Search Grants — Free, No Account Required

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.

NIMH - National Institute of Mental Health

Numerous studies have shed light on the capability of T cells in facilitating HIV entry into the central nervous system (CNS) and HIV-associated brain injury (HABI) in the era of combined antiretroviral therapy (cART); yet, one critical question remains - what differentiates and/or predicts T cell behavior in individuals with HABI from those without? Preliminary machine learning has identified unique signatures of viral adaptation in infected peripheral blood T cells from S[imian]IV-infected Rhesus macaques with mild-to-moderate neuroinflammation, begging the question as to whether select viral variants are capable of re-programming T cell migration. On the other hand, T cell migration is dictated by cell differentiation state (e.g., naive vs memory phenotype), and recent evidence indicates this differentiated state can be influenced by T cell receptor (TCR) sequence features. Somatic rearrangement of the genes forming the TCR sequence within an individual results in natural TCR heterogeneity that may not only explain differences in T cell neuroinvasive capabilities across HIV-infected individuals, but may be used to identify individuals who would benefit from therapies used in other T cell-mediated neurological disorders, such as multiple sclerosis. We propose to address the underlying questions of viral and TCR influences on differential T cell migration and neuroinvasion using a multitude of single-cell techniques applied to human tissue and an extensive collection of CNS and peripheral tissues from the macaque model of HIV infection in the presence and absence of T cell trafficking inhibitor - natalizumab. Combining strengths in viral, immunological, and computational research, we propose to tackle these long-standing questions specifically by 1) identifying unique viral and/or T cell properties associated with T cell infiltration in the CNS (Aim 1), 2) characterizing the relationship between viral infection, TCR features, and T cell migration potential (Aim 2), and 3) evaluating the impact of natalizumab on T cell trafficking, viral dynamics, and neuroinflammation (Aim 3). Importantly, recent findings of the role of the complex interplay of viral and T cell genetics in the neurological disorder - multiple sclerosis - point to a phenomenon that may span multiple diseases, indicating the in-depth characterization of this interplay has potentially broader implications than HIV infection.

NIMH - National Institute of Mental Health

Project Summary Social dysfunction following trauma is a pervasive reality for trauma victims in the United States, with one study finding that nearly half (45.2%) of trauma patients experience social deficits after the traumatic event. Traumatic events are often experienced in social contexts, yet most preclinical studies model trauma-related disorders with stressors experienced in isolation. Therefore, there is a gap in knowledge about how the social context in which trauma is experienced affects future social behavior. The experiments outlined in this proposal will fill this gap, and address Goal 1 of the NIMH Strategic Plan for Research to “Define the Brain Mechanisms Underlying Complex Behaviors.” Human studies have reported that an interesting phenomenon following trauma is social affiliation– the tendency to come together after traumatic events. Social buffering, which describes the presence of a conspecific attenuating the biological response to a traumatic experience, is thought to be a mechanism underlying the protective effects of social support. Yet, our understanding of the neural mechanisms underlying social buffering is poor. Despite the work from the field of social buffering that has studied the impact of social support during shared trauma, no research to date has studied alterations in the neural regulation of social affiliation after shared trauma. The neurons of the anterior cingulate cortex (ACC) are poised to facilitate this phenomenon as they are known to be involved in empathy, stress regulation, and observational fear learning. Using cutting-edge techniques in behavioral pose-estimation (Aim 1), and microendoscope calcium imaging in ACC (Aim 2), this proposal will test the central hypothesis that shared trauma, as opposed to solitary trauma, alters the neurobiology of ACC to foster social affiliation. As sex is among the most significant risk factors for the development of PTSD, with females having a two to three times higher risk of developing PTSD, both aims will be conducted in male and female mice. A successful outcome of this project would provide a mechanistic understanding of how shared trauma affects social behavior, revealing a circuit-level target to develop interventions for social dysfunction in trauma-related disorders. The proposed research will take place in the laboratory of Kay Tye at the Salk institute in affiliation with the University of California, San Diego. Through graduate coursework, mentorship, and hands-on learning, Jianna will gain experience in rodent behavior and calcium imaging techniques and analysis. These skills will be valuable for the completion of the proposed research, and for Jianna’s future career as a physician-scientist.

