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NIMH - National Institute of Mental Health

ABSTRACT HIV stigma, poverty, and racism contribute to high rates of mental health problems and impede treatment for young sexually minoritized men (YSMM) living with or vulnerable to HIV. HIV stigma is associated with poorer HIV medication adherence, and worse mental health, including increased odds of suicidality for youth living with HIV. Inclusive, culturally, and contextually appropriate intersectional interventions can promote access to health services and prevent poor health outcomes including HIV transmission related behaviors. Our project, Social Contact-Based Brief Video Interventions To Reduce Stigma and ImproVe Engagement in HIV Prevention and Care and Mental Health Care for Youth Living with and Vulnerable to HIV (STRIVE), will evaluate the effectiveness and implementation of intersectionally-tailored brief videos to reduce public and internalized HIV stigma (BVHS). Throughout the project we will engage partners from the New York City Department of Health and Mental Hygiene (NYC DOHMH) (See LOS) as well as our Youth Advisory Board comprised of 5-8 individuals recruited from three existing Community Advisory Boards (CABS): the AIDS Clinical Trials Group (ACTG) CAB, the ongoing HIV Vaccine Trials Network (HVTN) of the Columbia Collaborative Clinical Trials Unit (Columbia CTU) (see Letter of Support (LOS)) and Columbia University HIV Center Consultants (See LOS). Individuals from these groups represent diverse racial backgrounds, adolescent and young adult age ranges, and lived experience with HIV and/or mental health challenges. In Aim 1 we collaborate with our YAB to adapt and then test the efficacy of BVHS to reduce public HIV stigma compared to a control using crowdsourcing platforms with pre/post/30-day follow-up assessments. In Aim 2 we test the efficacy of BVHS to reduce internalized stigma and increase linkage to HIV prevention, HIV care and mental health treatment among a subset of YSMM living with or vulnerable to HIV on social media. In Aim 3 we use a Consolidated Framework for Implementation Research (CFIR)-informed multi-method analytical plan in order to understand implementation outcomes (e.g., acceptability, feasibility) and inform scale up and dissemination (e.g., identifying key barriers). In Aim 4 we evaluate engagement and treatment-seeking behavior from the NY area dissemination of evidence-based BVHS via Instagram. Through STRIVE we will reduce HIV stigma, facilitated by emotional engagement and identification. This reduction in HIV stigma will mediate proximal outcomes by increasing HIV prevention, HIV care and mental health treatment-seeking among YSMM living with or vulnerable to HIV. This simple, intersectionally-tailored video intervention can potentially reduce duration of untreated HIV and mental health problems and alter public stigma about HIV.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Prior research has documented that social determinants of health such as neighborhood disadvantage and school context are associated with youth mental health3,7,10,11, with neighborhood effects on youth outcomes being mediated by parenting factors4. However, research on the role of these contextual factors in the trajectories of parenting and youth mental health and their relationships has been limited. Additionally, this prior work shows the importance of targeting parenting in family-focused preventive interventions in geographical areas with high contextual risk. While neighborhood economic disadvantage and subjective perceptions of neighborhood are associated with outcomes of preventive interventions32, 34, this prior work has used limited objective measures of social determinants of health, has had inconsistent longitudinal follow-up, focused on limited outcomes, and did not consider how social determinants of health influence intervention engagement. The proposed research will address these limitations with several aims: (1) Determine how neighborhood and educational risk and protective factors are related to youth mental health trajectories across childhood and adolescence and the role of parenting as a mediator between context and youth mental health trajectories, (2) Investigate whether neighborhood and educational risk and protective factors are associated with engagement in and response to the Family Check-Up, a family-focused preventive intervention, and (3) Determine whether findings from the first two aims differ based on urbanicity, race, or ethnicity. The results have implications for clinical practice and research in the development and dissemination of family-focused preventive interventions that promote positive family relationships and youth mental health for all families. The work addresses the NIMH Strategic Plan by aiming to examine trajectories of mental illness, strive for prevention, and advance services to strengthen public health. The proposed research and training plan, which will occur in a supportive, collegiate environment at Case Western Reserve University, will provide the researcher with critical training to support the transition to becoming an independent researcher in developmental psychopathology and prevention science. Specific training goals include (1) Develop a focused understanding of how neighborhood and educational social determinants of health influence parenting and youth mental health, focusing on how this perspective can inform development and dissemination of preventive interventions, (2) gain expertise in leveraging geocoded data to answer questions related to social determinants of health, family functioning, and intervention outcomes, and (3) master the use of complex quantitative methods to analyze longitudinal data. The applicant has assembled a mentorship team with an expertise in the areas which she plans to gain additional experience, and this team will provide superior guidance that will support her increasing independence as a researcher.