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National Institutes of Health

The purpose of this Notice of Funding Announcement (NOFO) is to encourage pilot research that is not an immediate precursor to testing a service intervention but is consistent with NIMH priorities for services research. While NIMH now requires use of an experimental therapeutics model for all intervention studies, there is recognition that some mission-relevant areas of services research do not involve clinical trials.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY First-ever data from Zambia on people who inject drugs (PWID) demonstrates major gaps in the HIV epidemic response. A recent biobehavioral survey show sharp health disparities along the entire PWID HIV care continuum, with gaps in HIV testing, linkage to ART, and viral suppression, and limited knowledge of PrEP. Failing to detect early HIV infections and address unsuppressed viral load poses a risk of ongoing community transmission as well as increased risk for HIV comorbidities and mortality, threatening the overall HIV epidemic control response in Zambia. The Zambia Ministry of Health has adopted a harm reduction approach to address the health disparities experienced by PWID. Starting in November 2024, the Zambia Ministry of Health will provide Medications for Opioid Use Disorder (MOUD) at two health facilities which also provide HIV services. There is currently minimal evidence in sub-Saharan Africa on MOUD integration with HIV care. The arrival of MOUD in Zamvia presents an exceptional opportunity to collaborate with Ministry of Health and key partners to develop a person-centered integrated collaborative care model for PWID and pilot testing implementation, feasibility, and preliminary effectiveness within the Zambian health system. We propose the Integrated Services for PWID using Person-centered Interactions, Reach, and Engagement (INSPIRE) study to co-adapt and evaluate an HIV status-neutral system-level integrated approach using a Collaborative Care Management Model (CoCM) for HIV prevention, HIV care, mental health, and MOUD. This implementation science study includes the following Aims: Aim 1: Assess the multilevel determinants of early implementation of MOUD services using rapid qualitative analysis. Aim 2: Co-adapt an HIV status-neutral CoCM with key stakeholders. Aim 3: Implement and evaluate the co-adapted CoCM, guided by Practical, Robust Implementation and Sustainability Model (PRISM), and including the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) outcomes. The research team, led by Multiple Principal Investigators (MPI), has expertise in psychiatry, HIV clinical care, implementation science, behavioral and social sciences, HIV clinical care, epidemiology, and mixed methods, and has a deep knowledge of HIV response and service delivery models in Zambia for marginalized populations, and experience implementing opioid use treatment both in the US, and in Kenya. We will also leverage the University of Maryland Baltimore’s decade of experience implementing MOUD and HIV programs in Kenya. Addressing the unmet needs of PWID is urgently needed to achieve and maintain HIV epidemic control; our findings will inform the implementation of integrated care models for PWID. Lessons learned from INSPIRE will help develop best practices for system-level approaches to improve OUD treatment and HIV prevention and treatment programs in both sub-Saharan Africa and the US.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Substance use disorders (SUD) and post-traumatic stress disorder (PTSD) are debilitating mental health disorders that frequently co-occur and have onset during adolescence. Approximately 9% of adolescents aged 12-17 meet criteria for a current SUD, with more than 70% of those having experienced a traumatic event and 35% meeting criteria for PTSD. If left untreated, a cyclical relationship between substance use and PTSD serves to maintain or exacerbate the other, leading to a chronic course of illness. Adolescents with co-occurring SUD/PTSD are at increased risk of developing other serious mental health problems (e.g., depression, suicidal ideation), HIV-related risk behaviors, and academic and interpersonal problems. There is a critical need to intervene earlier in the developmental trajectory to prevent the long-term deleterious outcomes associated with SUD/PTSD in adulthood. However, there are no effective individual treatments for adolescents with SUD/PTSD. Clinicians agree that comorbid SUD/PTSD among adolescents is a significant problem, and that a feasible and effective intervention is clearly needed. Efficacious, evidence-based treatments for adults with SUD/PTSD have been developed over the past two decades and can be adapted to address the unique developmental needs of adolescents with SUD/PTSD and improve outcomes and functioning for this highly understudied population. Based on promising preliminary data, the proposed study will directly address this need by evaluating an integrated, trauma-focused intervention, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE), specifically adapted for adolescents (COPE-A). A Stage Ia study of COPE-A demonstrated safety, feasibility, and significant pre- to post-treatment reductions in SUD and PTSD symptoms, while a Stage Ib pilot RCT comparing COPE-A to Person Centered Therapy (PCT) showed safety, feasibility, and preliminary efficacy in significantly reducing substance use and PTSD severity. Stage I studies also resulted in a treatment manual, clinician training protocol, and fidelity monitoring procedures, all of which will be used in the proposed study. The primary objective of this Stage II RCT is to evaluate the efficacy of COPE-A, compared to PCT, in reducing (a) substance use frequency and amount, and (b) PTSD severity among a larger sample of adolescents (N = 120) with co-occurring SUD/PTSD. Secondary objectives are to examine the effects of COPE- A on associated areas of functioning including depression, HIV risk behaviors, interpersonal functioning, and quality of life. In line with our prior work, we will recruit nationally and deliver the intervention via telehealth. Ecological momentary assessment (EMA) will monitor daily substance use and PTSD symptoms to examine their temporal and reciprocal relationship and identify underlying mechanisms of change to inform future research.

NIDA - National Institute on Drug Abuse

Substance use disorder (SUD) is a leading public health challenge, with long-term consequences for physical and mental health. In-person peer support groups are well-established as beneficial for recovery. However, as digital platforms increasingly serve as spaces for peer support, little is known about how engagement in online peer support recovery groups is associated with recovery outcomes. Emerging research has yielded conflicting results, with some studies suggesting benefits while others indicating relapse risks. This underscores the need to examine the content of discussions beyond engagement frequency. The present application seeks support for Xiangyu Tao, Ph.D., a postdoctoral associate at the Rutgers Addiction Research Center, gain the necessary training and set up a line of research to examine the role of online peer support recovery communities in SUD recovery. Specifically, she will integrate state-of-the-art artificial intelligence (AI) techniques, including Large Language Models (LLMs), with co-production to identify communication patterns and to examine their associations with recovery outcomes. LLMs offer a promising avenue for analyzing large-scale online discussions, yet they require human oversight to address challenges such as contextual misinterpretation and ethical concerns. Co-production, i.e., involving individuals with SUD recovery experience in all research stages, mitigates LLM limitations and ensures that results reflect lived experience. The mentored K99 phase will identify and characterize communication patterns in online recovery groups. Peer support and co-rumination patterns will be classified using LLMs and co-production (Aim 1); latent class analysis (LCA) will identify distinct communication profiles among users engaging in these online groups (Aim 2). During this phase, Dr. Tao will receive mentorship in co-production and AI methodologies, longitudinal data analysis and management, and responsible AI research. The independent R00 phase will build upon this foundation by examining how communication profiles are associated with recovery trajectories using longitudinal survey data from online recovery group participants (Aim 3). This project is highly innovative in its integration of LLMs and co- production to analyze large-scale digital recovery discussions, ensuring that AI-driven insights are both computationally rigorous and socially informed. Findings will enhance understanding of digital peer support for SUD recovery and will inform future mechanistic studies and SUD interventions. By identifying communication patterns associated with recovery trajectories, this project will guide digital health platforms, peer support programs, and clinicians in optimizing online recovery environments to better support individuals with SUD. This project aligns with the NIDA Strategic Plan Cross-Cutting Priority to "Leverage Data Science and Analytics to Understand Real-World Complexity" by utilizing advanced computational methods to analyze digital recovery support interactions. The project is highly significant in bridging advanced AI computational tools with the lived experiences of individuals to produce impactful research to promote substance use recovery.

