Search Grants — Free, No Account Required

NIMH - National Institute of Mental Health

Project Summary We live in an ever-constant Ʋuctuation of sensory input, and navigating this can be easily overwhelming. To remedy this, our brains have devised sensory sampling behaviors to rhythmically parse out this input and optimize sensory processing by weighting sensory experiences time-locked to behavior while dampening behaviorally unrelated neural activity. Such “active sensing” is commonly achieved through rhythmic behaviors such as sniffing and saccadic eye movements and can be mechanistically explained by the combination of neural entrainment and phase-amplitude coupling (PAC). Neural entrainment describes the alignment of peak neural excitability to the phase of self-generated sensory input, allowing the brain to better predict and process incoming information. This entrainment can further improve sensory processing through PAC, in which the timing of lower-frequency oscillations (e.g., delta) modulates more localized higher-frequency oscillations (e.g., gamma) associated with sensory processing, enhancing coordination across different brain regions and frequencies. Rhythmic behaviors exist in many forms, with some being less obvious in sensory function, such as motor stereotypies (STY). STY are highly rhythmic and stereotyped behaviors prevalent in autism but also observed in the neurotypical (NT) population, albeit less frequently. Traditionally presumed purposeless, flrst-person accounts by autistics and NTs suggest STY serve as coping behaviors to reduce sensory under/overstimulation from the environment. Our flrst aim probes the relationship between rhythmic behavior and environmental sensory stimulation across diagnosis. We will collect motion-tracking data and ambulatory EEG from autistic and non-autistic children and adolescents (5–17 years) while they explore augmented reality environments of low, medium, and high sensory stimulation. In pursuit of this goal, we will use video recordings and motion-tracking data to build a database for the automated classiflcation of motor stereotypies. We hypothesize motor rhythmicity differences across diagnostic groups and environmental conditions, expecting increased rhythmic movement in autistics compared to neurotypicals, and increased motor rhythmicity during low- and high-sensory stimulation conditions. Our second aim explores the neural mechanisms underlying the sensory processing beneflts of STY. We hypothesize that STY serve an active sensing role in both autistics and NTs by entraining low-frequency neural oscillations, with reduced entrainment and delta-gamma PAC in autistic participants. This novel framework of STY may inform how we design sensory environments to tailor individual sensory needs and assist autistics in developing more efficient sensing behaviors.

NIMH - National Institute of Mental Health

Major Depressive Disorder (MDD) is a serious problem that keeps aggravating yearly. Its pathophysiology remains unclear despite vast amounts of research and the advancements in diagnostics. Common antidepressants have delayed onsets and are unsuccessful in 30% of patients, suggesting other factors play a role. Indeed, a very strong link exists between neuroinflammation and treatment resistant depression (TRD). Hallmarks of depression, like disruption of monoaminergic activity and neural structural/functional abnormalities within mesolimbic regions, have been observed to occur after inflammatory response. However, it remains unclear how inflammation affects circuits dysfunction and MDD development. Our long-term goal is to elucidate the neurobiological correlates of MDD by enabling the investigation of the core neural circuits that underpin its pathomechanisms in humans in vivo. The goal of this project is to elucidate the circuits connecting limbic regions with the nucleus tract solitarii (NTS) in the brainstem. Converging evidence from clinical and preclinical studies points to this circuitry as a major neural route through which inflammatory processes affect limbic regions involved in MDD. We will leverage multi-modal data in non-human primates (NHPs) and humans to: 1. map ground truth anatomy of the limbic-NTS circuits using tracer in NHPs and guide in vivo reconstructions of these connections from high-resolution diffusion MRI (dMRI) in healthy volunteers; 2. map the glia populations of the limbic-NTS circuits using immunohistochemistry in NHPs and guide the interpretation of changes in dMRI measures of glia processes in subjects with TRD in relation to changes in depression severity. DMRI allows to noninvasively delineate neural circuits and detect microstructure changes along them, making it a promising tool to elucidate the relationship between neuroinflammation and depression. However, the study of neural circuitries in depression has been largely limited to major cortical pathways, due to the resolution limits of conventional dMRI and the lack of anatomical ground truth for finer subcortical circuits. Here, we propose a multi-modal approach to generate a novel, validated atlas of the circuits involved in neuroimmune communication between visceral and limbic regions, that will allow accessing the anatomical substrates of neuroinflammation in vivo at unprecedented resolution and accuracy. We will use this atlas to perform retrospective analyses of high- resolution longitudinal dMRI from TRD patients undergoing long-term ketamine treatment. In TRD, ketamine has a rapid antidepressant effect that has been linked to anti-inflammatory mechanisms. The evaluation of advanced dMRI measures of neuroinflammation along these circuits in relation to changes in depression severity will provide novel insights into the interplay between depression and inflammation. By providing a validated atlas for the in vivo investigation of the NTS circuits and candidate imaging biomarkers of neuroinflammation we will unlock more specific approaches to probe the mechanisms of MDD in relation to neuroinflammation, monitor progression, and evaluate treatment response.

