, we will treat the cells with fluoride and analyze mitochondrial function.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract Chronic widespread pain (CWP) is a chronic pain subtype that affects multiple body sites, and is strongly associated with poor function and disability. Although CWP is highly prevalent in adults with obesity, CWP outcomes are disproportionately worse in non-Hispanic Black (NH Black) and Hispanic/Latino/a/x adults. Thus, the obesity-related health disparity in CWP could augment existing racial and ethnic pain disparities in these populations. Bariatric surgery is often prescribed to treat obesity and musculoskeletal pain comorbidities. However, there is significant variability in weight loss and pain trajectories after bariatric surgery. Moreover, many patients experience recurrent or unresolved pain after bariatric surgery that can inhibit weight loss or facilitate weight regain. There are critical gaps in our knowledge of the primary driver(s) of CWP outcomes and how driver(s) of CWP respond to weight loss, particularly in racial and ethnically diverse groups. As such, the main objective of the proposed mentored project for the Mentored Patient-Oriented Research Career Development Award (K23) is to fill these knowledge gaps by: 1) comprehensively characterizing pain at rest and movement- evoked pain (MEP) in NH Black and Hispanic/Latino/a/x adults after bariatric surgery, and 2) identifying potential key driver(s) of intra-group variability in the resolution or maintenance of pain after bariatric surgery. We will focus on pain sensitivity, joint motion and mechanical loading biosignatures, and psychosocial factors. The aims proposed in this K23 application feature highly innovative methods that synergize mechanism-based pain phenotyping with obesity and health disparities research approaches. The methodologies employed represent a substantive departure from static, self-reported pain assessment to the integration of rigorous assessment and measurement multiple dimensions of pain at rest and MEP using precise quantification of nociceptive processing and joint motion and loading biosignatures in ethnically diverse populations. For the K23, I have assembled a strong interdisciplinary and multicultural cadre of highly successful clinical, basic, and translational scientists who have a strong and demonstrable commitment to the successful implementation and completion of my career development plan and research project milestones. The primary training goals that are the linchpin of my research training and career development are: 1) developing expertise in the integration of weight loss and lifestyle change evaluations with pain phenotyping data, 2) to develop and implement clinical trial designs that identify and address pain disparities, and 3) to enhance training in advanced statistical methods to inform clinical trial design to examine pain disparities. New York University (NYU) and the University of Florida are very strong incubators of pain, obesity, and rehabilitation research. Furthermore, these institutions are robust research environments that have the resources available to me to build on my previous training to foster independence in research that is focused on improving pain management in racially and ethnically diverse adults with obesity.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY On July 16, 2022 “988” will become the national toll-free dialing code for the National Suicide Prevention Lifeline (Pub. Law 116-172). The Lifeline receives 3.5 million calls annually and has demonstrated effectiveness at decreasing suicidality, hopelessness, psychological distress, and suicide death. The transition from the current 10-digit Lifeline dialing code to 988—a three-digit code like 911—is projected to potentially triple call volume. The impact of 988, however, will likely be determined by state policy responses to financing its implementation. The federal law that creates 988 encourages states to pass user fee legislation (e.g., a flat fee monthly per every cellphone plan holder in the state, identical to how 911 is financed). The current state policy landscape is extremely varied. As of January 2022, four states had passed user fee legislation and many others were considering such legislation. The proposed policy implementation project focuses on the characteristics, determinants, and impacts of 988 user fee legislation and other policy strategies used by states to finance 988 implementation. The project’s Specific Aims are to: 1) Characterize states’ 988 implementation financing strategies and identify determinants of implementation strategy adoption; 2) Explore perceptions of the financing determinants of 988 policy implementation success and acceptability and feasibility of legislative financing strategies to improve implementation; and 3) Determine the effects of 988 user fee legislation on the policy implementation outcomes of fidelity (Lifeline in-state answer rates) and reach (Lifeline state call volume rates), the effectiveness outcomes of suicide death and emergency department use for mental health crises and self- harm, and