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Social experiences are indispensable for mental health, and this is particularly important in younger populations where there is a developmental need for peer-peer social interactions. Atypical social experiences in the form of social isolation or deprivation became common during the COVID19 pandemic and have been particularly harmful for adolescent mental health. This can be seen with impaired age-specific social behaviors, like play in adolescent rats and investigation in adult rats. The poor social opportunity that arises from social deprivation alters brain function that contributes to adolescent vulnerabilities to social perturbations. The amygdala is a candidate brain region to investigate the impact of social deprivation on social development, as it is important for regulating social behavior and is sensitive to atypical social experiences. Adolescent amygdala maturation is epitomized by increases in inhibitory parvalbumin (PV) GABAergic tone and in activity evoked by the infralimbic region of the medial prefrontal cortex (IL). The adult basomedial amygdala (BMA) in particular receives dense inputs from the IL and is regulated by GABAergic neurons. Further, the adult BMA dynamically responds to social stimuli and is unique in that its activity directly correlates to the degree of social interaction. Our preliminary data show that BMA principal neuron activity regulates adolescent and adult social engagement. Within the BMA, we have identified IL inputs as a source of BMA principal neuron activation. This IL-evoked principal neuron activation is greater adolescents relative to adults, and the age-dependent reduction in IL-driven excitation is regulated by inhibitory GABAergic neurons in adults. However, it is unclear how social deprivation compromises unique developmental features of the BMA to subsequently impair social development. Our goal is to understand the initial effects of adolescent and adult social deprivation on BMA-driven changes in social behavior, as these initial changes will identify the adolescent-specific vulnerabilities when contrasted with adults. Our aims address a novel central hypothesis that social deprivation shapes BMA activity through reductions in principal neuron activity driven by the IL at both ages and reduction of PV activity in adults. This social deprivation-driven change to BMA activity impairs social interaction across ages. Our central hypothesis will be tested in three specific aims quantifying the contribution of excitation (Aim 1), PV activity (Aim 2), and the ILBMA pathway (Aim 3) to adult and adolescent social behavior and how this is neural circuitry is impacted by social deprivation. Each aim will use a combination of in vitro electrophysiology to mechanistically quantify BMA maturation, fiber photometry for functional changes in BMA activity time-locked to social investigation, and chemogenetics to understand the BMA regulation of adolescent and adult social behavior. The results from the proposed project are expected to create a novel framework through which social deprivation shapes BMA activation underlying adolescent and adult social dysfunction. This will identify distinguishing factors between ages that may contribute to age-specific mechanisms of social abnormalities and adolescent vulnerability to social perturbations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Social media use is associated with increased risk of psychopathology in adolescents, yet the underlying mechanisms linking social media use with mental illness are poorly understood. Social media use facilitates near constant peer evaluation and social feedback, which amplifies the potential for rejection sensitivity, the heightened physiological and emotional responses to social loss or rejection. Rejection sensitivity is of particular importance given that it is a transdiagnostic prodromal symptom of severe psychopathology (e.g., depression), that emerges during adolescence. Social media use engages social reward neural circuitry, which is altered in depression and modified by estradiol (E2), making it a promising neurophysiological candidate linking social media use and female adolescent depression. There is limited data on what makes an individual more sensitive to the impact of social media use, and what neurophysiological and psychological factors contribute to increased risk of depression linked to online experiences. To address this gap and extend the research in an innovative new direction, the primary objective of this project is to elucidate the social media characteristics (network features and positive/negative online experiences) and endocrine contexts in which online experiences have the largest impact on rejection sensitivity and depressive symptoms. We will focus on the perimenstrual window of the menstrual cycle as a vulnerable or “risky” context that contributes to disruptions in social reward neurophysiology, rejection sensitivity related to online experiences, and depressive symptoms in female adolescents. Two counterbalanced neurobehavioral testing sessions with EEG during perimenstrual E2 change and stable, mid-follicular E2 change will probe the cycle-related neurophysiological indices of social media- related reward responsiveness and how they relate to rejection sensitivity. Further, we will use data donation packages to code for online positive and negative experiences and conduct network analyses grounded in graph theory to characterize social media networks to determine the impact of network density (i.e., number of online connections), clustering, and communities (social groups), perceived and extracted online experiences on rejection sensitivity and depressive symptoms. This multimodal design will allow us to address the following specific aims: determine the extent to which rejection sensitivity is characterized by perceived social media experiences and neurophysiology of reward responsiveness, particularly during perimenstrual E2 change (Aim 1), and social media network characteristics (Aim 2), to determine how these measures may interact to predict depressive symptoms (Aim 3). Our central hypothesis is that greater rejection sensitivity will be associated with disrupted social reward responsiveness and greater perceived negative social media interactions, particularly during perimenstrual E2 change and in the context of high-density social media networks with fewer defined social groups. This research will help identify neurophysiological indices of social reward responsiveness and social media network characteristics that precipitate rejection sensitivity and susceptibility to depression.