NIMH - National Institute of Mental Health

Modified Project Summary/Abstract Section Early identification and intervention for autistic children significantly improve developmental and family outcomes, yet systemic barriers limit access to early intervention (EI) services. Many families experience difficulties in service access due to stigma, mistrust in healthcare systems, financial constraints, and a lack of responsive services. Family Navigation (FN), a casemanagement and family-support approach, has demonstrated effectiveness in improving access to some services, such as autism diagnostics, but its integration into Part-C EI systems remains understudied. Given that EI systems serve as a critical entry point for young autistic children and their families, embedding FN into EI services has the potential to improve caregiver engagement, increase adherence to evidence-based autism interventions and information, and enhance overall service delivery. However, to ensure successful implementation, tailored strategies are needed to address the unique challenges and constraints of EI systems, providers, and families. To address this gap, this study systematically examines FN implementation within Part C EI systems to enhance caregiver engagement and improve child outcomes. Guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework, this R21 project employs implementation mapping to identify key determinants and develop tailored implementation strategies for FN integration in EI across three states (GA, TX, WA). Using a convergent mixedmethods design, we will assess FN barriers and facilitators through surveys and focus groups with caregivers, EI providers, and administrators (Aim 1). We will then apply human-centered design strategies, including rapid prototyping, to refine implementation strategies, ensuring feasibility, acceptability, and scalability (Aim 2). This study is innovative in integrating FN alongside autism-focused EI services in Part C systems, which serve over 400,000 children annually. By engaging stakeholders and aligning strategies with existing EI service models, the project enhances the sustainability of FN in various EI settings. Findings from this study will inform a subsequent R01 effectiveness-implementation hybrid trial to evaluate FN’s impact on service access, caregiver engagement, and child outcomes. By addressing long-standing issues in autism service access, this research has the potential to transform EI service delivery by providing structured, evidence-informed strategies for FN integration. Ultimately, this project aims to improve quality in autism EI services, ensuring that all families receive the support they need to engage in high-quality, evidence-based intervention during the critical early years of their child’s development.

NIDA - National Institute on Drug Abuse

Project Abstract/Summary This Type 1 R34 implementation research pilot will provide critical, highly sought data to determine whether the unique and innovative biomedical profile of lenacapavir (LEN) pre-exposure prophylaxis (PrEP) is feasible and acceptable to people who use drugs (PWUD) in two street medicine contexts. PWUD remain vulnerable to HIV outbreaks in communities like Everett (Snohomish County), Washington, which lack the extensive HIV prevention infrastructure found in major urban centers. While twice-yearly, long-acting injectable LEN offers a promising advance by reducing dosing burden relative to daily oral or bi-monthly injectable formulations, its actual public health impact will depend on rigorously addressing barriers to LEN engagement, follow-up, and acceptability in real-world settings. This study meets a critical implementation gap regarding how workforce composition, same-day access, and differentiated mobile engagement models may influence LEN uptake and continuation among the most vulnerable PWUD. The project leverages two established, low-barrier mobile outreach programs in Everett: the Emergency Mobile Opioid Team Everett (EMOTE), offering immediate linkage to substance use and mental health treatment to all-comers and led by peers with lived experience in drug use and exchange sex; and the Harm Reduction Center (HRC) street medicine van, offering street-based advanced wound care, buprenorphine, phlebotomy, infectious disease testing/treatment and other medical services, and led by medical practitioners. In Aim 1 we will conduct formative, iterative work guided by the Consolidated Framework 2.0 for Implementation Research (CFIR 2.0). We will convene a Community Advisory Board and focus groups to co-design two tailored PrEP engagement models, each maximizing unique traits of EMOTE or HRC (EMOTE-PrEP and HRC-PrEP) to address LEN messaging, initiation, and retention for PWUD. In Aim 2, we will pilot these models by screening approximately 300 clients and enrolling about 70 eligible participants, with an anticipated 20 LEN initiations across both settings, to assess feasibility, acceptability, and PrEP cascade outcomes. Initiation and 6-month retention will be treated as implementation signals rather than efficacy endpoints. In Aim 3, qualitative interviews with participants who initiate, decline, or discontinue LEN will examine mechanisms influencing engagement, including trust, messenger effects (peer versus practitioner), perceived burden, and decision-making. Without evidence to inform engagement and retention strategies that support both initial uptake and six-month follow-up, the unique advantages of long- acting LEN PrEP will fail to reach the populations most vulnerable to outbreaks. Findings will have a significant public health impact, setting the stage for a fully powered trial of scalable LEN PrEP engagement and retention strategies for PWUD.