assess effect heterogeneity across demographic groups. These aims will be achieved by a legal mapping study, national surveys of 250 suicide prevention stakeholders (e.g., Lifeline call center leaders), 60 semi-structured interviews, and a difference-in-differences analysis comparing trends in implementation and effectiveness outcomes pre (2015-2021) and post (2022-2025) 988 implementation between states that did and did not pass 988 user fee legislation. The project team has expertise in policy implementation science (Purtle, Raghavan), suicide (Lindsey), law (Pomeranz), and quantitative policy analysis (Stuart). Practice partners include Vibrant Emotional Health, which administers the Lifeline, and the American Foundation for Suicide Prevention. The project is innovative because it advances the understudied area of policy-focused implementation science. The project is significant and will have impact because it focuses on a major federal policy in the early stage of implementation and because it will generate knowledge to inform implementation financing decisions related to 988—which is likely to be a primary gateway to mental health crisis and suicide prevention services for the foreseeable future. The project is aligned with NIMH’s Strategic Plan, which prioritizes suicide prevention, and the NIMH pledge to reduce the suicide rate by 20% by 2025.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY Animals can exhibit goal-directed behaviors in novel environments, despite limited experience with them. How does the brain make and use inferences about the underlying statistics and generative structure of environments to guide behavior? The field of reinforcement learning refers to this capacity as “model-based” reasoning, meaning that it relies on an internal model of the structure of the world. Critically, this internal model can be used to flexibly estimate the best actions by mental simulation or planning, without direct experience. In contrast, in “model-free” reinforcement learning, an agent chooses the best action based on direct experience, without explicit knowledge of the underlying sequential transition structure of a task or environment. Model-based and model-free mechanisms coexist in the brain and are mediated by distinct circuits, although the neural circuit mechanisms by which the brain arbitrates between these decision systems remains unknown. Theoretical and behavioral studies suggest that human brains use the system that yields value estimates with the lowest uncertainty. The lateral orbitofrontal cortex (lOFC) is a compelling candidate to perform arbitration because while it is implicated in model-based reasoning, for instance by enabling inferences about hidden task states, it lies upstream of the dorsal striatum, which is critical for both model-based and model- free decision making. Intriguingly, we have found that lOFC neurons project exclusively to the dorsolateral striatum (DLS), a region critical for model-free behavior, and not the dorsomedial striatum (DMS), which is critical for model-based behavior. We hypothesize that projection specific neural circuits in lOFC arbitrate between these systems by suppressing the model-free system. I will use state-of-the-art viral, electrophysiological, and computational methods to determine whether DLS-projecting lOFC neurons mediate uncertainty-based arbitration between decision-making systems (Aim 1) and characterize the underlying circuit logic that supports arbitration (Aim 2). By optogenetically tagging DLS-projecting lOFC neurons I will selectively characterize and perturb their activity while monitoring the behavioral strategy rats use in a task with latent structure. To determine how arbitration is instantiated in the dorsal striatum I will optogenetically activate OFC→DLS neurons while recording from different genetic cell types in the striatum, in vivo and in vitro. We predict that OFC→DLS neurons enable model-based behavior by activating inhibitory interneurons to suppress the DLS and the model-free system.

NIH Research Projects · FY 2025 · 2023-02

In population samples, segregating recessive variants at low frequency are largely inaccessible to study. This project uses an experimental system in which rare alleles have been made common, recessive alleles can be homozygosed on demand, and cumulative effects of large numbers of small-effect variants can be measured in an unbiased way. The project centers on the nematode Caenorhabditis becei, which has all the experimental virtues of C. elegans but with a mating system and population biology that make it better suited to questions about genetic diversity in general and recessive variation in particular. This project will measure sex-specific competitive fitnesses and sex- and allele-specific transcript abundances in a specially designed panel of C. becei to reveal the architecture of segregating recessive variation and its molecular characteristics. The data will address basic questions in evolutionary biology while generating generalizable gene- and variant-scale models that predict whether variants are likely to have recessive effects.