NIMH - National Institute of Mental Health

ABSTRACT/PROJECT SUMMARY Anxiety is one of the most common and debilitating comorbidities with ADHD, affecting 57% of youth and 84% of adults, with particularly high rates in girls and women. Despite its widespread prevalence, this co-occurrence is often overlooked and poorly understood, contributing to worse mental health outcomes and greater economic costs than either condition alone. Social processes (i.e., social cognitions and relationships) appear to contribute to the emergence of anxiety in youth with ADHD, but extant work has most often relied on mother-reports in community samples, lacking a multi-informant perspective and consideration of how ADHD and anxiety co-occur across development or in clinical populations. These gaps hinder our ability to provide effective, timely interventions, leaving those at highest risk—especially girls and women—without the necessary support. There is also a notable lack of research on girls and women with ADHD and potential sex differences, despite growing identification of ADHD in girls and women, many of whom are identified with anxiety prior to diagnosis of ADHD. Aligned with Goal 2 of the NIH Strategic Plan (Examine Mental Illness Trajectories Across the Lifespan), this project will address these gaps using three existing datasets with large samples of girls and women. Aim 1 will use ongoing clinical cohort data from a specialized lifespan ADHD clinic to identify developmentally relevant social processes in the co-occurrence of ADHD and anxiety in children and adults, utilizing one of the most well- characterized and ecologically valid samples of girls and women with ADHD to date. Aim 2 will use data from two completed studies and one ongoing study to examine electroencephalography (EEG) measures of social processing as markers of ADHD and anxiety, as well as sex differences, in adolescents—a critical period for anxiety onset and heightened social sensitivity, particularly in girls. Findings will provide developmentally and sex-specific insights into altered social processing as a mechanism for co-occurring ADHD and anxiety, along with neural biomarkers during a critical risk period. With mentorship from experts in lifespan ADHD and sex differences (Babinski), EEG methods for assessing anxiety risk (Pérez-Edgar), measurement-based ADHD care in clinical settings (Waschbusch), and translational analytics/bioinformatics in clinical data (Tuan), this project is designed with an integrated training plan to provide the applicant with real-world clinical research experience, focusing on advanced data analytics to how altered social processing contributes to co-occurring ADHD and anxiety across the lifespan, alongside innovative EEG methods to identify neural markers of these processes. The exceptional mentorship team, coupled with the resources and infrastructure at Penn State College of Medicine, offers the optimal environment to support the applicant’s training goals, foster professional development, and promote growth as an independent ADHD researcher focused on identifying developmentally and sex-specific comorbidity risks in ecologically valid populations across development.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The social environment can be a source of stress. Social stress is normal, but when persistent, it causes oxidative stress in the brain, which contributes to a variety of mental health and neurodegenerative diseases. Mitochondria could mediate the link between the social environment and oxidative stress as they are a major source of reactive oxygen species (ROS) and play a role in stress adaptation. Previous research has focused on chronic social defeat stress and resulting elevation in glucocorticoid levels, which causes oxidative stress in specific brain regions. Androgens modulate many metabolic responses, yet despite their responsiveness to social stressors and relevance to many age-related diseases, the role of androgenic signaling in regulating oxidative challenges in a social context is understudied. My goal is to study how androgens and social stress influence the regulation of oxidative stress in the brain by leveraging the highly social cichlid fish Astatotilapia burtoni, a well-established model system for neurogenomics and integrated animal behavior. Male A. burtoni exist as two reversible phenotypes: dominant and subordinate. Dominant males aggressively defend a territory, have high androgen levels, large gonads, and mate with females, while subordinate males are nonterritorial and reproductively suppressed. Territorial defense is physically and cognitively demanding for dominant individuals, while subordinate males experience social suppression and intimidation from higher ranking individuals. Females engage in aggressive competition for shelter and form distinct dominance hierarchies when housed in all-female groups, allowing us to study the effect of distinct social stressors in high- and low-ranking individuals of both sexes. The overarching goal of this five-year proposal is to assess how competition-induced social stress combined with androgen receptor signaling influences the regulation of oxidative balance in the brain. In Research Direction 1, we will define the effect of social stress and androgen receptor signaling on oxidative stress and mitochondrial function across different parts of the brain. To this end, we will integrate social manipulations with androgen receptor pharmacology to study how distinct social and metabolic stressors across the dominance hierarchy influence the regulation of oxidative stress in the brain. In Research Direction 2, we will determine how social experience and androgen receptor signaling influence protection against an acute oxidative insult to the brain using a validated hypoxia-reoxygenation paradigm. Our integrative approach provides an opportunity to discover unanticipated cytoprotective mechanisms in the brain against both chronic and acute stressors. The proposed activities will allow me to develop a research program aimed at dissecting variable strategies used to cope with stressful experiences to maintain organismal homeostasis. My research program may lead to novel insights into intervention strategies or therapeutic targets that reduce oxidative stress and improve effective recovery from oxidative challenges.