NIMH - National Institute of Mental Health

ABSTRACT HIV treatment is an essential pillar of the End the HIV Epidemic (EHE) strategy. Yet, in 2021, of the 1.2 million people living with HIV (PLWH) in the US, only 50% were retained in care, 58% achieved viral suppression and significant racial inequities persisted for Black Americans. HIV treatment outcomes are driven by poor access to HIV clinics; and for those who are on treatment, many forget to take their daily oral antiretroviral therapy (ART). Long acting injectable (LAI) ART, approved for every 1- or 2-month administration, can combat memory barriers related to taking a pill every day, but HIV clinic access remains a challenge, especially for Black Americans who are less likely to live near an HIV clinic. To increase equitable LAI ART access and viral suppression, we propose integrating LAI ART in pharmacies. Despite promising evidence that pharmacies with specialized HIV training can increase ART adherence and viral suppression, pharmacies with specialized HIV training are uncommon, likely because no free, widely available HIV treatment pharmacy trainings exist. Our work has shown that expanding HIV services in pharmacies could drastically increase access, but training is critically needed to develop a model for integrating LAI ART specifically into pharmacy workflow. Thus, we propose the Pharmacy- based LAI ART versus Clinic Effectiveness (PLACE) study to evaluate administration of LAI ART within pharmacies versus HIV clinics. We aim to 1) Examine the policy- and pharmacy staff-level barriers and facilitators of adopting LAI ART services in pharmacies among key stakeholders (policy members, pharmacy staff, HIV- clinic staff, and PLWH), 2) Develop and evaluate a pharmacy-based LAI ART training, and 3) Test the integration of pharmacy-based LAI ART delivery in pharmacies compared to HIV clinics on effectiveness, implementation, and clinical outcomes. Guided by the Exploration, Preparation, Implementation, Sustainment framework, this study will include three phases. An exploration phase of 300 online pharmacy staff surveys, and in-depth interviews of 10 Board of pharmacy members who shape pharmacy policy, 40 pharmacy staff, 10 HIV clinic staff (clinicians and nurses) and 40 diverse PLWH that examine the barriers and facilitators to pharmacy-based LAI ART provision. These data will inform the preparation phase which will develop a hybrid (virtual/in-person) LAI ART pharmacy training that will be tested among 100 community pharmacy staff. Finally, an implementation and sustainment phase, will evaluate the acceptability, feasibility, reach by race and ethnicity, uptake, costs, viral suppression and visit adherence of LAI ART service integration in 5 community pharmacies compared with 2 Ryan White funded HIV clinics among 222 LAI ART patients. Findings will inform a model that could be implemented across Ryan White funded clinics to scale pharmacy-based LAI ART services in the US Southeast where efforts to improve equitable HIV treatment and reduce HIV transmission are desperately needed to EHE.

Administration for Children & Families - ACYF/FYSB

The Primary Prevention Youth Homelessness Demonstration Program provides funding to identify and implement strategies and services for youth and young adults between ages 12 and 26 in order to prevent homelessness, including strategies designed to serve youth and young adult populations with a high likelihood of experiencing homelessness, housing instability, particularly among youth at risk of human trafficking; struggling with substance abuse or mental health concerns; or transitioning out of foster care, the juvenile justice system, or a residential behavioral health system. Primary prevention efforts should focus on reasons youth become homeless, such as a lack of affordable housing, poverty, and family dynamics.Grant recipients must also work with youth who have experienced homelessness, are self-sufficient, and can assist with helping design and implement their projects. This includes establishing local youth advisory boards. In addition, grant recipients awarded under this funding opportunity must participate in a federally sponsored evaluation.

Pritchard Beach Waterfront Center Project

Demand for water-dependent programming in SE Seattle is strong. This diverse community deserves safe ACCESS to the unique asset at its back door: Lake Washington. Current Pritchard Beach bathhouse facilities located at 8400 55th Ave S Seattle WA are little used but offer excellent potential as a site for a waterfront center like those at Green Lake or Mt. Baker. This project seeks to create a welcoming, inclusive, fully ADA accessible community boating center that will allow more people, but in particular youth, to experience the mental and physical benefits of recreating & competing in the outdoors, safe access for all, and a variety of programs with material health and academic benefits for youth. Phase I of the project will focus on a community engagement process to document the demand for repurposing the bathhouse and prepare proposals for Phase II. The anticipated project completion date is January 31, 2026.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Adolescence is a postnatal developmental period observed across many species, marked by large changes in behavior driven by extensive remodeling of neural circuitry. It is critical to elucidate how the brain changes in this transient period between childhood and adulthood: the adolescent brain is powerfully dynamic, but this plasticity induces high sensitivity to both beneficial and adverse alterations, including onset of neuropsychiatric disorder. Despite this necessity for scientific understanding to improve neuropsychiatric health outcomes, the biological drivers of adolescent behavior are only partially understood, in part due to limits of human neuroimaging studies and the short duration of adolescence in model species. A plethora of behavioral work emphasizes adolescent hypersensitivity to rewards, resulting in heightened risk-taking and novelty-seeking; a smaller body of evidence suggests adolescents also show altered sensitivity to aversive outcomes. These studies are often limited in interpretation due to risk/reward tradeoff task designs, from which it is difficult to parse out pure reward versus aversion signals. The neural circuitry that underlies sensitivity to both reward and aversion outcomes critically includes the nucleus accumbens (NAc), a region necessary for motivation and decision-making. Two vital regions sending glutamatergic projections to the NAc are the amygdala, known to receive and send signals for affective processing and fear encoding, and the prefrontal cortex (PFC), which is critically involved in executive function and decision-making. High level changes to these systems are well-characterized in the context of adolescent development; however, these changes are most certainly driven mechanistically by alterations at the level of individual synapses. Mechanistic studies at high resolution are necessary to build an accurate model of adolescent behavior and understand how synaptic development drives the transition from childhood to adulthood in both typical and atypical states. With the goal of uncovering the synaptic developmental mechanisms that define adolescent sensitivity to aversive behavioral outcomes, this proposal will use a combination of superresolution histology, ex vivo electrophysiology, behavior, fiber photometry, and optogenetic approaches. The proposed study will test the central hypothesis that different developmental timeframes of synaptic connectivity from two glutamatergic inputs to NAc neurons, the amygdala and the PFC, underlie age-specific sensitivities to aversive outcomes. In addition to providing description of the exceptional training environment and resources available to complete this work, the fellowship training plan in this proposal details specific scientific training goals in histological interrogation of synaptic biology, ex vivo whole-cell patch clamp electrophysiology to quantify functional connectivity, and in vivo studies of synaptic function using fiber photometry. Additionally, the training goals include development of mentorship and pedagogical skills in the laboratory.

