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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.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This proposal will address the critical need for evidence-based transdiagnostic sleep interventions for autistic adolescents and young adults (AYA). Autistic AYA frequently report a multitude of pervasive sleep and circadian problems, including difficulties initiating and maintaining sleep, excessive sleepiness, delayed phase, and irregular sleep–wake schedules. These sleep and circadian problems often occur in unison rather as isolated problems, and contribute to the onset, worsening, and continuation of mental health disorders. This project will adapt and pilot the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C), an effective sleep intervention, so that its content and delivery are effective and sustainable for autistic AYA. Aim 1 is to iteratively adapt as needed and pilot TranS-C for autistic AYA (12-25 yrs). Preliminary data, iterative pilot testing with autistic AYA (N=15-24), and input from an advisory panel of autistic AYA (N=4), caregivers (N=4), medical providers (N=2), and behavioral health clinicians (N=2) will guide needed adaptations. Assessments for Aim 1 include multidimensional sleep health (MSH) (actigraphy, self-report measures), as well as implementation science outcomes (feasibility, acceptability, engagement, and fidelity). Aim 2 is to conduct a pilot randomized trial of the adapted TranS-C to examine intervention efficacy, as well as feasibility, acceptability, engagement and fidelity. Autistic AYA (12-25 yrs) (N=90) will be randomly assigned to the adapted TranS-C, traditional TranS-C, or a wait-list control, with assessments of multidimensional sleep health (MSH) (actigraphy, self-report measures), as well as self-report measures of anxiety, depression, emotion regulation, social functioning, and suicidal ideation and behavior, at pretreatment, posttreatment, and 3-month follow-up. Aim 3 is to evaluate hypothesized mediational processes that may explain relationship between sleep and circadian problems and mental health outcomes in autistic AYA. The resources and expertise of the assembled research team of interdisciplinary researchers will provide an outstanding context to successfully execute this project. This project will also provide necessary data for Dr. Lenker’s future R01 submission of a large-scale effectiveness trial of a transdiagnostic sleep intervention trial for autistic AYA. This project aligns with NIMH’s priorities, as it focuses on assessing and treating sleep and circadian problems within a multidimensional and transdiagnostic context to better understand underlying mechanisms related to mental health, as well as optimizing patient-centered treatment options for autistic individuals.

NIMH - National Institute of Mental Health

PROJECT SUMMARY To inform the origin and treatment of mental health and neurological disorders, there is a need to access specific cell types of the brain and determine how their interactions produce cognition, affect, and behavior. The long- term goal of this project is to understand the biology of an understudied cell type, semilunar granule cells (SLGC), in hippocampus-dependent processes. The dentate gyrus (DG) is a “gate” to the hippocampus. The principal cells of the DG, Granule Cells (GC), broadly excite CA3 pyramidal cells, which in turn excite CA1 pyramidal cells. Therefore, tight control of GC activity prevents hippocampal hyperexcitability that could impair memory and produce seizures. It is thus critical to understand how this gate functions, to determine how GC activity is constrained. In this proposal, the central goal is to develop tools to test the hypothesis that SLGCs function in vivo to limit GC activity. Based upon literature from ex vivo slice work, it has been determined that, in response to excitatory input, SLGCs fire persistently and activate interneurons to inhibit GCs. Thus, SLGCs are poised in the circuit to limit GC activity, but this model has gone untested. Whereas the in vivo roles of GCs are well defined thanks to genetic tools for their specific access, a barrier to progress has been a lack of tools that grant experimental access to SLGCs in vivo. This project pursues methods for recombinase expression in SLGCs of the mouse in vivo and the implementation of these tools to test the hypothesis that SLGCS constrain GC activity. To pursue this objective, 2 Aims are pursued. In Aim 1, strategies for recombinase expression in SLGCs of the mouse will be optimized. Aim 1 will be achieved through two independent strategies. The recombinase Cre is broadly utilized, e.g. Cre-on viral tools or conditional knockout of floxed alleles. In Aim 1, a tamoxifen-Inducible strategy Cre in SLGCs will be optimized. The approach is to characterize at least three promising mouse lines. However, SLGCs and GCs are spatially intermingled and have a high degree of transcriptional similarity, so a single gene approach may not succeed. Therefore, the second strategy of Aim 1 is an Intersectional method to achieve action of the alternative recombinase Flp in SLGCs. The approach is to utilize virus mediated expression of Flp, the expression and activity of which is gated by the SLGC selective expression of two different genes. By either strategy, this project will yield the first methods to selectively access SLGCs in vivo. Aim 2 is to determine if SLGC prevent GC hyperactivity in vivo. The strategy is to utilize recombinase mediated silencing of SLGCs and determine the impacts upon GC physiology and upon hippocampal circuit function using varied ex vivo and in vivo electrophysiology, imaging, and behavioral assays. This project will facilitate studies of the cell and circuit basis of learning and memory and will inform models of hippocampal development and pathologies, serving NIMH Goal 1 to Define the Brain Mechanisms Underlying Complex Behaviors.