NIA - National Institute on Aging

PROJECT SUMMARY Over 50% of the 12.8 million low-income individuals who are dually eligible for Medicare and Medicaid (“dual eligibles”) qualify for Medicare because of disability. This varied population experiences physical, intellectual, developmental, cognitive, or mental disabilities that substantially limit major life activities. People with disabilities die 10-20 years earlier than those without disability, and much of this premature mortality is preventable. Dual eligibles with disabilities have high prevalence of multiple chronic medical (e.g., diabetes) and behavioral health (e.g., depression) conditions and high need for long-term services and supports (LTSS) for daily activities. Medicare and Medicaid have been poorly integrated to serve dual eligibles, leading to conflicting financial incentives, fragmented care delivery, and complicated administrative processes. Together, these issues drive high healthcare spending and poor health outcomes, including 40-60% avoidable premature mortality, among dual eligibles with disabilities. Integrated SNPs) or for with dual eligible special needs lans (integrated D- are a type of Medicare Advantage (MA) plan that contracts with state Medicaid agencies to cover some all Medicaid services coordinate Medicare and Medicaid benefits and streamline administrative processes dual eligibles. These plans aim to better align financial incentives toward “whole person” care consistent clinical guidelines and to provide comprehensive care management for chronic conditions. p , , Integrated D- SNP enrollment among dual eligibles with disabilities grew 12-fold between 2018 and 2024. Despite rapid growth, there is little evidence on the impact and implementation of integrated D-SNPs overall and none for dual eligibles with disabilities. This study aims to fill this gap using novel linked data capturing the entirety of Medicare and Medicaid services for 100% of dual eligibles with disabilities from 2018-2027. We will use a concurrent-embedded mixed-methods design integrating a quantitative trial emulation approach with difference-in-differences (Aim 1) and survival (Aim 2) analyses with qualitative study of integrated D-SNP implementation (Aim 3). Aims 1-2 will assess how integrated D-SNP enrollment influences care utilization, quality indicators, and chronic diseases management (Aim 1) and mortality (Aim 2) among dual eligibles with disabilities. Aim 3 will characterize integrated D-SNP implementation for dual eligibles with disabilities with the goal of identifying promising practices and areas for improvement. This project is well aligned with the NIH Strategic Plan for Disability Health Research FY26-FY30 and NIA's priority of promoting adherence to medical and behavioral regimens for healthy and adaptive aging in later life.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Despite concerted efforts by states, counties, agencies, and researchers to promote evidence-based treatments (EBTs) for youth in community mental health (CMH) settings, youth mental health outcomes are often still poor. Implementing regular assessment of outcomes, or “progress monitoring” (PM), alongside EBTs can support EBT implementation and improve youth outcomes. However, barriers such as competing demands and fear of PM data potentially being used punitively against clinicians hinder the widespread adoption of PM in routine practice. Many studies have investigated ways to address PM implementation barriers, though most neglected addressing important barriers that are perceived to be low in feasibility to address, potentially jeopardizing successful PM implementation. Additionally, system leaders could have valuable insights on solutions for addressing these barriers, but they are rarely included in implementation research efforts. Guided by the Exploration, Preparation, Implementation and Sustainment (EPIS) Framework, the current study engages constituents from both the inner (clinic partners) and outer context (system leaders) to understand barriers to PM identified as priorities by clinics and implementation strategies needed to address these barriers. Findings will be used to develop a tailored implementation blueprint, or plan of action, for PM across the Preparation, Implementation and Sustainment phases in one CMH center serving youth. This study leverages an ongoing Washington (WA) state-wide EBT training initiative called CBT+ that trains youth- focused CMH clinicians on the common elements of cognitive-behavioral therapy (CBT) for anxiety, depression, trauma and behavior disorders. For the proposed project, we will partner with a WA state payer, Community Health Plan of Washington. We use innovative methods from the NIMH-funded ALACRITY Center, IMPACT. Study aims are to: Aim 1. (1a) Identify which barriers to PM implementation are priorities to address using the IMPACT Center barrier prioritization method and (1b) Understand the goals and perceptions of PM from constituents at multiple levels through qualitative focus groups and quantitative assessments; Aim 2. Collaboratively match implementation strategies to prioritized barriers from Aim 1. Clinic partners and system leaders will brainstorm strategies using Ideation (IMPACT method) for prioritized barriers, with a particular focus on engaging system leaders to identify strategies for high importance, low feasibility barriers. Participants will match strategies to barriers and develop enactment plans for a subset of the strategies; Aim 3. Develop and evaluate a 3-phase tailored implementation blueprint for PM at a CMH center that serves youth. Findings from this study will be used to develop practical methods for implementing PM in CMH settings that are scalable and generalizable to other settings, with the ultimate goal of improving youth mental health services and outcomes.

NIMH - National Institute of Mental Health

Project Abstract This proposal aims to develop statistical models that associate brain connectivity with human health outcomes. It uses a mathematical framework that quantifies not only pairwise co-activation of brain regions (nodes), but also encodes three-way and higher-order interactions, and their densities, using the mathematical framework of simplicial complexes (SCx). The methods developed here will enable the statistical analysis of cognitive function in large neuroimaging studies by modeling connectivity patterns in ways that are more extensive than those currently used. These methods will provide new insights into the complexities of brain-related health conditions because they quantify neuro-activation patterns in new and interpretable ways. Aim 1, extends the investigators’ previous scalar-on-matrix regression to include generalized linear and mixed models, then moves beyond adjacency matrix predictors to upper-adjacency edge (UAE) matrices, defined via three-way co- activation. These higher-order analogues of connectivity matrices involve edge relationships and have a low- rank structure not captured by standard approaches. They also lead to a new concept of edge communities (1- simplexes) that share a triangle (2-simplexes), or maximal edge communities (MEC). In Aim 2, estimated health-associated connectivity patterns in penalized regression models also incorporate higher-order simplicial structures—as predictors and regularizers. These model path structure by viewing node-pairs as boundaries of paths, and modeling their effective resistance (ER), which quantifies network-wide robustness of communication among nodes. Aim 2 leverages the UAE matrix to define a “lifted graph”, and the corresponding lifted-graph Laplacian is used for penalized regression on edges. These models encompass kernel-based methods that involve subject similarities based on simplicial structures. Aim 3 considers matrix- on-scalar regression models to estimate community-level associations between scalar predictors and adjacency-matrix responses. Rather than regressing based on prescribed mesoscale structure associations this form of model is extended to higher-order adjacencies structures, including MECs and other SCx structures. Aim 4 explores the recent concept of persistent Laplacians. This new operator relates the properties of two simplicial complexes when one is embedded in another. This allows analysis of a population of networks/simplices, which do not necessarily share all edges or triangles, by relating them to a common “core” SCx. Participant-wise discrepancies from this core, using the SCx algebra framework, leads to a new type of analysis. Successful completion of the proposed research will provide urgently needed extensions to current analytical methods with new models and software tools aimed at understanding common neurobiological disorders.