NIDCR - National Institute of Dental and Craniofacial Research

Project Summary/Abstract Psychological stress is an established contributor to bone and tooth loss and impaired bone growth. In the US, more than 50 million people currently experience bone loss while a similar number is afflicted by anxiety (40 million) and/or depressive disorders (16 million). Bone and tooth loss resulting from psychological stress has been observed in all age populations. A murine model of stress, repeated social defeat (RSD), recapitulates key physiological, immunological, and behavioral alterations in humans exposed to psychosocial stress such as bullying and loss of social status. RSD activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system to create a state in which primed, pro-inflammatory monocytes traffic from the bone marrow to the brain to generate neuroinflammation and anxiety-like behavior. In addition, RSD rapidly induces bone loss through increased activity of osteoclasts, and bone growth plate reduction. However, the precise mechanisms by which RSD influences bone have not been identified. Therefore, the overall goal of this project is to exploit a rodent model of psychological stress to better explore the relationships between immunological processes, mental and bone health. This will be accomplished in three Specific Aims. Aim 1 will examine the kinetics of bone loss and growth plate reduction in adolescent male and female mice following a period of RSD. Aim 2 will investigate a central role for osteoclast activation and chemokine (CXCL12) signaling in RSD-induced monocyte mobilization. Aim 3 will investigate mechanisms of RSD-induced growth plate reduction. Outcomes of this project will help achieve the long-term goal of developing more specific interventions to treat psychological stress-related disorders of skeletal physiology.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT This NIH K08 proposal describes a four-year career development training program in autism spectrum disorder (ASD) genomics research. With this research program, Dr. Mo will develop expertise in human genetics, analysis of next-generation sequencing data, and interpretation of somatic variants in non-neoplastic tissue. These skills complement Dr. Mo’s prior research and clinical training and ideally position her to transition to an independent investigator position studying somatic mutations in ASD. Dr. Mo’s mentor for this proposal is Dr. Christopher A. Walsh, a Professor of Neurology at Harvard Medical School, an HHMI Investigator at Boston Children’s Hospital, and a leader in the genetics of human neurological diseases. With over 25 years of mentorship experience, Dr. Walsh has an established track record of mentoring trainees to successful academic careers in biomedical research. Dr. Mo will be supported by a scientific advisory team and collaborators with complementary expertise in autism genetics, computational genomics, genotype-phenotype correlations of somatic mutations, and career mentorship. The institutional resources available at Boston Children’s Hospital, which is affiliated with Harvard Medical School, are world- class and provide an ideal environment to foster the development of a physician-scientist career. The primary scientific objective of the proposed research plan is to study the role of somatic (post- zygotic) variants in ASD. Dr. Mo’s central hypothesis is that somatic variants contribute to ASD risk. Dr. Mo provides pilot data indicating that somatic single nucleotide variants (sSNVs) are increased in gene exons in ASD probands compared to controls, particularly in highly constrained genes with loss-of-function intolerance. Furthermore, Dr. Mo shows that sSNVs in non-coding gene regulatory regions can be efficiently detected using ATAC-seq, which allows the detection of non-coding sSNVs in larger sample sizes than previously possible using whole genome sequencing. To achieve the research objective, a combination of whole exome sequencing, ATAC-seq, whole genome sequencing, amplicon sequencing, and computational analysis will be used. These strategies will systemically examine two independent, but related, aims: (1) the burden of sSNVs in functionally-relevant genes in ASD compared to neurotypical individuals; and (2) the distribution of sSNVs in non-coding gene regulatory regions in postmortem human brain neurons from ASD and neurotypical individuals. Findings from this study may improve our understanding of the genetic architecture and mechanisms of ASD as well as the genetic diagnosis of ASD in clinical practice.