NIMH - National Institute of Mental Health

PROJECT SUMMARY This NIH F30 application describes a three-year plan for mentored research and career development for the PI, Jana Badrani. The scientific premise of this proposal is focused on the role of GR-1+ non-microglial myeloid cells (NMCs) on brain development and adulthood behaviors under normal conditions and following maternal immune activation (MIA). MIA encompasses any pro-inflammatory response within the mother during pregnancy and can be caused by infectious and non-infectious stimuli. MIA is a known risk factor for psychiatric and neurodevelopmental disorders, like schizophrenia and autism, in offspring. MIA is also implicated in hematopoietic changes and disruptions in immune cell development and differentiation. Here, we will elucidate the cellular and molecular mechanisms of meningeal and brain non-microglial immune cell interactions with neurons during normal brain development and following a representative MIA model of maternal systemic challenge with polyI:C (PIC). Our preliminary flow cytometric data identifies a prominent GR- 1+ NMC population that increases within the brains of male MIA offspring. scRNA-seq analysis identified GR-1+ neutrophil populations in the brain, with significant gene expression changes in PIC offspring compared to vehicle offspring. Male MIA offspring also demonstrated behavioral deficits in the elevated plus maze (EPM). Systemic depletion of GR-1+ cells improved the EPM behavioral deficits in PIC male offspring. Thus, our central hypothesis is that GR-1+ neutrophils in the brain impair neuronal function and behaviors via MMP in male PIC offspring. We will test this hypothesis through immunohistochemistry, flow cytometry, single-cell transcriptomics, and a variety of in vivo experiments, including the use of anti-GR1 depleting antibodies and MMP inhibitors. Understanding the involvement of GR-1+ non-microglial myeloid cells in brain development and following MIA will have a significant impact on our understanding of immune-brain interactions underlying brain homeostasis. The proposed training plan for the PI is sponsored by Dr. Shin-ichi Kano, MD, PhD, and Dr. Farah Lubin, PhD. Included in the training plan are experiences that will help Jana develop in three major areas: (1) rigorous neuroimmunological research in neuro-immune interactions, which includes developing familiarity with existing literature, critical evaluation of data, and training in responsible conduct of research; (2) rigorous training in advanced bioinformatics, high dimensional data analysis, and scRNA-sequencing analysis; and (3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research in immunology, neuroscience, and bioinformatics necessary for the PI’s future career as a clinician-scientist focused on neuropsychiatry and immunotherapy.

NIMH - National Institute of Mental Health

Project Summary Epidemiological data consistently show that exposure to chronic stress precedes the onset of several psychiatric disorders. However, there are profound individual differences, with some people demonstrating resilience to the deleterious effects of chronic stress. The biological underpinnings of this individual difference remain poorly understood, hindering efforts to develop new and improved therapeutics. Emerging evidence suggests that long non-coding RNAs (lncRNAs), epigenetic regulators enriched in the human brain, contribute to individual differences in stress responses. LncRNAs comprise a large portion of the human genome and give rise to a comparable number of transcripts as protein-coding genes, yet our understanding of their contribution to human brain function is in its infancy. Several studies profiling the genomic and transcriptomic landscape of depression, a disorder associated with susceptibility to chronic stress, highlighted the regulation of lncRNAs. However, the role of lncRNAs in brain function, including those associated with chronic stress, remains uncharacterized, limiting mechanistic insight and translational potential. We hypothesize that lncRNAs play a key role in individual differences in responses to chronic stress. To test this hypothesis, we propose this study with the overarching objective to expand our knowledge of lncRNAs associated with the response to chronic stress. Bioinformatic integration of genetic, transcriptional, and epigenetic datasets offers a powerful strategy to pinpoint lncRNAs that mediate stress susceptibility and resilience. Specifically, we would harness published genetic analyses of depression to conduct extensive bioinformatic analyses to identify a subset of candidate lncRNA for future experimental analysis (Aim 1). As a proof of concept, we will experimentally explore LINC02977, identified through a multi-omics analysis (Aim 2). These aims will be addressed by: A. further bioinformatic analysis of genome-wide association studies (GWAS) results for depression, focusing on lncRNA and overlaying with data sets from transcriptional and epigenetic studies. B. Combination of genetic expression of LINC02977 in the medial prefrontal cortex of mice of both sexes, with a chronic stress model, followed by behavioral, molecular, and morphological analysis. In summary, this research program is poised to generate critical insights into the contribution of lncRNAs to the molecular basis of individual differences in response to chronic stress. Our application has potential implications for mental health as it may catalyze the development of therapeutic interventions for stress-induced mental health disorders.

NIMH - National Institute of Mental Health

Project Summary The mechanistic target of rapamycin (mTOR) is a serine/threonine-protein kinase that regulates cell growth, proliferation, and synaptic plasticity. Dysfunction in mTOR signaling has been implicated in several neurological disorders, including seizures, autism, and attention deficit hyperactivity disorder. However, there is limited understanding of how abnormal mTOR signaling in specific cell types leads to neuropsychiatric and behavioral disorders. The mTOR controls protein synthesis by sensing nutrient and energy levels. Midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have large somata and widespread axonal arborizations rich in mitochondria. Their high energy demands make dopamine neurons highly sensitive to the status of mTOR signaling. To investigate the role of mTOR signaling in midbrain dopamine neurons, we generated dopamine neuron-specific mTOR conditional knockout (mTOR-cKO) mice by crossing mTOR-floxed mice with DAT-Cre mice. We made the serendipitous discovery that mTOR-cKO mice exhibited a pronounced increase in basal locomotor activity in an open field compared with that of wild-type mice, and a low dose of the stimulant amphetamine increased locomotor activity in wildtype mice but produced a paradoxical calming effect on locomotor activity in mTOR-cKO mice. In addition, mTOR-cKO mice exhibited impulsive behavior and attention deficits. Although mTOR-cKO mice share a striking resemblance to the distinct behavioral endophenotypes of hyperactivity, impulsivity, and inattention, this proposal does not seek to create a mouse model of a human neurodevelopmental illness. Instead, the long-term goal of this application is to investigate cellular and circuit mechanisms underlying the hyperactive and impulsive behavioral phenotypes. Three Specific Aims are proposed. In Aim I, we will examine how mTOR-cKO alters dopamine neuron physiology. In Aim II, we will investigate the mechanisms that underlie differential locomotor responses to amphetamine between the two genotypes. In Aim III, we will investigate the molecular and circuit mechanisms underlying impulsive behavior and attention deficits in mTOR-cKO mice. Together, these studies will elucidate mechanisms that govern hyperactive and impulsive behavior and provide novel insight into the role of mTOR signaling in regulating the function of dopamine neurons.