NIA - National Institute on Aging

PROJECT SUMMARY The rapid aging of the global population presents a significant societal challenge, with an increasing number of older adults experiencing chronic diseases that compromise their health-span despite advances in medical technologies. This paradox results in substantial economic burdens due to lost productivity and healthcare expenditures. To address this, there is a critical need for strategies that enhance health-span, enabling older adults to maintain functional abilities, independence, and quality of life. The proposed Translational Gerontology and Geroscience (TG2) Training Program at the University of Alabama at Birmingham (UAB) aims to develop the next generation of interdisciplinary, aging-focused scientists. This program will support 5 predoctoral and 3 postdoctoral trainees; providing them with collaborative, interdisciplinary mentoring and comprehensive research training. The goal is to inspire and develop dedicated, motivated, and well-trained scientists capable of tackling society’s big challenges in the field of aging. TG2 will emphasize bidirectional training to create an interdisciplinary experience that addresses physical, mental, and social aspects of health necessary for healthy aging. The program will leverage an exceptionally rich institutional environment that offers a robust infrastructure in aging research, including NIA P30 awards for an Alzheimer’s Disease Research Center, Nathan Shock Center in the Basic Biology of Aging, and Resource Center for Minority Aging Research; as well as one of four McKnight Brain Institutes sites and a VA Geriatric Research, Education, and Clinical Center (GRECC). The program integrates 40+ faculty from five UAB Schools and Colleges (Medicine, Arts & Sciences, Nursing, Optometry, Health Professions) and includes established, independent investigators with strong mentoring history as well as rising stars in the aging field who will be part of our Mentoring on Mentoring Program. Together the trainee, mentor, and a Translational Mentoring Team will craft an individual development plan that includes coursework, laboratory and clinical research, professional development programs, workshops, presentations locally and at national meetings, and training in the responsible conduct of research. Overall, the program will build and develop a multidisciplinary cohort of scholars that will support, learn from, and challenge one another to think critically about how to address the complex challenges of aging and how to develop successful careers in gerontology and geroscience.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT The proposed Translational Neuroscience Training for Clinicians (TNTC) T32 program leverages the breadth and depth of the Boston clinical and neuroscience community to provide outstanding postdoctoral research training for clinician-scientists. Our program addresses a pressing need in the psychiatry research workforce: strengthening the pipeline for clinically trained individuals to enter translational neuroscience research careers. We are well-positioned to address this important gap, with access to both a talented pool of trainees from outstanding psychiatry residency and psychology internship programs, as well as an expansive network of basic, translational, and clinical investigators across Harvard and its affiliates. Program faculty members are seasoned investigators and mentors based at the MGH Department of Psychiatry or the Broad Institute, and each has independent funding as part of a multidisciplinary research portfolio. We are requesting support for a total of five postdoctoral fellows, who will each be co-mentored by one clinical and one translational/basic scientist. Two to three new trainees, either psychiatrists or psychologists who have recently completed their clinical training, will enter the program each year and receive a maximum of three years of support. Trainees will receive cross-disciplinary mentorship that spans two of four research “hubs,” consisting of (1) the numerous clinical research programs within the MGH Department of Psychiatry, (2) the Martinos Center for Biomedical Imaging, (3) the MGH Psychiatric and Neurodevelopmental Genetics Unit, and (4) the Stanley Center of the Broad Institute. Leveraging vast datasets from across these programs, trainees will develop mentored research projects that bridge the domains of clinical research, brain imaging, genomics, animal models, and cell/molecular biology through forward and/or reverse translation. Specialized didactic training encompasses these domains and general issues in translational research, including biostatistics, ethics, scientific writing, and career planning, in preparation for career development awards or other independent funding applications to be submitted during the fellowship period. Our trainees will, therefore, enter the fellowship period with a deep, first-hand knowledge of unmet clinical needs in psychiatry; they will graduate with a foundation of cutting-edge tools to address these needs over their careers. We have an accomplished and experienced faculty in terms of scientific expertise and methodology who have enthusiastically participated in primary mentorship and teaching in our didactic program. This T32 program will provide a strong, longitudinal mentored research experience for fellows, guided by program faculty, to foster critical scientific contributions and enhance the career development of trainees, supporting their transition to productive, independent careers in academic medicine.