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

PROJECT SUMMARY Multiple sclerosis (MS) is a chronic and debilitating disease of the nervous system that has widespread effects, impacting physical and mental function. Among the most common symptoms experienced by people with MS (PwMS) are balance dysfunction and fatigue, rated as having the most profound negative impacts on quality of life. Although evidence suggests that fatigue and balance dysfunction are related, the specific mechanism that determines this relationship among PwMS is not known. However, evidence supports somatosensory impairment as a major contributor to balance dysfunction and fatigue among PwMS; we hypothesize that somatosensory impairments mediate increased attentional and physical demands that drive cognitive and physical fatigue, thereby increasing MS-related fatigue. The somatosensory system is vital to postural coordination because it is the most sensitive sensory modality to postural instability; thus, degraded or delayed somatosensory feedback leads to greater postural instability that must be counteracted by the neuromuscular system to maintain balance. We hypothesize that this requires increased motor output to prevent balance loss, increasing the physical load and consequently physical fatigue. Although somatosensory feedback is degraded among PwMS, we believe that compensatory mechanisms attempt to mitigate these effects; these include compensation by other sensory modalities (primarily vision), referred to as sensory reweighting, and greater attentional resources to maintain balance. We hypothesize that these compensations require additional cognitive resources that lead to increased cognitive fatigue. To test these hypotheses, we will systematically assess balance tasks that will increase the physical load, cognitive load and available sensory feedback to directly evaluate somatosensory impairment as a mediator of physical and cognitive fatigue, and balance dysfunction in PwMS. This study will leverage advances in wearable motion-tracking technologies to quantify postural sway dynamics, and portable functional near infrared spectroscopy to quantify changes in cortical blood flow indicative of changes in cortical activation. Thus, we will assess changes in the motor cortex related to physical load, the dorsolateral prefrontal cortex (which directs attentional resources to balance control) related to cognitive load, and the visual cortex to evaluate sensory reweighting. These measures, paired with subjective and objective assessment of fatigue, will provide new mechanistic insight into the role of somatosensory impairment in modulating balance dysfunction and fatigue. The expected outcomes of this research include: a new target for early therapeutic intervention that could mitigate MS-related fatigue and balance dysfunction, and improve quality of life among those with MS; and determination of potential differential impacts of somatosensory loss on balance and fatigue among nonprogressive and progressive MS subtypes—knowledge that could aid in identifying and tracking progression among those with MS.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Fragile X syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). It is caused by a CGG trinucleotide repeat expansion in the 5’-UTR of the FMR1 gene, leading to the loss of fragile X messenger ribonucleoprotein (FMRP), a key RNA-binding protein that regulates transcription, translation, and mRNA localization. The absence of FMRP results in profound translational dysregulation, impairing synaptic plasticity and disrupting neuronal circuits. While FMRP primarily functions as a translational repressor, its precise spatial and activity-dependent regulation in the brain remains poorly understood due to limitations of bulk and conventional transcriptomic methods. To address this critical gap, we will employ advanced spatial genomics technologies to construct the first high-resolution, single-cell map of translational regulation in the FXS mouse brain. In Aim 1, we will generate spatial transcriptomics and translatomics maps of FXS and control mouse brains using STARmap-PLUS and RIBOmap. These datasets will allow us to quantify the abundance and translation of FMRP-target mRNAs, non-targets, cell-type markers, and regional markers, revealing how loss of FMRP alters mRNA localization and translation at brain-region- and cell- type-specific levels. In Aim 2, we will investigate how synaptic activity modulates spatial mRNA translation by inducing activity-dependent long-term depression (LTD) in brain slices using a well-established protocol. This approach will provide the first direct link between synaptic stimulation and localized mRNA translation dynamics in FXS, offering novel insights into how synaptic dysfunction contributes to disease pathology. This study represents a significant technical and conceptual advance in FXS research, offering an unprecedented spatially resolved view of FMRP-mediated regulation at single-cell and subcellular levels. By uncovering activity- dependent translational dysregulation in FXS, our findings will generate critical mechanistic insights and inform novel therapeutic strategies targeting dysregulated local translation in neurodevelopmental disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The release of neurotransmitters at synapses occurs in three distinct modes: synchronous release, which is tightly coupled to an action potential (AP); asynchronous release, which lingers for hundreds of milliseconds after an AP; and spontaneous release, which happens independently of an AP. While our labs and others have begun uncovering the molecular machinery behind asynchronous release, major gaps remain – especially at the quantal level. This is largely because most of what we know about neurotransmitter release comes from electrophysiological studies, which lack direct spatial resolution. To address this problem, I will leverage the power of iGluSnFR3, a third-generation intensity-based Glutamate-Sensing Fluorescent Reporter, to directly visualize asynchronous release at the single-synapse level and dissect its molecular and physiological drivers. Aim 1 will determine if distinct molecular drivers of asynchronous release generate unique quantal and spatial phenotypes at the single synapse. First, I will further optimize iGluSnFR3 for reliable detection of quantal neurotransmitter release (subaim 1.1). My preliminary data demonstrates that iGluSnFR3 can detect quantal neurotransmission with single-synapse resolution. Subaim 1.2 will investigate how different extrinsic and physiological conditions can uniquely desynchronize neurotransmitter release. Although these conditions are often used interchangeably in the literature and assumed to have the same effect on facilitating asynchronous release, it remains unclear whether they influence release kinetics at the single-synapse level in the same way. My preliminary data shows that while these conditions increase the cumulative charge transfer of asynchronous release measured by electrophysiology, iGluSnFR3 imaging reveals striking differences at the single-synapse level. Finally, subaim 1.3 will investigate whether this desynchronization is organized within separate sub- domains of the same active zone. Aim 2 will test whether synaptotagmin-7 mediated asynchronous release regulates postsynaptic signaling (subaim 2.1) and plasticity thresholds (subaim 2.2). My preliminary data indicates that synaptotagmin-7 not only drives increased multivesicular release but also elevates postsynaptic calcium levels, leading to the activation of downstream target proteins. The overall hypothesis of my proposal is that asynchronous neurotransmission constitutes a distinct signaling pathway, separate from other modes of release, with unique regulatory mechanisms and functional consequences. Therefore, the completion of this project will further our understanding of the molecular mechanisms shaping neurotransmission and synaptic communication. Additionally, this F31 proposal, supported by a highly individualized mentoring plan and team, will help prepare me for my next career stage as I apply to psychiatry research-track residency programs, and, ultimately, to become an independently funded physician-scientist.