NIMH - National Institute of Mental Health

Youth living with HIV (YLWH) experience mental health (MH) challenges that compromise their HIV care. Though the MH gap is well described, integrated MH service delivery to YLWH is rare, both in the United States (U.S.), and lower resourced settings. MH professionals are rarely available in HIV clinics and few youth are willing to engage in outside care. Interventions tailored to the needs of this population are scarce and critically needed. Streamlining the Sauti ya Vijana (SYV, The Voice of Youth) intervention offers a way to bridge the MH gap. SYV is a peer-led, group-based treatment designed with and for YLWH to address their self-reported MH challenges. SYV incorporates components of evidence-based psychotherapeutic models to address the needs youth described in formative interviews. Preliminary data estimated effects towards improved MH, antiretroviral therapy adherence, and a 10% greater increase in viral suppression in the intervention arm compared to standard of care. Our prior research shows similar levels of depressive symptoms among U.S. YLWH and a desire to bring this model to the U.S. context through reciprocal innovation (Dow, Pediatrics 2025). The central hypothesis is that the new integrated “i" SYV will be acceptable, feasible, and effective to improve virologic suppression and improve retention in care. The mechanism of change is that improved MH leads to better medication adherence, viral suppression, and care engagement. The rationale is twofold: 1) MH screening is being initiated in HIV clinical visits, but the MH treatment gap persists; 2) the iSYV stepped-care package could be an effective approach to support integrated MH care for YLWH. Evidence generated in the African context can be obtained more cost-efficiently and applied to inform solutions for American YLWH. The central hypothesis will be tested in a hybrid type-2 effectiveness-implementation trial. The first aim will leverage the Fit to Context Framework, using an iterative Designing for Dissemination and Sustainability approach. SYV peer-group leaders (PYL) with extensive experience delivering SYV will co-design the new iSYV package. The iSYV in-person sessions will be delivered by trained PYLs and be aligned to the Tanzanian differentiated care model: stable youth (those fully suppressed) attend clinic every 6 months; and unstable youth (those with HIV RNA > 50 copies/mL) attend enhanced adherence counseling monthly, similar to U.S. guidelines. Youth with symptoms of MH difficulties on screening (PHQ9-depression, GAD7-anxiety, Trauma-related stress) will join the unstable group. To support engagement between visits, iSYV will explore use of a mHealth gamification strategy. The second aim includes a pilot and a four-arm cluster randomized trial. A large U.S. based implementing partner, Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) will support testing the iSYV care package. The third aim will evaluate implementation determinants and outcomes, including acceptability, feasibility, fidelity, and cost informed by the Consolidated Framework for Implementation Research. The proposal is significant because it is expected to help address the MH gap for YLWH with implications for HIV care in Tanzania as well as the U.S.

NIMH - National Institute of Mental Health

Rates of depression in adolescents are high (~24%). Early adversity exposure can affect brain development and function and lead to depression. However, only some youth, who may be less genetically resilient, develop psychopathology after adversity, suggesting neurobiological and genetic differences. Previous studies from our research team found in both mice and humans that depressive-like behaviors only developed after adversity, when the hippocampus was compromised. Moreover, using postmortem brains, the team found hippocampal genetic pathways associated with adversity exposure or resilience in mice and with depression in humans. This proposal will determine whether individual differences in expression of these genetic pathways in humans increases susceptibility, or conversely resilience, to adversity and thereby the likelihood that individuals will develop depression. The research team with expertise across basic neuroscience (rodents and humans), clinical and developmental psychology, translational epidemiology, statistical genomics and biostatistics is uniquely suited for this proposal, which sits at the intersection of neuroscience, genomics and epidemiology. Aim 1 will determine if innate differences in hippocampal adversity-, resilience- and depression-related gene expression pathways modify risk for depression after early adversity. However, levels of hippocampal gene expression cannot be directly measured in living humans. Therefore, first relevant hippocampal gene networks from causal mouse models and postmortem human brains will be defined. Then, we will use data from the Adolescent Brain Cognitive Development Study (the largest US longitudinal study of adolescent neurobiological development; n=11,700) and leverage innovative, data-driven “expression-based polygenic scores (ePGSs)”, which reflect individual variation in predicted hippocampal expression of the gene networks of interest. Using these techniques, we will determine if differences in expression of these gene networks (ePGSs) predict depression development after adversity exposure. In Aim 2, we will test how these genetic scores moderate possible mediation pathways between early adversity and depression through altered hippocampal and brain- wide task-based and resting-state connectivity. In Aim 3, we will test replication and extension of the findings to lifetime depression in a cohort of middle-aged adults (UK Biobank; n=500,000). Then, in both cohorts, lifestyle factors known to promote hippocampal function will be examined as modifiable mitigating factors for those with high depression risk. We hypothesize that individuals with highest genetic risk measured by ePGSs who have had substantial early adversity exposure, have altered hippocampal activity and increased risk for depression. By elucidating the interactions between genetic risks and environmental stressors, and how they affect brain function, we aim to identify the individuals most vulnerable to depression development after adversity to ultimately steer prevention efforts towards those who need it most, in line with the NIMH’s goals to better understand brain and genomic mechanisms underlying psychopathology and to prevent mental illness.

NIMH - National Institute of Mental Health

In the wake of a youth mental health crisis, soaring rates of mental disorders have been accompanied by increased demand for child mental health services. Half of children with a mental disorder receive no mental health services. This gap has fueled calls for investments in effective mental health prevention programs in schools. Many mental disorders first onset in childhood, and the benefits of prevention and early intervention are largest when focused near the time of onset. Untreated, mental disorders in childhood can undermine adult mental and physical health, quality of life, educational attainment, and employment. Research shows that coordination, collaboration, and alignment between health and educational sectors are essential to the implementation and sustainability of effective mental health interventions in schools. However, focused training for scholars who want to build research careers at the intersection of health and education is lacking. Advancing the science and practice of school-based prevention of mental disorders requires a fundamentally new, interdisciplinary approach to training. The goal of this first-of-its-kind training program is to equip postdoctoral scholars to become leaders in school mental health and school-based prevention science, leveraging resources across the Johns Hopkins University Schools of Medicine, Public Health, Nursing, and Education. To accomplish this goal, participants will receive rigorous training and high-quality mentorship in 1) frameworks and effective practices in school health; 2) fundamentals of prevention and implementation science; and 3) rigorous research designs and analytic methods for school mental health. Trainees will receive focused training in all three competency areas and tailor the program to their specific area of interest. Trainees without previous graduate training in health research can undertake coursework leading to a Master of Science degree in public health. Trainees will participate in a biweekly Science of School Health T32 seminar that includes career development and professional skills and integrative activities to complement didactics. Administratively housed in the School of Medicine’s Department of Pediatrics, the program’s three trainees per year will come from any of the participating schools. Trainees will be intensively mentored by an experienced and dedicated group of 20 Core Faculty. The program’s four MPIs are national leaders in school health, public mental health, prevention science, quantitative methods, community nursing, and education. The MPIs will be supported by a three- member External Advisory Committee to ensure the program best meets the needs of trainees and the field. The training program will ensure there is a robust pipeline of scholars prepared to lead the next generation of rigorous school-based mental health research; trainees will complete the program with the tools they need to transition to career development awards, and ultimately to independent research careers that address this critical need.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The hippocampus is necessary for episodic memory. It is believed that spatial episodic memory is supported by ensembles of hippocampal place cells, with each cell responding selectively to specific spatial locations. Recently, we and others have demonstrated that the responses of hippocampal place cells are not stable but rather drift over time, raising questions about how exactly these drifting representations can support stable and specific memories and whether this drift can be targeted at the circuit level to influence memory function. I aim to address these questions by employing a novel approach that combines ultra-high-density recordings, circuit modeling, and cell-type-specific optogenetic perturbations in behaving mice. In Aim 1, I will perform ultra-high-density recordings in the dorsal hippocampal CA1 area while mice perform a spatial memory task across different mazes to test two competing hypotheses regarding hippocampal drift: whether the dynamic ensembles perform meaningful computations through temporal evolution or whether the neural instability is merely noise. This will be enabled by a novel analytical method to identify latent structures of population dynamics. In Aim 2, I will use theoretical modeling to predict potential circuit mechanisms underlying hippocampal drift, and I will further identify the circuit mechanisms by causally testing these predictions with cell- type-specific optogenetic manipulations. Next, I will evaluate the causal role of hippocampal drift in memory- guided behavior using the identified circuit-specific perturbation protocol. In Aim 3, I will explore the nature and role of dorsal-ventral hippocampal interactions during representational drift in flexible memory-guided decision- making. To achieve this, I will perform dual-site recordings in both regions with brain-region-specific optogenetic manipulation while mice learn to flexibly adjust their choice strategies. By linking circuit connectivity, neural dynamics, and behavior, this proposal will provide a new framework for understanding hippocampal computations through dynamic cell ensembles for episodic memory, reveal the circuit mechanisms underlying representational drift, and establish a causal link between this drift and memory-guided behavior. Moreover, these Aims will deepen our understanding of the neural mechanisms associated with various diseases and disorders related to episodic memory impairment, including epilepsy, Alzheimer’s, and schizophrenia. I will achieve these aims with the guidance of an exceptional mentoring team led by Antonio Fernandez- Ruiz and Alex Kwan, and in collaboration with Azahara Oliva and Christiane Linster. During my mentored phase, I will gain expertise in theoretical modeling, cell-type-specific optogenetics, and ultra-high-density recording in deep brain structures, such as the ventral hippocampus. These new technical skills I will acquire will be crucial for the proposed experiments and for laying the groundwork for my independent laboratory's research program on dorsal-ventral hippocampal interactions. Additionally, the complementary skills I will acquire through training in writing, project management, and leadership will further propel me into launching my independent career.