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

Summary: The negative effects trauma exposure, such as those that promote PTSD, can be passed to offspring. While the environment in which affected parents raise their offspring clearly plays a role, a significant genetic component also exists. However, some of this genetic influence, typically revealed by twin studies, may stem from epigenetic inheritance; as implied by studies in male rodents, where trauma-specific changes in sperm miRNA content can lead to trauma-specific behavioral changes in all offspring. Evidence for epigenetic inheritance in humans is mainly epidemiological, but recent studies have revealed stress-induced sperm miRNA changes consistent with this idea. For example, we found that men with high Adverse Childhood Experiences (ACEs), whose children can be negatively affected, show reduced sperm levels of miR-34/449 family members; mirroring findings in mice exposed to chronic social instability (CSI) stress across generations. In mice, these sperm miRNA changes persist in preimplantation embryos post-fertilization, altering early embryonic gene expression that leads to elevated anxiety and impaired sociability in female offspring as well as reduced levels of sperm miR-34/449 in males. Our new data driving this proposal reveals another example. The degree of men’s exposure to adult trauma, as assessed by the Trauma History Questionnaire (THQ), which measures PTSD risk, correlates with the levels of miRNAs 532, 361, 375, and 491 in their sperm. The highest THQ scores are associated with 4- to 130-fold increases in these levels. In contrast, these miRNA changes do not correlate with ACE scores and miR-34/449 does not correlate with THQ score. Notably, miRNAs-532 and 375 are two of the 9 sperm miRNAs whose enhanced levels in male mice mediate how chronic variable (CV) stress leads to a suppressed HPA axis response in offspring, a trait linked to mental health disorders. This proposal investigates how elevated levels of sperm miRNAs-532,361,375 and 491 in men with high THQ scores might affect their offspring using the mouse model that previously demonstrated how elevated levels of sperm miRNAs transmit the stress-related effects of paternal CV stress across generations. Aim 1 tests how injecting THQ-associated miRNAs, at levels found in sperm of men exposed to high levels of trauma, into mouse zygotes affects the phenotypes of resulting offspring. Aim 2 will begin to reveal how these injected miRNAs lead to phenotypic changes revealed in Aim 1 by i) identifying gene expression changes induced by them in mouse blastocysts, and ii) looking for similarities to those occurring in discarded blastocysts from IVF procedures using men’s sperm with elevated THQ associated miRNAs derived from an ongoing, independently funded project. This study has the potential to: a) provide strong support for using mouse models to understand epigenetic inheritance in humans; and b) drive future research showing that a significant portion of inherited susceptibility to mental health disorders arises from epigenetic inheritance, and how to reverse it before fatherhood.

NIMH - National Institute of Mental Health

Project Summary/Abstract Post-traumatic stress disorder, or PTSD, is a mental health condition that develops following exposure to traumatic events. In the United States, it affects approximately 5-10% of the general population. Although multiple treatments are available, a significant gap persists in the current understanding of the underlying mechanisms and objective predictors (i.e., treatment-related biomarkers) of the treatments for PTSD. Our study aims to develop a framework, called “Trauma Recovery via EEG and Actigraphy Tracking” or TREAT, to address this gap. TREAT utilizes advanced neurophysiology and imaging technologies, including conventional, portable, and dry EEG, as well as actigraphy-based sleep pattern monitoring, to track the physiological and electrophysiological brain-based changes modulated by Written Exposure Therapy (WET), a robust and scalable treatment paradigm. Comparing pre- versus post-treatment EEG and sleep data, Aim1 will identify clinically relevant biomarkers of WET. This aim is to pinpoint the key EEG channels that are most responsive to WET, thereby providing insight into the spatial effect of WET in PTSD. It will also pinpoint key EEG and sleep biomarkers associated with symptom reduction, providing objective measures to track WET outcomes. Aim2 will longitudinally track neurophysiological and sleep-related markers to identify a critical time point when the shift in EEG/sleep markers begins during WET. Creating a temporal map of the WET effect on EEG and sleep enables clinicians to optimize treatment duration and intensity for each individual patient in the future. Finally, Aim3 will provide models that predict WET outcome only based on baseline EEG and sleep markers, supporting personalized treatment selection and avoiding ineffective interventions in the future. This aim will determine which baseline EEG channels, EEG biomarkers, and sleep markers predict treatment outcomes prior to the initiation of therapy. Finally, it will identify subgroups of patients (i.e., biotypes) characterized by distinct EEG and sleep profiles at baseline, which will enable the prediction of treatment response and advance personalized intervention strategies. By drawing on expertise from clinicians, therapists, biostatisticians, engineers, and computational neuroscientists, this project will establish TREAT as a comprehensive biomarker identification framework for PTSD treatment and potentially for other neuropsychiatric conditions.