NIMH - National Institute of Mental Health

ABSTRACT Recovery from viral infections is influenced by social interaction, yet the underlying mechanisms remain poorly understood. Our preliminary studies in a murine model demonstrate that socially housed mice recover faster from virally induced sickness behaviors (using the viral mimic poly(I:C)), and this accelerated recovery is associated with elevated interleukin-10 (IL-10) levels. Moreover, we found that IL-10 delivery into the brain of individually housed mice mimics the faster recovery observed in socially housed mice. We also provide preliminary data showing that oxytocin (OT), a neuropeptide induced by social interactions, can modulate IL-10 levels, suggesting a potential mechanism linking social interaction, oxytocin, and IL-10-mediated recovery. This research aims to explore how social touch and oxytocin facilitate immune modulation and recovery, providing novel insights into the neural-immune mechanisms underlying recovery from viral illness. Specifically, we hypothesize that social-touch-mediated oxytocin release promotes recovery from virally associated sickness behaviors via upregulation of IL-10. We will test this hypothesis through the following aims: (1) determine whether social interaction promotes recovery by engaging specific sensory neurons responding to social touch (Mrgprb4+ neurons); (2) investigate whether the oxytocin system mediates the recovery effects of social touch; and (3) characterize how IL-10 upregulation induced by social touch and OT influences the brain and periphery during recovery. By elucidating the neural and immune pathways linking social interaction, oxytocin, and IL-10, this research aims to provide a fundamental understanding of how social behaviors influence recovery from viral infections.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Individuals with psychotic disorders often experience significant social dysfunction that contributes to both individual suffering and societal burden – even during the initial onset of illness (i.e., early psychosis; EP). Social cognition is a key predictor of social and functional outcomes in EP, and mentalizing – the social cognitive ability to make inferences about the perspectives and mental states of other people – is both robustly impaired and particularly associated with social functioning. Unfortunately, mentalizing impairments are not addressed by psychiatric medications and psychosocial interventions for social cognitive dysfunction are often difficult to access or inconsistent with regard to improving real-world outcomes. Though mentalizing has known neural underpinnings in the cerebral brain regions that comprise the mentalizing network (MN; i.e., medial prefrontal cortex, precuneus, temporoparietal junction), emerging data indicate that a specific region of the posterior cerebellum (Crus II) plays a critical role in mentalizing that has been overlooked in models of social dysfunction in psychosis. Recent data from the neuroanatomical and developmental literatures further demonstrate that the posterior cerebellum undergoes a unique, protracted process of development from the years spanning adolescence and early adulthood – which intersects with the years of life when EP tends to emerge and escalate. Despite evidence of structural and functional abnormalities of the cerebellum in psychosis, how these alterations manifest in EP and their contribution to social dysfunction remain unknown. In this proposal, we utilize a neurodevelopmental framework to clarify the impact of the posterior cerebellum on social dysfunction and further characterize the comprehensive functional brain circuitry of mentalizing during EP. We will recruit a large sample (n=120) of EP participants, as well as 60 age-matched non-clinical control participants for comparison purposes. Participants will undergo MRI to delineate the structural and functional posterior cerebellum features underlying mentalizing dysfunction. Participants will also complete a comprehensive clinical assessment of social cognition, psychiatric symptoms, neurocognition, and functional outcomes. The specific aims of this proposal are to: i) elucidate the nature of localized alterations of the posterior cerebellum during early psychosis (EP); ii) to delineate the functional network dynamics underlying posterior cerebellum-cerebrum interactions during mentalizing in EP; and iii) to parse the specific impact of posterior cerebellum dysfunction on social outcomes in EP. Successful completion of these aims will advance our understanding of how the posterior cerebellum influences social dysfunction during key developmental phases within the early time-course of psychosis, further informing translational interventions during a critical period of illness and thus advancing NIMH strategic goals to define brain mechanisms underlying complex behavior and examine mental illness trajectories across the lifespan.

NIMH - National Institute of Mental Health

Project Summary Deficiencies in interpretation and memory of emotional social interactions are debilitating symptoms in many neuropsychiatric disorders including autism and schizophrenia and lack effective treatment. This is largely due to a poor understanding of the neural basis underlying valence-association of social memories which enables normal functioning of these processes. While neutral social memory (novel versus familiar) has been extensively explored, the circuit and synaptic underpinnings of valence-associated social memories are largely unknown. Recent findings indicate that distinct neural circuits mediate social and non-social memory. Moreover, due to the dynamic nature of social relationships, social valance representation requires more flexible updating compared to object valence and thus likely underlies distinct mechanisms. Therefore, there is an urgent need to investigate social memory valence in order to understand the pathogenesis of maladaptive social behaviors. The hippocampal subregion ventral CA1 (vCA1) has been found to regulate neutral social memory and non-social valence and indeed hippocampal abnormalities are prevalent in autism spectrum disorder (ASD). To address this knowledge gap, our overall objective is to uncover the circuits mediating positive and negative social memories and identify hippocampal cell types supporting the distinct valence representations and valence updating. Our preliminary data show several vCA1 input regions with differential activity following a positive or negative social interaction. Further, inhibition of the vCA1 impaired valence-associated social memories, which is likely dependent on differential neuromodulation. Based on those results, we hypothesize that differential inputs activate selective cell types in the vCA1 to mediate the formation and updating of specific social emotional memories. Therefore, we will pursue three Specific Aims: 1) Identify and manipulate neuromodulatory inputs into the vCA1 which selectively mediate positive social memory, 2) Uncover and manipulate neuromodulator inputs into the vCA1 which selectively control negative social memory, 3) Identify vCA1 cell type interactions involved in positive and negative social memory updating. In Aim 1 and 2 we will use optogenetics in Cre-driver lines to manipulate neuromodulatory inputs into the vCA1 as well as in vivo fiber photometry to record neuromodulator activity during positive and negative social interactions. In addition, we will use conditional knockout lines to delete neuromodulators in vCA1 input projections and assay the effect on valence-associated social memories. In Aim 3 we will combine TRAP2;Ai14 with RNAscope to identify distinct vCA1 cell types involved in positive and negative social memory representations and use slice electrophysiology to elucidate synaptic interactions between “positive” and “negative” ensembles. Since impaired social memory and emotional processing of social interactions are prevalent symptoms of ASD, research elucidating the neural basis of these social cognitive processes is essential for the much-needed therapeutic progress.