NIDA - National Institute on Drug Abuse

Project Summary Investigating and Addressing Modifiable Factors in the HIV Care Continuum for People with HIV (PWH) affected by Substance Use and Mental Health Social determinants of health like poverty, and unstable housing, combine synergistically with comorbidities like substance use (SU) + mental health (MH) as a syndemic to disproportionately burden disadvantaged populations people living with HIV (PWH). Substance use and mental health comorbidities are associated HIV Continuum of Care Outcomes (HCC) like delayed entry into care, lower retention in care, reduced ART adherence, poor VL suppression, and higher mortality for PWH. For the US to end the HIV epidemic (EHE) by 2030, the underlying mechanisms of SRD- driven health disparities on viral suppression and HCC outcomes among all PWH experiencing substance use and mental health syndemic must be elucidated and addressed. The lack of suitable comprehensive longitudinal data to examine substance use, and mental health impact on dynamic changes in HCC outcomes limits our ability to end the HIV epidemic. Defining and describing the impact of substance use and mental health on HCC outcomes requires examining the complex interactions of sociocultural, economic, environmental, and geographic contexts influencing these interactions. To address the knowledge gaps on modifiable factors related to the intersection between SU+MH, we propose using real-world multiple linked datasets, including enhanced HIV/AIDS surveillance (e-HARS), Electronic Health Records (EHR), Department of Mental Health data, Department of Alcohol and Other Drugs of Abuse (DAODAS) data, corrections data administrative claims, and other relevant public data sources, to investigate the disparities in SU, MH recognition, treatments, and HCC outcomes using data science. We will use qualitative methods to examine interpersonal and intra-individual factors to identify modifiable factors for moderating the effects of the intersection of SU+MH on viral suppression and the HCC. The specific aims are to: 1. Examine and visualize the longitudinal patterns/trends, heterogeneity, and disparities arising from SU on viral suppression and other HCC outcomes among PWH in SC; 2. Determine the interactive effect of SU+MH on viral suppression and other HCC outcomes; and 3. Understand experiences and impact of SU+MH on viral suppression and other HCC outcomes among PWH population in SC using focus group discussions/in-depth interviews.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Negative affectivity (NA) is an individual difference trait with high levels characterized by frequent and intense negative emotional responses such as fear, sadness, and frustration. NA can be reliably assessed within the first months of life; infants high in NA are at an increased risk for developing anxiety and depression later in life. Identifying the neural correlates of NA in early infancy—prior to the onset of psychopathology symptoms— can provide valuable insights into the mechanisms underlying emotional functioning in early development and inform early interventions. Previous research has established links between macrostructural gray matter (GM) variations and behavioral phenotypes associated with NA. However, these approaches lack the specificity needed to understand the underlying neurodevelopmental processes. Cortical microstructure, indexed by the Neurite Density Index (NDI) and the Orientation Dispersion Index (ODI), reflects cortical myeloarchitecture and cytoarchitecture, offering a more detailed view of neurodevelopment. Additionally, in human adults, behavioral phenotypes linked to NA, such as anxiety and depression, are characterized by hyperactivity in the arousal/salience systems and/or hypoactivity in the regulation systems. Importantly, emerging evidence suggests that some of the dysfunctions in arousal/salience and regulation systems are present at birth, before the onset of symptoms, and are linked to NA in early infancy. Given that brain structurual integrity is fundamental to supporting functioning, it is plausible that dysfunction in arousal/salience and regulation systems is driven by structural substrates in cortical microstructure. Thus, we will examine associations between cortical microstructure and prospective NA and psychopathology symptoms from a network perspective, specifically focusing on the arousal/salience systems (ventral attention network [VAN] and cingulo-opercular network [CON] and top-down regulation systems (default mode network [DMN] and frontoparietal network [FPN]). Our central hypothesis is that higher microstructural indices in VAN/CON and lower indices in DMN/FPN shortly after birth would be associated with higher levels of NA later in infancy and psychopathology symptoms in toddlerhood. This project will fill a critical gap in the developmental neuroscience literature by mapping the associations between cortical microstructure in early infancy and later NA and psychopathology symptoms. Through this project, the candidate will develop valuable expertise in early manifestations of psychopathology, neuroimaging data processing and computational skills, clinical neuroscience, and advanced writing and presentation skills. Obtaining such training will position the candidate as a competitive postdoctoral researcher and eventually an independent investigator at a research university, significantly contributing to mapping affective neurodevelopmental risk for psychopathology.