Administration for Children and Families - OFVPS

The purpose of the Specialized Services for Abused Parents and Their Children is to expand the capacity of family violence, domestic violence, and dating violence service programs and community-based programs to prevent future domestic violence. This is done by addressing the needs of children who have been exposed to family violence, domestic violence, or dating violence in an appropriate manner. Required activities include providing direct counseling; providing developmentally and age-appropriate services to victims and their children; providing advocacy on behalf of victims and their children; and supporting non-abusing parents in their roles as caregivers and in meeting social, emotional, and developmental needs of their children. Where appropriate, services may also work with a non-abusing parent and child together.Optional activities include providing early childhood development and mental health services; coordinating with and providing technical assistance to community-based organizations that serve victims or exposed children and providing additional services and referrals to services for children. These may include childcare, transportation, educational support, respite care, supervised visitation, or other necessary services.

Veterans Affairs Department

VA is announcing the availability of funds for suicide prevention grants under the Staff Sergeant Fox Suicide Prevention Grant Program (SSG Fox SPGP). The SSG Fox SPGP directs efforts to reduce Veteran suicide by awarding grants to community-based organizations to provide or coordinate the provision of primarily non-clinical suicide prevention services, including outreach and linkage to VA and community resources, to eligible individuals and their families. The SSG Fox SPGP furthers VA's public health approach to suicide prevention by combining community-based efforts with linkage to clinical care to prevent Veteran suicide for those inside and outside of VA health care. The goal of these grants is to reduce Veteran suicide risk by improving mental health status, well-being, financial stability, and social support for eligible individuals and their families.

NCCIH - National Center for Complementary and Integrative Health

Major Depressive Disorder (MDD) is a common mental health disorder that affects 8% of US adults, including more than 18% of young adults between the ages of 18 and 29. Decades of research indicate that music-based treatments are broadly effective against depression, but their impact remains tightly restricted by a shortage of trained practitioners and a lack of readily deployed standard protocols. Our overall objective here is to develop and test the feasibility of a new “Standardized Tunable Music Medicine for Depression” as one such protocol. STAMM-D integrates progress across music therapy, neuroscience, and technology within a compact, personalized, mobile health (mHealth) treatment protocol designed to leverage music’s core effects on emotion and reward against MDD’s core symptoms of low mood and anhedonia. Our hypothesis is that we can feasibly develop STAMM-D as an engaging mHealth intervention that will be attractive to a large proportion of young adults with MDD diagnoses (e.g., 75%), a disproportionately affected demographic that also exhibits peak engagement with music, listening for an average of four hours per day. Aim 1 is to develop STAMM-D around three specific innovations, each designed to address a key design principle derived from literature review. These innovations are: (1) “iso music” for mood elevation, adapted from industry wellness applications to MDD treatment; (2) a protocol for creating therapeutically-appropriate individually-tuned music playlists on the basis of a combination of patient-facing music preference interviews and modern music recommendation algorithms; and (3) easy-to-use digital “musical agency” controls that give listeners the power to modulate key musical features (e.g., tempo and spectrum), encouraging behavioral engagement towards affective synchronization. Aim 2 is to deploy STAMM-D alongside a therapeutically credible control condition (Relaxation Music; RM) in a small-scale feasibility trial (N=68) aimed at evaluating recruitment rates, retention rates, treatment fidelity, and acceptability, ahead of a follow-on efficacy trial. Feasibility trial protocol details (dosage, duration, outcomes, etc.) are thus designed to closely match those required to test STAMM-D’s capacity to effectively treat MDD in an appropriately powered and rigorously controlled future trial. Finally, trial operations are designed to generate as much data towards STAMM-D refinement as possible, deriving extensive quantitative and qualitative feedback directly from young adults with MDD (i.e., stakeholders). The significance of this work lies in developing and establishing STAMM-D as a first-in-kind musical treatment with the capacity to radically expand access to music-based treatment for depression. More broadly, we expect this work to outline a template for developing other standardized musical treatments at the intersection of music therapy, neuroscience, and technology—e.g., targeting anxiety and insomnia—thus making an important practical contribution to ongoing efforts to expand the role for music in medicine. Key Personnel include one interdisciplinary neuroscientist (PhD), one music therapist (MT-BC), an academic psychiatrist (MD), two clinical psychiatrists (MDs), and one biostatistician (PhD).