NIMH - National Institute of Mental Health

Project Summary: Rett Syndrome (RTT) is a progressive neurological disorder characterized by severe cognitive and motor impairments caused primarily by mutations in MECP2. The molecular mechanisms by which disruption of MECP2 gives rise to RTT remain unclear. MECP2 is known to bind to methylated DNA in the brain, regulating the expression of neuronal genes. However, previous studies have shown complex patterns of gene dysregulation in RTT that challenge this model, such that only a subset of genes appear to be regulated by MECP2 binding to DNA methylation. We recently discovered that MECP2 preferentially binds to specific gene enhancers that we named MECP2-Binding Hotspots (MBHs). Surprisingly, MECP2 binds to these MBHs independently of DNA methylation, contrasting with its well-established role in binding methylated DNA. At MBHs, MECP2 appears to act as a repressor of enhancer activity. Importantly, over 60% of genes derepressed upon MECP2 deletion are associated with MBHs, suggesting that MBHs might be a major mechanism by which MECP2 controls genes. Preliminary analyses indicate that MBHs, but not MECP2 bound to methylated sites across the genome, are bound by histone deacetylase-containing nuclear receptor co- repressor (NCOR) complex, suggesting that MBHs may repress enhancer activity by recruiting the NCOR complex to enhancers. Taken together, our findings indicate a previously uncharacterized mechanism of transcriptional regulation by MECP2. Moreover, these results implicate dysregulation of specific enhancers as a possible mechanism underlying RTT. To gain insights into how MECP2 regulates genes and how dysregulation of MECP2 leads to RTT, we propose to (1) define the interaction between MECP2 and MBHs, and (2) elucidate the molecular mechanisms by which MBHs repress enhancers. This work has significant implications for understanding the molecular basis of MECP2 function and the complex gene dysregulation observed in RTT and will uncover new therapeutic targets and strategies for treating RTT.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY The overall goal of this application is to provide the principal investigator with targeted training in advanced methods for capturing and analyzing daily family dynamics relevant to child mental health. In the long term, the applicant intends to establish an independent research career focused on how everyday family processes shape children’s development, with the goal of informing interventions that strengthen family functioning and support mental health. To support this trajectory, the proposed training plan includes focused development in three key areas: (1) interdisciplinary collaboration to integrate technology into the study of family interactions, (2) advanced statistical methods for analyzing large, multimodal datasets, and (3) the conceptualization and dissemination of findings on adaptive and maladaptive family processes in daily life. Together, these components will lay the groundwork for a research career focused on advancing the science of family processes and enhancing interventions that support child and family well-being. Children’s exposure to family conflict can significantly shape their development, influencing both mental health symptoms and how they manage conflict in the future. While some conflicts promote problem-solving and emotional growth, others escalate into maladaptive patterns that increase the risk for mental health symptoms. Yet, key questions remain about the core features that distinguish adaptive from maladaptive conflict. This study addresses that gap by examining how conflict unfolds in daily life, focusing on natural escalation within individual episodes as well as broader day-to-day conflict patterns over two months. Findings will identify the features that contribute to maladaptive conflict, shedding light on when and how conflict becomes harmful. By identifying these distinguishing features, this research will inform the development of targeted interventions aimed at supporting healthier family relationships. This project addresses two complementary aims, offering both detailed and broad perspectives on parent-child conflict. The first aim takes a “zoomed-in” approach, examining naturally occurring conflict episodes captured through at-home audio recordings. It focuses on specific features such as baseline intensity and the trajectory of escalation, and how these dynamics are linked to same-day and next-day changes in child mood and parent- child interactions. The second aim takes a “zoomed-out” view, using ecological momentary assessment surveys to track daily patterns of conflict intensity, frequency, and duration over a two-month period. This broader approach will examine how families’ overall conflict patterns relate to child mental health symptoms and parent-child relationship quality. By integrating these two levels of analysis, the project will provide a more complete picture of how parent-child conflict unfolds in everyday life—offering valuable insights to guide interventions that strengthen family relationships and promote child well-being.

NINR - National Institute of Nursing Research

PROJECT SUMMARY / ABSTRACT Sedentary behavior is often negatively associated with cancer, cardiovascular disease, diabetes, mental health and early death among all adults. Furthermore, of concern for older adults, sedentary behavior has been linked with a decline in cognitive function, falls and reduced function and/or disability. Our team has been refining our Worksite Heart Health Improvement Project (WHHIP), which aims to improve physical activity (PA), among staff working in assisted living (AL) facilities. Our past WHHIP projects were deemed feasible and showed significant improvements in staff health behaviors and outcomes. We found residents attended PA sessions with staff, and staff encouraged residents to engage in PA as a result of participating in the WHHIP. Additionally, engaging residents in PA has been demonstrated repeatedly through Function Focused Care (FFC). FFC is a philosophy of care that teaches staff how to engage and encourage residents in PA during care interactions. One of the major challenges to implementation of FFC, however, was workers’ lack of beliefs in the benefits of PA for themselves and residents. To optimally engage staff and residents in PA we have merged the WHHIP and FCC interventions to increase PA in both groups. The WHHIP+FFC has four steps: Step 1: Development of a stakeholder team and identification of an AL champion; Step 2: Environment and policy assessments to increase PA among staff and residents; Step 3: Individual education and goal setting for PA with staff; and Step 4: Mentoring and motivation of staff to engage in and facilitate resident participation in PA. Using an incomplete stepped wedge cluster randomized trial in eight AL facilities (staff n=224, resident n=120) with six data collection timepoints we aim to: Aim 1: Evaluate the feasibility of the combined WHHIP+FFC approaches. Hypothesis 1: The WHHIP+FFC will be deemed feasible as evidenced by delivery, receipt, and enactment. Aim 2: Evaluate the impact of the WHHIP+FFC to improve PA among AL staff and residents. Hypothesis 2: AL staff exposed to the WHHIP+FFC will demonstrate improvements in objective and subjective PA and FFC engagement, and residents will demonstrate improvements in objective PA and function. Aim 3: Evaluate the impact of the WHHIP+FFC on physical and psychological outcomes. Hypothesis 3: AL staff exposed to the WHHIP+FFC will demonstrate improvements in blood pressure, sleep hours, sleep quality, body composition as well as in depression, anxiety, stress, and burnout symptoms. Aim 4: Evaluate the impact of the WHHIP+FFC on staff retention. Hypothesis 4: Organizations exposed to the WHHIP+FFC will demonstrate decreased AL staff turnover and intention to leave.