NCI - National Cancer Institute

ABSTRACT Cigarette smoking is the leading preventable cause of premature cancer-related mortality in the US. Quitting smoking lowers cancer risk, improves mental health, and can increase life expectancy by 10 years. Women are less successful in their attempts to quit smoking and their rates of quitting are lower than that of men. Women experience greater smoking-related disease and increased risk of mortality from smoking. Women face distinct challenges which can impede smoking cessation. One particularly important factor is psychological trauma. Women have a greater prevalence of trauma exposure and are three times more likely to experience post- traumatic stress disorder compared to men. Trauma is a significant risk factor for smoking initiation and is associated with lower quit rates and increased cancer risk in women. However, no national studies have examined the impact of trauma on difficulty with tobacco cessation in women. Further, though the use of trauma- informed approaches has improved treatment engagement and outcomes for patients with alcohol and other substance use, studies have not evaluated trauma-informed approaches to tobacco cessation in women. The proposed training and research plan for this K08 application will enable Dr. Anita Hargrave to obtain the necessary skills to achieve her career goal of becoming an independent NIH-funded clinician-investigator leveraging expertise in advanced statistical analyses, implementation science, and clinical trials to improve tobacco cessation and women’s cancer prevention using trauma-informed approaches. With a highly experienced mentorship team and a thorough training plan, Dr. Hargrave will build on her prior experience in trauma and cancer-related research to obtain mastery in using nationally representative survey data, applying implementation science behavior change theory, and conducting a pilot randomized controlled trial. This training will complement and facilitate the completion of her research aims: (1) assess challenges to successful tobacco cessation among women with and without trauma histories using a national survey; (2) conduct a formative evaluation using an implementation framework to adapt an evidence-based tobacco cessation intervention by incorporating trauma-informed approaches; (3) determine the feasibility and acceptability of the novel trauma- informed tobacco cessation intervention in a 12-month pilot randomized controlled trial (RCT). The proposed research will inform the development of an R01 application to evaluate the trauma-informed tobacco cessation intervention in a full-scale RCT, with the goal of improving tobacco cessation and cancer prevention for women with histories of trauma.

Office of Juvenile Justice and Delinquency Prevention

Grants to federally recognized tribes for juvenile justice, delinquency prevention, and mental health programs for tribal youth.

NIMH - National Institute of Mental Health

Trichotillomania (TTM) is a chronic and impairing obsessive-compulsive and related disorder that involves repetitively pulling one’s hair, causing visible hair loss. TTM in youth and emerging adults is associated with shame, low self-esteem, academic and social impairment, and comorbid anxiety and depression. Despite the substantial morbidity associated with this condition, existing treatments have clear limitations. There are no known effective medications. Frontline psychotherapy is habit reversal training (HRT), a simple behavior therapy with modest efficacy and durability, perhaps due to its lack of focus on core emotional and cognitive experiences (e.g., shame, perfectionism) that maintain and exacerbate hairpulling. HRT is also extremely difficult to access, due to a scarcity of trained clinicians, high costs of specialty care, and logistics of receiving care (e.g., needing appointment times after school hours) - barriers which disproportionately affect young people. Indeed, less than one-fifth of youth with TTM receive frontline care. To address critical care gaps in this undertreated specialty population, and in line with NIMH Strategic Goal 4 to improve the efficiency, effectiveness, and reach of mental health services, we seek to develop TrichTok, a novel digital self-help TTM treatment for adolescents and emerging adults that (1) is specifically designed with and for adolescents and emerging adults, (2) is delivered in brief TikTok-style videos, to be scalable, accessible, and engaging for teens, (3) incorporates coach-moderated peer support, to further address shame and isolation that affect youth with TTM, and (4) builds on HRT to also incorporate novel cognitive skills that target mindset shifts around shame and perfectionism, for greater efficacy. Initial pilot data from clinician and teen end-user stakeholders provides very strong support for the idea as important, innovative, and feasible, and underscores the value of adapting the program’s design and content specifically for young people with TTM. To accomplish objectives, we will build a functional beta version of the program via iterative user-centered design and development in collaboration with 10 licensed clinicians with expertise in adolescent TTM and 10 adolescents and emerging adults with TTM (Aim 1). Next, we will test the program’s feasibility, usability, and acceptability in 30 adolescents and emerging adults with TTM nationally, via an open pilot trial. Results will be evaluated against pre-registered success criteria. Our team consists of developers, designers, and people with lived experience who created the HabitAware online community and device (a smartwatch that passively detects hairpulling and supports HRT, developed under R43MH114773) and NIH-funded psychologists with expertise in research and treatment of TTM across the lifespan. If we achieve success criteria, we will seek Phase II funding to validate TrichTok’s efficacy and potential for commercialization via a randomized controlled trial as a next step. If successful, this proposal will uniquely result in a relatable, engaging, and novel intervention for adolescent TTM that can dramatically enhance access to care and effectiveness of care.