NIMH - National Institute of Mental Health

ABSTRACT Autism is a highly heritable neurodevelopmental condition, and males are over-represented in autism diagnoses. The X chromosome is enriched for genes associated with autism, suggesting it may contribute to the observed male bias. Loss-of-function coding mutations within these genes are often lethal in males, but females experience monogenic forms of autism. It is then possible that mild mutations within these genes are sufficient to cause autism in males but spare mosaic females. Males with idiopathic autism are enriched for maternally inherited noncoding mutations in cis-regulatory elements (CRE) proximal to these genes. The broad objective of this proposal is to characterize these X-linked CREs and autism-associated mutations found within them. MECP2 is a dosage-sensitive gene where loss- or gain-of-function mutations cause neurological disorders. Although MeCP2 levels are tightly controlled in typical individuals, the mechanisms by which its CREs, such as the promoter, control gene expression remain unclear. There are at least four mutations within the MECP2 promoter that are maternally inherited and segregate with autism in males. Using CRISPR-Cas9 technology, these mutations will be independently edited into the endogenous MECP2 promoter in human iPSCs (AIM 1). After differentiating these iPSCs into neurons, these mutations will be evaluated for their impact on MeCP2 levels and two representative target genes. For mutations that significantly alter MeCP2 levels, deep RNA sequencing will determine the effects of these mutations on the molecular phenotype of neurons. This dosage sensitivity could extend past MECP2. There are thousands of mutations in male autism probands that are inherited from the mother and localize to 197 different X-linked CREs in open chromatin in excitatory neurons. A majority of these CREs are proximal to 57 different X-linked genes known to cause neurological disease. Using a massively parallel reporter assay, these mutations will be functionally assessed in an unbiased, high-throughput screen (AIM 2). Downstream analyses will determine which genes and which specific regions are most impacted by autism-associated noncoding mutations. The top-ten autism-associated mutations that disrupt CRE activity will then be validated using a luciferase reporter assay. The overall impact of this proposal is to broaden the spectrum of known mutations that cause autism, addressing some of the missing heritability of autism. Additionally, by studying 197 X-linked CREs, this proposal will provide insight into the regulation of 57 separate X-linked genes known to cause neurological disorders, and it will provide a framework for investigating noncoding mutations. These results will enhance the current understanding of noncoding mutations and how they contribute to neurological disease.