NIMH - National Institute of Mental Health

Project Summary/Abstract: Project Abstract: Neurodevelopmental disorders are increasingly prevalent, and no mechanism-based therapeutics are available. Discovering the cellular and molecular alterations that are driving synaptic and circuit disruptions in these disorders is essential for developing targeted treatment strategies. In previous work, we and others identified an accelerated rate of protein synthesis in neurons of the Fmr1-/y mouse model of Fragile X Syndrome (FXS), the most commonly identified monogenic cause of intellectual disability. In more recent work, we now show that protein degradation by the ubiquitin proteasome system (UPS) is similarly elevated in Fmr1- /y neurons. Furthermore, inhibiting this pathway lowers neuronal hyperactivation and seizures in the Fmr1-/y mouse. This suggests the constitutive elevation of proteasome activity in Fmr1-/y neurons is detrimental. In this proposal we will: (1) Interrogate the mechanism driving increased UPS activity in Fmr1-/y brain. Specifically, we will test the hypothesis that increased proteasome activity in Fmr1-/y neurons is driven by excessive translation of aberrant proteins. (2) Determine the link between accelerated protein degradation and increased excitability. Specifically, we will test the hypothesis that excessive misfolding and degradation of GABA-ARs contributes to hyperexcitability in Fmr1-/y neurons. (3) Investigate UPS inhibition as a novel therapeutic strategy for FXS. Specifically, we will test the hypothesis that proteasome inhibition can resolve multiple hippocampal and cortical plasticity phenotypes in the Fmr1-/y mouse.

NINDS - National Institute of Neurological Disorders and Stroke

Project summary Circadian clocks optimize metabolism, physiology and behavior with the time-of-day. Thus, they play a key role in human health and well-being, and their disruption is associated with increased risks of mental disorders, metabolic diseases and cancers. Circadian pacemaker neurons, located in the brain, determine the timing of essential behaviors such as the sleep-wake cycle and feeding. These neurons express core circadian proteins, which form a network of transcriptional feedback loops that determines the timing of gene expression. Interestingly, in Drosophila, these neurons show synchronized oscillations of their circadian molecular clock, but also extraordinarily diverse phases of neural activity between functional groups of neurons. For example, the M-cells, which drive morning behavior, are mostly active at dawn. On the other hand, the E-cells, which promote evening activity, fire action potentials preferentially at dusk. This diversity in temporal neural activity is essential for determining the timing of behaviors, but it raises a fundamental question: how can synchronized circadian clocks generate desynchronized neural activity rhythms? Our hypothesis is that local circadian clocks regulate the time-dependent and neuron-specific expression of membrane proteins such as ion channels and receptors. To identify these proteins, we propose to use cutting-edge proteomic approaches combined with biotin proximity labeling to survey the membrane proteome of circadian neurons during the day/night cycle. The function of rhythmic membrane proteins will be tested in circadian behavior and sleep screens. This project should thus shed light on the mechanisms by which circadian clocks determine the temporal patterns of neural activity in diverse populations of pacemaker neurons, and thus the timing of behavior. It will also considerably help with the development of novel proteomic approaches that should be broadly applicable to study circadian rhythms and other neural processes in various species. Moreover, since the mechanisms underlying circadian rhythms are highly conserved in animals, our work could ultimately help understanding how the timing of the sleep/wake cycle is determined in humans and contribute to the design of therapeutic approaches aimed at alleviating ailments associated with circadian disruption.

National Institutes of Health

Executive Summary This funding opportunity announcement (FOA) solicits Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) for support of research and development of novel, or the enhancement of existing, commercializable products to mitigate (e.g., tools to be used in assessment, preventive or treatment interventions, and information dissemination) or understand (e.g., research tools) the mental health effects brought on or exacerbated by the aftermath of national disasters, such as Hurricanes Katrina and Rita, including victims and those who responded to their needs. These tools might be used by researchers, mental health professionals, other health care providers, as well as by those in the broader community, including educators, day care providers, family members of victims, etc. These tools must take into account the cultural context of the target population to assure their effectiveness and validity. -Budgets up to $250,000 total costs per year and time periods up to 2 years for Phase I may be requested. Budgets up to $450,000 total costs per year and up to 3 years may be requested for Phase II. -No funds have been specifically set aside for this program; the number of awards and the amount of funds provided for awards will be determined by the quality and number of applications as well as availability of funds. -This FOA will utilize the SBIR (R43/R44) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with a FOA of identical scientific scope, PA-06-336 that solicits applications under the Small Business Technology Transfer (STTR) (R41/R42) grant mechanisms. -Eligible organizations: Only United States SBCs are eligible to submit SBIR applications. A SBC is one that, on the date of award for both Phase I and Phase II funding agreements, meets ALL of the criteria as described in Section III. -Eligible individuals: Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. On an SBIR application, the Project Director/Principal Investigator (PD/PI) must have his/her primary employment (more than 50%) with the SBC at the time of award and for the duration of the project. -Applicant SBCs may submit more than one application, provided each application is scientifically distinct.