NIMH - National Institute of Mental Health

Project Summary HIV-1 associated neurocognitive disorders (HAND) affect 15 to 40% of people living with HIV (PWH), despite the use of anti-retroviral therapies (ART). Persistence of HAND in the presence of ART suggests that factors outside of viral replication contribute to neurocognitive impairment. The HIV-1 transactivator of transcription (Tat) is a neurotoxic viral protein that recapitulates cognitive impairment in the absence of viral replication and persists in virally suppressed PWH, likely generated from cellular reservoirs including microglia and astrocytes. Prior studies have separately shown that in the presence of Tat, the microglial transporter xCT is upregulated – increasing extracellular glutamate – and astrocytic EAAT2 is downregulated. Nonetheless, these mechanisms have been demonstrated with varying techniques and agnostic to how Tat expression within cellular reservoirs affects Tat-mediated toxicity and cognitive symptoms of HAND. Thus, we hypothesize that Tat expressed independently from microglia and astrocytes promotes aberrant glutamatergic neurotransmission causing NMDAR dependent excitotoxicity in the prefrontal cortex and cognitive impairment in HAND. In this proposal, we will use lentiviral transduction to model Tat expression from microglia and astrocytes, as the HIV-1 reservoirs of the CNS. We will then assess glutamate toxicity in this model in vitro and in vivo, by evaluating 1) EAAT2 or xCT expression and markers of gliosis [GFAP, Iba1], 2) extracellular glutamate levels in culture supernatants, 3) neuronal NMDA receptor expression and signaling via calcium levels. These outcomes will provide an understanding of how microglia and astrocytes respond to Tat and influence NMDAR- mediated neurotoxicity. To understand how these cell types drive toxicity and cognitive impairment in turn, lentivirus will be injected intracerebrally to prefrontal cortex of Sprague-Dawley rats. Two weeks after surgery, we will assess behavioral and molecular outcomes; or calcium levels in neurons and astrocytes. Animals will undergo testing in novel object recognition, spatial object recognition, and attentional set-shifting tasks, to assess learning and memory and cognitive flexibility. Brain tissue will then be assessed by immunoblot, RT- PCR, and calcium imaging to correlate cognitive impairments with molecular mechanisms; further paralleling the in vitro results to contextualize the contribution of Tat-mediated mechanisms to cognitive impairment. This study will elucidate the role of microglia and astrocytes as separate sources of Tat for their effects on glutamatergic neurotransmission and PFC-mediated cognitive functions. The proposal addresses a significant gap in the literature on microglia as the primary viral reservoir generating Tat, while accounting for the distinct impacts of each cellular reservoir on Tat-mediated glutamate toxicity and cognitive impairment. This will prompt future study into the microglial reservoir, and glutamatergic disease mechanisms that could be refined as therapeutic targets that are clinically relevant to neuropathology in PWH.

NIMH - National Institute of Mental Health

Summary: Chronic stress is a growing public health problem that contributes to the development of mental illnesses such as major depressive disorder (MDD). While maladaptive responses to environmental stressors are clearly fundamental to some individuals developing pathology, we still do not know why others remain resilient to chronic stress. Recently, using recording electrodes in a mouse model of chronic stress-induced maladaptation, we identified a robust and specific brain network signature prior to chronic stress exposure that predicts which animals will show a susceptible behavioral phenotype following chronic stress. Animals with this predictive pattern of network activity before stress exposure have been termed vulnerable while animals with a depressive-like phenotype after chronic stress are termed susceptible. This study opens the door for identifying underlying mechanistic causes of stress vulnerability-conferring neural signature that may be useful for the development of therapeutics targeting specific brain networks. It also enables us to study a brain state that has largely not been characterized: stress-naïve vulnerability to chronic stress. To examine the naturally occurring regulation of the stress-naïve vulnerable brain state, our specific aims combine the use of multi-site in vivo neurophysiology, fMRI, behavioral and telemetric measurements, single cell RNA-Seq, spatial transcriptomics, epigenetic investigations, and viral manipulations. This project will help us to better understand and quantify the relationship between our brain network signature and behavior following chronic stress. Further, it will provide an in-depth assessment of the similarities and differences in brain networks that predispose males and females to the ill effects of chronic stress. It will also reveal new insight into how individual differences in gene expression and epigenetics can produce such brain network signatures. These studies will provide an important first step in the development of therapeutics that are designed to target specific network activity that can prevent network activity that confers vulnerability. We will apply molecular profiling and validations to the stress-naïve vulnerable brain to determine pre-existing molecular alterations that predict stress susceptibility. This work fills an important gap in stress neurobiology, which has focused primarily on defining the molecular hallmarks of stress susceptibility (i.e., compensatory changes after stress), not vulnerability (i.e., before stress exposure). Identifying the molecular signatures of the vulnerable brain state enables the possibility of preventative therapeutic approaches. Furthermore, by identifying molecular contributions to brain network activity, this study enables the possibility of brain network-based pharmacotherapeutics, which could be useful for targeting medications to specific individuals (i.e. precision medicine).

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Memory formation is thought to involve long-lasting changes in the synaptic connections between neurons to form memory circuits, but the precise molecular mechanisms remain poorly understood. One key player in memory is the immediate early gene Arc, which is critical for memory consolidation. The Shepherd lab discovered that Arc self-assembles into virus-like capsids that can traffic RNA and protein between cells in extracellular vesicles. We recently found that when Arc is transferred between primary cultured neurons, recipient neurons exhibit changes in synaptic neurotransmitter receptors. This suggests a novel form of intercellular synaptic plasticity, where Arc transfer modulates the activity of surrounding neurons. However, the significance of this mechanism in memory formation is unknown. My preliminary data suggest 1) Arc intercellular transfer occurs in vivo and 2) the fear memory deficit in Arc knockout (KO) mice can be rescued by expression of wildtype Arc in adulthood. This proposal will test whether Arc intercellular transfer facilitates memory consolidation in vivo. To investigate the role of Arc intercellular transfer in memory, I will evaluate its dynamics and necessity in vivo. In Aim 1, I will directly characterize intercellular Arc transfer in the brain using a novel molecular reporter to visualize Arc donor and recipient cells. I will determine the spatiotemporal dynamics of intercellular Arc transfer during memory consolidation. I will also evaluate the cell-type specificity of recipient cells and determine whether Arc intercellular transfer captured with our tool is behaviorally induced. In Aim 2, I will express Arc mutants that either disrupt intercellular signaling or Arc-dependent regulation of synaptic receptors in Arc KO mice, using a “rescue” approach to restore memory deficits. This experiment will inform which of Arc’s molecular functions are necessary for fear memory. These experiments may reveal a novel form of brain plasticity that uses viral-like intercellular signaling, shedding light on how memories are formed, stabilized, and stored in the brain. Elucidating the molecular mechanisms of Arc in normal memory stands to inform potential points of failure in neurological disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) often result from mutations in genes essential for brain development and function. Recent advances in gene replacement therapy have shown promise for rescuing molecular and behavioral deficits in mouse models, even when gene restoration occurs postnatally. However, the context and feasibility of gene replacement for specific disorders remain unclear. This project focuses on Tatton Brown Rahman Syndrome (TBRS), a rare NDD caused by mutations in DNMT3A, a gene critical for DNA methylation and neuronal development. TBRS patients exhibit intellectual disability, overgrowth, joint hypermobility, and seizures. In mice, loss of DNMT3A leads to altered neuronal differentiation and synaptic function, emphasizing its importance in early brain development. Kim will explore the potential for restoring DNMT3A function using innovative mouse models and gene therapy approaches. In Aim 1, Kim will employ spatial transcriptomics and single-nucleus RNA sequencing to assess how DNMT3A loss impacts cell type distributions and gene expression in the cerebral cortex and whether these changes can be reversed by restoring DNMT3A expression. In Aim 2, she will evaluate the feasibility of gene replacement therapy for TBRS using adeno-associated viruses (AAVs). These studies will address timing, delivery methods, and baseline efficacy of DNMT3A reinstatement in both tamoxifen-inducible and disease-relevant mouse models. This work will determine whether postnatal DNMT3A restoration can rescue molecular, cellular, and behavioral deficits associated with TBRS and provide a foundation for gene therapy strategies targeting NDDs. The findings will contribute to understanding the therapeutic potential of gene replacement, with implications for improving outcomes and quality of life for patients and families affected by TBRS and related conditions. This project will be conducted at Washington University in St. Louis, a phenomenal research environment that integrates cutting-edge genomic technologies, advanced imaging platforms, and expertise in neurodevelopmental disorders. The lab is supported by collaborations with leading researchers in mouse behavior, epigenetics, and computational biology, ensuring access to unparalleled resources and mentorship. This environment fosters innovation, collaboration, and rigorous scientific inquiry, creating the ideal setting to achieve the goals set forth by this proposal.