NIMH - National Institute of Mental Health

The absence of a clear understanding of mechanisms that drive the symptoms of schizophrenia represents a critical need, hindering our ability to develop effective interventions for this debilitating condition. Bayesian predictive learning offers a formal computational perspective on how the brain processes and integrates incoming sensory information to form higher-level beliefs about the world. Abnormal predictive learning has emerged as a key candidate mechanism to explain core features of schizophrenia, including auditory hallucinations and impaired cognition. Notably, abnormalities occurring at different levels of the predictive learning hierarchy (i.e., low-level sensory perception vs. high-level beliefs about the state of the world) may differ in terms of their stability and their relationships to specific illness features (e.g., auditory hallucinations, impaired cognition). Building upon promising preliminary data and in alignment with the NIMH Strategic Plan, we will use an innovative electroencephalography (EEG) paradigm to characterize specific neural abnormalities associated with aberrant predictive learning in schizophrenia and relationships with specific illness features over time. Ninety adults with schizophrenia, 60 of whom experience active auditory hallucinations at the baseline assessment, will complete an EEG assessment of auditory predictive learning three times over a six-month follow-up period. Thirty non-psychiatric comparison participants will be assessed at baseline only. Stability of the EEG predictive learning indices and associations with auditory hallucinations will be assessed over the follow-up period. Leveraging the specialized scientific expertise and the extraordinary clinical research and participant recruitment infrastructure available at the University of Manitoba and the strong domestic scientific leadership and Veteran representation available at the Minneapolis VA, we anticipate that the project will contribute to the health of the American public by identifying key biological markers and clarifying our understanding of the pathophysiology of this debilitating mental health condition in order to support the development of new treatments.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Proper cerebellar function is important for many aspects of mental health, as evidenced by the wide range of neurological and neuropsychiatric disorders that have been associated with impaired neural processing in the cerebellum, from ataxia and dystonia to schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). To understand how the cerebellum contributes to both motor control and cognitive functions it is necessary to define what kind of inputs it receives, particularly via the massive mossy fiber system, which carries the bulk of all sensory, motor and cognitive signals sent to the cerebellum from the rest of the brain. Furthermore, variations in brain state are likely to alter the information content of mossy fiber inputs and have a major impact on how well and reliably the cerebellum can perform its function. Unfortunately, conventional extracellular recording methods do not offer enough stability and often fail to distinguish signals of mossy fibers from other cell types in the cerebellar cortex. As a result, there is very limited knowledge about mossy fiber activity in cerebellar tasks, and no information at all about state-dependent modulation of mossy fiber responses or which mossy fiber states may be associated with enhanced cerebellar function. The experiments in this application take advantage of Neuropixels probes and a recent semi-supervised deep learning algorithm to overcome previous technical limitations and record for the first time from identified mossy fiber populations while mice perform a cerebellar-dependent eyeblink conditioning task. The analysis of mossy fiber activity, both before and during conditioning trials, is meant to achieve the following goals: (1) to provide new biological insight into the moment-to-moment variability of mossy fiber states, (2) to help define which mossy fiber states are associated with ‘faulty’ vs ‘reliable’ cerebellar function and, (3) to reveal how locomotion and non-invasive stimulation of the prefrontal cortex can be used to steer mossy fibers toward favorable states that are linked to improved performance of cerebellar-driven motor responses. Thus, the findings will have important implications for enhancing cerebellar function, both in health and disease, by developing new therapeutic interventions that can be used to promote beneficial mossy fiber states. Given the well-established role of the cerebellum in the control of movement, it is expected that the findings will impact patients with motor problems most directly. However, cerebellar dysfunction has also been associated with impairments in executive function, abstract reasoning, working memory, high-level language processing and attentional control. To the extent that the neural signature of ‘faulty’ and ‘reliable’ mossy fiber states is similar in regions of the cerebellum involved in these cognitive functions, the aims of this application and the implications for future treatments may apply to them as well.