National Institutes of Health

Executive Summary This funding opportunity announcement (FOA) solicits Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) that propose to support research and development of novel, or the enhancement of existing, commercializable products to mitigate (e.g., tools to be used in assessment, preventive or treatment interventions, and information dissemination) or understand (e.g., research tools) the mental health effects brought on or exacerbated by the aftermath of national disasters, such as Hurricanes Katrina and Rita, including victims and those who responded to their needs. These tools might be used by researchers, mental health professionals, other health care providers, as well as by those in the broader community, including educators, day care providers, family members of victims, etc. These tools must take into account the cultural context of the target population to assure their effectiveness and validity. -Budgets up to $250,000 total costs per year and time periods up to 2 years for Phase I may be requested. Budgets up to $450,000 total costs per year and up to 3 years may be requested for Phase II. -No funds have been specifically set aside for this program; the number of awards and the amount of funds provided for awards will be determined by the quality and number of applications as well as availability of funds. -This FOA will utilize the STTR (R41/R42) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with a FOA of identical scientific scope, PA-06-335 that solicits applications under the Small Business Innovation Research (SBIR) (R43/R44) grant mechanisms. -Eligible organizations: Only United States SBCs are eligible to submit STTR applications. A SBC is one that, on the date of award for both Phase I and Phase II funding agreements, meets ALL of the criteria as described in Section III. -Eligible individuals: Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. On an STTR application, the Project Director/Principal Investigator (PD/PI) may be employed with the SBC or the participating non-profit research institution as long as he/she has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the small business concern and that individual. -Applicant SBCs may submit more than one application, provided each application is scientifically distinct.

NINDS - National Institute of Neurological Disorders and Stroke

This education project is a continuation of our current, national class, Training in Advanced Statistical Methods in Neuroimaging and Genetics. Over the past 15 year the National Institutes of Health has greatly increased funding of grants that utilized advanced neuroimaging methods, genetic methods, and advanced statistical methods. While introductory courses are offered, ours is the only advanced course offered in the United States that provides an intensive, hands-on (“doing”) learning opportunity to better prepare biomedical and clinical researchers in advanced statistical methods. In one decade the combined budgets that utilize these advanced analysis techniques from the National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute on Aging, National Institute on Drug Abuse, and National Institute of Biomedical Imaging and Bioengineering grew 5-fold, and there continues to be a great need to provide an educational opportunity to ensure the workforce is well positioned to carry out important work that has been identified by these and other institutes. Our program will continue to meet this need. We bring together a group of diverse world-class scientists and educators in a two-week intensive format to provide theoretical lectures paired with hands-on computer tutorials. Our course has served 103 students (55 total in 2021-2022 via Zoom due to COVID-19), and in 2023 (our 1st year of in-person) we taught 20 students, and 28 students in 2024 (in-person). We will enroll 26-30 students in April 2025 session. In our competitive renewal we will continue to enroll 26-30 students per year. With this being an advanced course, we ensure that the students accepted are a good education-level match for the content. We also implement mechanisms to maximize diverse perspective in our students and our teaching faculty. These students are accepted from across the United States, with attention to attracting a diverse student cohort. This education program will continue to distribute Tuition Awards based on financial need. We have evolved our course based on feedback from our current course alumni. In our class, over two weeks, students learn and put into practice methods such as: hierarchical statistical models, Bayesian statistics, network science, functional and structural connectomics, disease driven degeneration of the brain, and methods for analysis of genetics data such as polygenic risk scoring and structural equation modeling. The course concludes with lectures and labs on multi-modal analysis (imaging and imaging-genetics), and classification methods for biomarker development. Our course now includes 5 guest lecturers and team building activities outside of the classroom. To ensure students apply the acquired knowledge and skills to their independent research projects back at their home institutes, we supplement the course with our innovative continuing education: zoom-based sessions with the faculty for 8-months post formal course and students having near-real-time access regarding technical implementation questions through the Slack. This continued education portion greatly increases success utilizing their new practical skills in their own research.