NIMH - National Institute of Mental Health

Expanding upon the parent PHLHousing+ Study (5R01NR021122-02), the overarching goal of this proposal is to test whether interventions addressing housing insecurity as a modifiable social determinant of health (SDOH) improve youth mental health outcomes and outpatient service utilization in households of low-income renters in Philadelphia. This objective is aligned with the strategic aim of the NIMH (Goal 3) to identify opportunities to implement interventions that target modifiable SDOH (see Strategy 3.3.A). The PHLHousing+ Study comprises three groups, all of whom earn below 50% area median income, have at least one child under the age of 16 years living at home, and are renters: 301 households who receive monthly direct cash payments in lieu of a rental voucher for 3.5 years(Cash group), 169 households who receive a rental voucher (Voucher group), and 711 households on the Philadelphia Housing Authority (PHA) waitlist unlikely to receive rental assistance during the entire study period. Our analytic plan combines Cash and Voucher groups into a single Intervention group. Of the 1,181 households in the study, 95.4% are headed by single women and 86.3% are Black. There are 1,965 children in the sample, ranging in age from 3 to 15 years at baseline (M= 8.66, SD= 4.70). Monthly cash payments range from $89 to $2079, with a median payment of $881; payments vary based on household income, family size, and fair market rent. All three groups are surveyed every six months for four years; the first wave of online surveys was deployed in August 2022. Existing surveys include measures of youth emotional and behavioral problems (EBP) reported by primary caregivers. Recent approval from Philadelphia’s Department of Behavioral Health and Intellectual Disability Services (DBHIDS) allows us to pair the repeated survey assessments with de-identified Medicaid claims data for youth participants. I hypothesize that Intervention group youth will demonstrate significant decline in EBP and rates of clinically significant EBP (indicated by increased rates of symptom remission) over time compared to Control group youth (Aim 1). I hypothesize that a subsample of Intervention group youth with clinically significant EBP will be significantly more likely to initiate and retain use of outpatient mental health services compared to Control group youth (Aim 2). Study findings will inform research and policymakers of broader social and health benefits of economic interventions targeting housing as a SDOH. My fellowship training at the University of Pennsylvania will leverage extensive mentorship, coursework, workshops, and seminars. With guidance from a strong mentorship team (Drs. Jaffee, Reina, Mandell, Candon, and the Penn BAC), my proposal and the accompanying training plan provide an ideal foundation for my planned career as an independently funded, leading clinical scientist studying mental health policy and evaluating the implementation of social programs that might affect mental health and service use.

NIMH - National Institute of Mental Health

ABSTRACT The development of the cerebral cortex is one of the most intricate processes in neurobiology. Disruptions to this complex and highly regulated process are central to neurodevelopmental disorders (NDDs), which collectively impact an estimated 317 million individuals globally. Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by the ADAR (adenosine deaminase acting on RNA) family, has emerged as a potent regulator of post-transcriptional gene regulation in the brain. A-to-I editing is highly dynamic in the developing human brain and has been implicated in a range of NDDs, including autism, schizophrenia, and epilepsy. A growing body of evidence suggests editing may contribute to neuronal maturation, synaptic regulation, and the diversification of the brain transcriptome. Yet, a single-cell resolution map of A-to-I editing and direct evidence of essential ADAR function during human corticogenesis have never been achieved. This proposal presents a comprehensive and mechanistically focused investigation into how editing shapes transcriptional and translational landscapes during human cortical development. It represents the most comprehensive and detailed investigation of A-to-I RNA editing in the developing human brain to date (Aim 1). I propose to map the RNA editome at unprecedented scale: across over 2.3 million cells from both fetal brain tissue from 26 individual donors and human cortical organoids. This work will reveal cell type- and lineage-specific editing programs and evaluate the fidelity of organoids in modeling A-to-I editing dynamics. This work will be achieved without cell sorting or complex tissue pre-processing prior to sequencing with MARINE, a first-in-class computational tool for detecting editing that preserves single-cell resolution. Additionally, this proposal is the first systematic dissection of ADAR enzyme function in a complex human model of corticogenesis (Aim 2). To systematically evaluate the importance of the ADARs in corticogenesis, each ADAR is repressed in several cell lines engineered for CRISPR interference and ribosome-based translational profiling (Ribo-STAMP). ADAR-repressed cortical organoids are evaluated with several modalities to understand how ADAR shapes cell fate specification, lineage progression, and mRNA translation. The use of Ribo-STAMP provides the first transcriptome-wide readout of ADAR-dependent translation in the developing human cortex, revealing regulatory layers inaccessible by transcriptional profiling alone. By uniting high-resolution transcriptomic, translational, and morphological profiling in tractable human models, this study establishes a systems-level framework for decoding post-transcriptional regulation in the developing brain and lays critical groundwork for therapeutic advances in NDDs.