NIMH - National Institute of Mental Health

Neurological disorders constitute the largest global disease burden affecting ~43% of the world population, including but not limited to stroke, neonatal encephalopathy, dementia, Parkinson’s disease and epilepsy. Novel investigatory tools to study the fundamental basis for such nervous system malfunctions are critically needed to develop new therapies and prevention/rehabilitation strategies. Neurons are inherently different from most cell types; in that they are electrically active and form rich networks for communication and dynamic information storage. The proposed InVitreON culturing system will allow neuronal networks to be effectively investigated, modeled and used for screening potential therapies. It will significantly accelerate the mission to better Human health, while also allowing for fundamental studies to enhance scientific knowledge in behavioral areas pertaining to memory, pain, depression, anxiety and stress, among others. While in-vivo studies on Human and Animal subjects are used for clinically advanced stages in therapeutic development, a more ethical, well-controlled, and rapid approach has been to perform in-vitro studies of neuronal cultures. In-vitro culture systems allow live neuronal models of disease to be interrogated with a growing repertoire of molecular and cellular analysis techniques. Our InVitreON platform also allows for high-density neuro-electrophysiological functional studies. Over the past decades, in-vitro neuronal micro-electrode array (MEA) cultures have proven invaluable for disease modeling, neurotoxicity evaluations and drug screening. However, performing neuronal experiments with in-vitro MEAs has been plagued by several technical challenges that have discouraged use by typical neuroscientists (compared, for example, to optical microscopy). Current equipment solutions are complex, bulky, tedious to maintain, unreliable, inflexible, exhibit sub-optimal neuronal growth conditions and lack adequate contamination control. In addition, establishing closed-loop feedback via electrical, optical or chemical means, along with real-time raw data processing still requires deep engineering expertise, with no commercial product providing all these modalities. The focus of the proposed project is to disrupt this status quo, democratizing the use of neuronal in-vitro MEA platforms. This will be accomplished by Aim 1) Creating a single compact device that integrates live neuron culture incubation at physioxic (physiologically relevant) oxygen and carbon dioxide environments using mini-gas cartridges and capable of long-term MEA culture recording, with electromagnetic noise and contamination protection features. Aim 2) Demonstrating long- term >1 month live neuronal electrical recordings on primary rodent cortical, hippocampal neurons and Human iPSC derived neurons, while implementing stable automated media exchanges, and supported by integrated compute-rich single board processors for spike sorting and classification. Aim 3) Integrating flexible stimulation modalities including electrical, optical and chemical stimulation to expand the utility of the platform to support a diverse set of neuroscience experiments.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Recurrent genomic deletion at chromosome 3q29 (3q29Del) is associated with developmental delay (DD), ADHD, autism spectrum disorders (ASD), and is the strongest known genetic risk factor for schizophrenia (SCZ). However, the phenotypic spectrum associated with 3q29Del is variable and broad. Most individuals have been found to have clinically significant neuropsychiatric impairment, but it is not yet clear why some individuals are much more severely affected than others. The variable expressivity of this important variant suggests environmental factors may influence outcomes. In this R21 project, we propose to assess iron deficiency (FeD) as an environmental factor that may strongly impact 3q29Del clinical outcomes. The 3q29Del results in heterozygosity of 21 protein-coding genes including TFRC, which encodes the transferrin receptor (TFRC). TFRC is the primary cell surface receptor for iron-bound transferrin and is critical for cellular iron import. Iron deficiency is the most common nutrient deficiency worldwide, and recent reports indicate it continues to be highly prevalent in the United States, particularly in children, adolescents, and during pregnancy. While it is well established that childhood FeD can negatively impact neurodevelopment and increase risk for ADHD, ASD, DD, and SCZ, the mechanisms of these processes in human neural cells are not well understood. Innovative in vitro modeling techniques such as 3D brain organoids open new possibilities to causally test the impact of nutrient deficiencies such as FeD on certain aspects of human neurodevelopment. Our preliminary studies indicate that individuals with 3q29Del have more than 10-fold increased risk for anemia. Additionally, 3q29Del cells were found to contain less iron than control cells and had severely reduced viability and mitochondrial function in FeD-like conditions. Together these data indicate that 3q29Del individuals are at extraordinarily high risk for iron deficiency, which may disrupt key neurodevelopmental processes. The aims of this proposal are to (1) determine the risk for FeD and connection to neuropsychiatric phenotypes in individuals with 3q29Del and (2) to model the effects of iron deficiency on the developing human cortex in vitro. We will expand an active R01 project to collect new data related to history of iron deficiency and/or anemia in 3q29Del study participants using gold standard instruments to measure multiple domains of cognitive function, prodromal and psychosis signs. We will measure mitochondrial function in human forebrain-like cortical neurons exposed to FeD-like conditions from both neurotypical control and 3q29Del backgrounds. Lastly, we will determine the effects of FeD-like conditions on human cortical organoid development. These studies will illuminate effects of iron deficiency on the developing human cortex and test environmental interactions with an important neuropsychiatric risk variant.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Anorexia nervosa (AN) is a devastating eating disorder that has severe effects on mental and physical health, and one of the highest mortality rates of any psychiatric disorder. AN is characterized by persistent restriction of food intake below the body’s needs, and particular restriction of dietary fat, leading to relapse following treatment to restore weight. Maladaptive choices about what to eat are remarkably resistant to treatment in AN, even among patients expressing desires for long-term recovery. Decision making is guided by a valuation process in which the ventromedial prefrontal cortex (vmPFC) encodes a value signal that represents individual preference for a given choice option. The ability to assign value to choices that are aligned with longer-term goals, but which do not confer immediate benefit, is supported by the vivid imagination of future scenarios, or episodic future thinking (EFT), and the effects of EFT on valuation are related to connectivity between the hippocampus and vmPFC. Recovery is a future outcome of eating energy-dense foods in AN, which in the short-term may be unpleasant. In this study we will begin to address the question of whether underuse of EFT during food choice contributes to the misalignment between goals of recovery and restrictive eating behavior among treatment-seeking patients with AN. Patients with AN and normal-weight healthy controls will complete a food decision making task in which they rate their preference to eat a range of items as a snack, while undergoing functional MRI scanning. The task is completed under two conditions (order randomized and counterbalanced): EFT, in which participants are oriented toward a personalized future event; and standardized episodic thinking (SET), in which participants are oriented toward a recent past event (playing video games). We will compare the effect of EFT versus SET manipulations, relative to no manipulation, among individuals with AN and HC across behavioral (preference for high-fat foods) and brain (functional connectivity between the hippocampus and vmPFC) levels. Findings from this study will identify 1) whether EFT ameliorates restrictive eating in AN; 2) whether patients with AN are able to recruit the neural circuits supporting EFT during valuation; 3) whether recruitment of these neural circuits is associated with the behavioral effects of EFT. A monetary decision task will be administered to compare the effects and mechanisms of EFT between AN and HC groups (normal-weight HC are not expected to change food preferences due to an EFT manipulation). Exploratory analyses will compare EFT ability and general future orientation between AN and HC groups, and examine the relationship between EFT ability, effects of the EFT manipulation, and clinical characteristics, in the AN group. This developmental study will provide preliminary data for large-scale investigation into the role of disturbances in EFT in AN pathology and interventional research targeting future thinking to improve eating behavior among patients with AN.

NIMH - National Institute of Mental Health

Project Summary Dysfunction of the Wnt signaling pathway has been associated with mental ilness, but the underlying molecular and cellular mechanisms remain elusive. Our laboratory has discovered an evolutionarily conserved role for the Wnt transcriptional effector Lef1 in generating hypothalamic neurons and innate behaviors linked to stress. LEF1 variants could thus contribute to human stress-related mood disorders, and we propose that the distinct expression and function of two highly conserved protein isoforms could provide a way to separate this role from the other essential roles of Lef1 in development. We will use zebrafish to test the hypothesis that isoform- specific control of Lef1-dependent transcription regulates hypothalamic neurogenesis and stress- related behavior. In Aim 1 we will determine how the Lef1 N-tail and B-tail isoforms affect protein function, and in Aim 2 we will determine whether each isoform is specifically required for neurogenesis and behavior. Our goal is to establish an evolutionarily conserved model that we can eventually translate to human mental health.