NIMH - National Institute of Mental Health

Training the Next Generation of Clinical Researchers in Stress Mechanisms and Mental Health ABSTRACT This T32 postdoctoral training program prepares scientists to conduct high impact interdisciplinary research at the intersection of Psychology, Psychobiology, and Mental Health. It is in its 30th year, with 2 fellows per year, and 60 graduates, and has evolved over time to reflect new discoveries and approaches. In line with the NIMH strategic plan, we train fellows to conduct translational research on the interactions among biology, behavioral, and psychosocial factors that promote and exacerbate mental and physical illness and comorbidity. Fellows learn to apply psychological theories and cutting-edge research and quantitative methodologies to address issues in two interrelated tracks: (1) Biobehavioral mechanisms of stress, sleep, and health behaviors for mental health; and 2) Innovative interventions for preventing and treating mental disorders. Fellows focus on one or both tracks, and receive in depth training and research experience in understanding stress- related mechanisms (social exposome and early adversity, psychological and physiological stress, sleep and health behaviors, and biomarkers) across a broad range of communities, with opportunities to conduct research across the lifecourse—from pregnancy and infancy to older age. During their training, fellows share a didactic core, including Works in Progress and Professional Development seminars, Responsible Conduct of Research, and Biostatistics with a new opportunity to learn data science methods. They conduct independent research with at least two mentors, submit papers, present at conferences, and complete a grant application through a highly mentored process. The program benefits from being embedded in a leading health science campus with seed funds for pilot studies. Other strengths include internationally recognized experts as mentors and the addition of exceptional junior faculty, all of whom will receive further mentor training. We are grateful for the excellent feedback from reviewers, which has strengthened multiple aspects of our program. We have sharpened our focus on stress and the biobehavioral mechanisms that lead to affective and behavioral disorders (e.g., depression, anxiety/PTSD, insomnia, ADHD), and on a range of innovative intervention modalities (psychosocial, family interventions, biobehavioral/hormetic stress, pharmacological/psychedelic therapy, neuromodulation, and digital therapeutics). We have created a more structured training plan and increased training in clinical trials, issues of ethics, rigor, replication, and transparency. Finally, we have improved our recruitment plan so that our fellows now well represent a broad array of demographic groups. The program has produced outstanding leaders in the field, and over the last 5 years, our T32 scholars have published high impact papers (5-6 papers), and 100% have gone on to careers in medical or academic centers, with 90% in Assistant Professor positions, and 100% of our fellows have received a grant, mostly federal. Given the track record and many improvements suggested by reviewers, our program is ideally placed to train the next generation of high-impact mental health researchers.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY/ABSTRACT Instances of childhood internalizing, externalizing, and chronic pain symptoms are common and increasing in prevalence. As rates increase, so does the urgency of finding developmentally appropriate ways to address these concerns. Sibling relationships are a prime candidate to consider because of their relevancy in childhood and because existing literature highlights the protective nature of warm sibling relationships for children's physical and mental health. Sibling relationships have also traditionally been understudied in psychological literature, so there is a clear need for research which broadens this field to more complex longitudinal research and genetically-informed research. There is also a need for more research which combines physical and mental health to gain a comprehensive understanding of child wellness. The proposed study is innovative in that it will be novel in examining sibling relationship trajectories in childhood using latent growth mixture modeling, exploring genetic and environmental contributions to sibling relationship quality longitudinally, and investigating the association between sibling relationship quality trajectories and child internalizing, externalizing, and chronic pain symptoms. Overall, the proposed study will provide important and developmentally relevant information needed to prevent mental and physical challenges in children. The proposed research will use data from the Arizona Twin Project, an ongoing longitudinal study of twins and their families in the state of Arizona. The sample is diverse in race and socioeconomic status and allows for the assessment of sibling relationship quality (i.e. sibling warmth and conflict) at eight years, nine years, 10 years, 11 years, and 13 years, and the assessment of internalizing, externalizing, and chronic pain symptoms at 13 years. My training plan is designed to build expertise in advanced statistical techniques, such as latent growth mixture modeling and genetically-informed research methodologies, to examine sibling relationship trajectories and their association with childhood internalizing, externalizing, and chronic pain symptoms. Under the guidance of my specialized team of mentors, I will expand my strong background in family dynamics to understand the associations with childhood mental and physical health, positioning me to make significant contributions to research and interventions that address these interconnected areas.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

The World Health Organization characterizes neurological disorders as one of the greatest threats to public health, a leading contributor to disability-adjusted life years, and the second leading cause of global deaths. Across the world, mental disorders represent 10% of global disease burden, impacting an estimated 1 billion people. These disorders carry a huge economic burden, and while estimates and projections of total costs vary wildly, mental health carries a cost in the United States of at least $200 billion annually. This significant burden motivates improvements in understanding of disease etiology, diagnosis, prevention, and treatment. Many tools exist to examine such issues, but there is still a need for a functional imaging tool that is low-cost while maintaining high-spatial and temporal resolution. This need can be met with transcranial functional ultrasound imaging. Here, we build off new functional ultrasound imaging techniques demonstrated in rodent models, human neonates and in adult humans with exposed brains, to develop fully non-invasive, functional ultrasound for adult humans. Translating functional ultrasound to humans in a broadly useful way has been difficult because transcranial imaging requires lower imaging frequencies to better penetrate the skull, but this in turn reduces the sensitivity to small changes in blood flow-the source of the functional ultrasound's signal. New signal processing and machine learning techniques-developed by our group and others-enhance the performance of low velocity blood flow imaging, particularly in the high clutter and noise environments encountered transcranially, and using some of these methods, our preliminary data provides the first ever demonstration of transcranial functional ultrasound in adults. Additionally, because transcranial ultrasound struggles with establishing precise anatomical orientation and general localization, we will integrate image-to-physical tracking and a two-sided, dual-transducer imaging configuration with our advanced imaging methods to turn transcranial functional ultrasound into a broadly useful tool. We hypothesize that our advanced techniques integrated with tracking and multiple transducers will enable reliable ultrasound-based functional assessment in nearly all subjects.

NIMH - National Institute of Mental Health

Project Summary Mutations that reduce or alter the activity of repressive chromatin modifiers are frequent causes of neurodevelopmental disorders. The inaccessibility of the developing and the dynamic nature of neurogenesis so far have prevented an adequate understanding of how molecular pathologies arise downstream of the loss of specific chromatin regulators. This knowledge gap represents a hurdle for developing therapeutic interventions for neurodevelopmental disease. This proposal aims to combine targeted protein depletion with highly efficient directed differentiation regimens for human pluripotent stem cells to dissect gene regulatory functions of the autism-associated chromatin repressor EHMT1 during human cortical neurogenesis. Based on the extensive characterization of a novel, multipurpose (degradation/immunoprecipitation/visualization) degron allele, we hypothesize that interactions with cell type-specific co-factors allow EHMT1 to control the expression of stage- specific target genes during neurogenesis, resulting in the accumulation of molecular alterations and cortical neuron (CN) dysfunction when EHMT1 is lost from early development onwards. To systematically test this hypothesis, we will first determine whether molecular alterations caused by EHMT1 deficiency from earlier stages of neurogenesis onwards accumulate in CNs and to what degree dysregulated gene loci and CN function remain responsive to restoring physiological EHMT1 levels (Aim 1). We will then combine genomics, proteomics, and genetic approaches to identify how EHMT1, together with candidate recruiters and co-factors, regulates distinct gene loci at specific stages of cortical neurogenesis (Aim 2). Finally, we will expand our degron approach to dissect the functional interplay of different autism-associated H3K9 methylation regulators during human neurogenesis to identify interactions between these proteins that could be clinically exploited (Aim 3). Our experiments will determine currently unknown gene regulatory functions of disease-associated chromatin repressors at critical stages of human cortical neurogenesis. By generating mechanistic insight into how deficiencies of EHMT1 and other H3K9 methylation regulators introduce molecular pathologies in CNs, we anticipate revealing new opportunities for therapeutic interventions with specific neurodevelopmental diseases.