NIMH - National Institute of Mental Health

PROJECT SUMMARY: Fear generalization is an adaptive process by which a learned fear response to an aversive context is extended to a novel similar context. However, heightened fear generalization in the absence of persistent threat can lead to excessive fearfulness. Such overgeneralization of fear is observed in psychiatric disorders, such as generalized anxiety, PTSD, or depression. Early Life Adversity (ELA) is a major risk factor for these disorders, and generalization has indeed been proposed as a mechanism by which ELA increases risk for developing psychopathology. Understanding the neural mechanisms underlying fear generalization, and how they are affected by ELA, will thus be important to identify neural circuits regulating generalization during normal brain function, and how these circuits are affected in disease-relevant conditions. In this proposal, we will investigate how dopamine (DA) and norepinephrine (NE) release from locus coeruleus (LC) projections to the ventral dentate gyrus (vDG) of the hippocampus dynamically control and coordinate real-time neural responses during generalization, and how this regulation is disrupted by ELA. The vDG receives its main DA input from the LC. Our data show that ELA dampens DA signaling in the vDG, increases granule cell (GC) activity, and increases fear generalization. In Aim 1, we will now use in vivo imaging of DA biosensors and GC Ca2+ activity to study how ELA alters DA release in the vDG during fear generalization and how these temporal changes in DA release are associated with GC activity and freezing behavior. Because the predominant LC neurotransmitter is NE in addition to DA, we will also image NE release in combination with GC activity to compare how temporal dynamics of DA vs NE release in the vDG are associated with GC activity and freezing. In Aim 2, we will test whether LC-vDG projections increase fear generalization via NE, and whether they reduce fear generalization in ELA-exposed mice via DA. We will test these hypotheses using optogenetic stimulation of LC-vDG projections with simultaneous infusions of DA receptor antagonists or NE receptor antagonists into the vDG. In Aim 3, we will test the hypothesis that overlapping neural representations of an aversive and a novel context in the vDG are a neural correlate of generalization. We will use single cell in vivo Ca2+ imaging with head- mounted miniature microscopes to test whether GCs that encode an aversive context are reactivated more in a similar, but novel context in ELA-reared mice. We will then test whether DA release from LC projections disambiguates GC ensemble coding of fear and neutral contexts, and whether NE release from LC projections enhances overlap between GC ensembles for the two contexts. We will use machine learning techniques to predict how GC activity dynamics regulate freezing vs non-freezing behavior, and how they are affected by ELA and by DA vs NE. Overall, our study will use innovative neuroscience techniques to test a novel conceptual framework for how fear generalization is regulated at the neural circuit level, and how individual components of this circuit are modulated by ELA and by DA vs NE release from LC projections to the vDG.

NIMH - National Institute of Mental Health

Major depressive disorder is one of the leading causes of disability worldwide and approximately a third of patients develop treatment resistant depression (TRD). Cognitive impairments are a hallmark feature of depression and greatly impact severity of disability and quality of life. Current treatment options for TRD do not, however, specifically target cognitive impairments. Ketamine has recently been shown to be an effective treatment of TRD and improves cognition. Ketamine is known to work through the antagonism of N-methyl-D- aspartate (NMDA) receptors specifically on inhibitory interneurons. This suggests ketamine modulates the excitation/inhibition balance (E/I) and potentially indicates that alterations in E/I could underlie TRD. Intrinsic neural timescales (INT) are a resting state functional magnetic resonance imaging (rs-fMRI) measure can be acquired from the human brain and are theorized to be sensitive to the strength of recurrent excitation and therefore reflective of E/I function. Additionally, recurrent excitation (and E/I more broadly) is a property of canonical microcircuits responsible for the representation and processing of information, linking it as a possible mechanism underlying cognition. The main hypothesis of this proposal is that disruptions of E/I in canonical microcircuits are responsible for cognitive deficits and contribute to symptom severity in TRD. Further, we hypothesize that ketamine normalizes this disruption to improve cognitive deficits in TRD. Although preclinical work has highlighted E/I dysfunction as the potential mechanism of ketamine’s antidepressant effects, clinical work measuring E/I function has been limited specifically as a theoretically informed assessment of E/I in individuals with depression before and after ketamine treatment has not been conducted. This project will leverage a pre-existing large-scale neuroimaging dataset (HCP-PDC and HCP-A) including data from 180 TRD and 180 matched controls, with 58 TRD imaged at 3 timepoints (baseline; 24hr post 1st ketamine dose; 24hr post final ketamine dose). I will test for alterations in INT (measured using 3 Tesla rs-fMRI) in TRD (Aim 1a), relationships with depression severity (Aim 1b) and cognitive function, specifically the domains relating to working memory and processing speed (Aim 1c), as well as the impact of ketamine treatment on these measures and their relationships (Aim 2). Further, this project will investigate the potential of INT as a biomarker for identifying individuals who respond to ketamine (Aim 2c). The results from this project will provide mechanistic understanding for cognitive deficits in TRD and will identify individuals with impaired microcircuit function who would benefit from ketamine or other glutamatergic therapies, both for depression and cognitive deficits. The Icahn School of Medicine is an excellent training environment for novel research focused on using neuroimaging techniques to probe biological mechanisms that can be translated to improve clinical outcomes. Additionally, this project will facilitate professional development, mentorship, and technical skill expansion for a smooth transition into an independent academic research scientist.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The desire and ability to appropriately seek out rewards is crucial to the survival of most species. Several psychiatric disorders, including major depressive disorder and substance use disorder, are characterized by dysfunctional reward seeking. Identifying neural circuit mechanisms that support reward seeking behaviors will ultimately lead to new treatments for these disorders. One region that has previously been implicated in reward seeking is the lateral septum (LS). However, the mechanism by which the LS modulates reward seeking behavior is unknown. One potential mechanism is through the connection between the LS and ventral tegmental area (VTA). Dopamine neurons in the VTA encode a reward prediction error (RPE) to represent the difference between the expected and actual reward received. This RPE signal determines whether a reward is worth seeking or not, with positive RPE values driving learning reward associations and negative RPE signals driving extinction. There have been multiple hypotheses as to the origin of the RPE signal in VTA dopamine neurons, but whether the signal is locally generated or largely inherited from elsewhere in the brain remains debated. This raises the possibility that upstream regions could significantly contribute to or shape RPE in the VTA, such as the LS. The LS directly innervates the VTA and has been shown to be reward responsive, which suitably positions it as a possible candidate to modulate reward-related behaviors by influencing the RPE signal. This proposal aims to identify whether the LS modulates reward seeking via its projection to the VTA, and specifically how the LS contributes to the generation and modulation of the RPE signal in VTA dopamine neurons. In Aim 1, I will perform cellular resolution calcium imaging of the LS-VTA population while the animal engages with a series of operant assays designed to elicit an error signal. I predict that LS-VTA neurons, like the non-specific LS neurons, have a differential response to rewarded trials and unrewarded trials when the expected reward is omitted. In Aim 2, I will implement projection-specific, closed-loop optogenetic inhibition of LS-VTA neurons while simultaneously performing population-level calcium imaging of dopamine neuron activity to examine the causal role of the LS-VTA population in shaping the VTA RPE signal and in extinction of a learned behavior. These results will determine the extent to which LS-VTA neurons causally contribute both to the RPE signal and reward seeking behavior. Furthermore, the findings of this proposal could aid in identifying novel mechanisms to target in the treatment of several psychiatric disorders and substance use disorders.