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Non-suicidal self-injury (NSSI) is a prevalent and potentially devastating behavior that associates with severe psychopathology and suicide. Unfortunately, there are critical gaps in our understanding of variability in NSSI urges and behaviors over time. These scientific gaps limit our ability to develop more responsive, innovative, and effective interventions based upon temporally specific knowledge of brain-behavior relations. The proposed study will help disentangle static and dynamic fluctuations associated with longitudinal variabilityin NSSI. Ultimately, this could yield novel insights into NSSI-related biobehavioral mechanisms, which could be targeted clinically. With this proposed training grant, each scientific aim is structured to support the candidate’s development as an independent investigator with expertise in ecological momentary assessment (EMA; behavioral) and neuroimaging (biological) correlates of NSSI behaviors across time. This includes the use of a longitudinal design, allowing the candidate to build skills to understand dynamic change in NSSI as they relate to stable and changing risks for NSSI behaviors and the neural systems foundational to these risks. Specifically, she will determine whether proximal NSSI frequency and urges measured through EMA will covary with resting-state functional connectivity between the amygdala and regions associated with motor planning over time (Aim 1) and whether brain activation during rumination induction, which involves repetitive negative thinking, remains independent of NSSI changes (Aim 2). This will build her skills to successfully execute longitudinal studies in the future [Training Aim 1 (TA1)]. She will also acquire experience in collecting and analyzing data using EMA (TA2), and integrating EMA with neuroimaging data (TA3). The increasing rates of self-injurious thoughts and behaviors, including NSSI, among youths makes this research critically important. The Nationwide Children’s Hospital in Columbus, OH is home to the Center for Suicide Prevention Research, which includes phenomenal resources and some of the world’s leading experts on youth self-injurious thoughts and behavior, making NCH an exceptional setting for this project. The proposed project will collect clinical, EMA, and MRI data from 50 adolescents ages 14-17 with NSSI. Participants will complete 5 epochs of EMA spaced two months apart (T1-T5), with three of these timepoints also including clinical and MRI data spaced four months apart (T1, T3, and T5). By collecting data at five timepoints, the candidate will be able to leverage naturalistic environmental changes that potentiate NSSI, as measured by EMA, and identify specific neurobiological features that are associated with propensity for NSSI. This project provides the candidate with the opportunity to acquire critical skills that will greatly benefit the field of NSSI while collecting an extraordinarily rich dataset that will support a highly competitive R01 for the candidate.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Identifying individuals likely to respond to a specific intervention is a critical challenge in medical research. In the age of big data, where vast amounts of information are accessible, the potential for personalized interventions based on individual characteristics has become increasingly feasible. However, advancement comes with significant challenges. The sheer volume of data often leads to datasets with numerous factors which might influence outcomes. Moreover, the data may exhibit clustering or repeated measurements, with potentially informative cluster sizes, adding complexity to the analysis. For instance, researchers are interested in understanding why some pregnancies are more vulnerable to maternal immune activation (MIA), which impacts brain and behavioral development in offspring and increases the risk of autism, schizophrenia and other neurodevelopmental disorders. However, this task is complex due to the multitude of biomarkers and clustered or repeatedly measured outcomes over time and brain regions. Current statistical tools available are inadequate for handling the complexities of such data, thus impeding the progress of precision medicine. To address this significant gap, this proposal underscores the urgent need for innovative statistical methodologies that can adeptly handle the complexity of clustered and longitudinal datasets with numerous covariates, thereby advancing the field of precision medicine. By developing novel methods building on our preliminary statistical framework, integrating machine learning techniques, rigorously evaluating these methods through simulation studies that mimic real data, and applying these methodologies to real-world longitudinal and clustered datasets, we aim to make significant contributions to this field. Our preliminary simulation results and real-world examples demonstrate both the scientific merit and computational feasibility of these methods. We will apply these newly developed statistical tools to existing datasets as a proof-of-concept to uncover factors that predict susceptibility and resilience to MIA regarding the brain and behavior development outcomes in offspring. The innovative statistical methods developed hold significant promise for identifying biomarkers that elucidate the link between environmental exposure during human pregnancy and brain mechanisms associated with neurodevelopmental disorders. This advancement will assist in identifying high- risk pregnancies and tailoring interventions for offspring at risk due to MIA exposure. Furthermore, these innovative statistical approaches can be adapted to various interventions and a wide range of medical conditions. We will provide free, user-friendly programs and software to enable research communities to apply these methods easily. Consequently, this project presents a unique opportunity to tackle a complex issue in precision medicine and leverage existing datasets for groundbreaking insights.

NIA - National Institute on Aging

Abstract Over half of people living with HIV in the U.S. are now 50 or older, and this number is projected to increase to 70% by 2030. Aging with HIV presents a unique array of physical and mental health challenges. High prevalence of cardiovascular risk factors (e.g., obesity, dyslipidemia, hypertriglyceridemia, vascular dysfunction) and worsened mental health increase vulnerability to cardiovascular disease (CVD), depression and anxiety. Therefore, innovative, evidence-based interventions are needed to address the realities of aging with HIV and offer timely, practical solutions for improving physical, mental, and HIV-related outcomes. In the proposed study, 180 older adults with HIV age 50+ with documented cardiovascular risk will be randomized to either: (a) the Happy Older People are Engaged (HOPE) health promotion intervention (n=90) or (b) psychoeducation control (n=90). Assessment of cardiovascular risk, mental health, and HIV-related outcomes will be obtained at baseline, post intervention, 6-, and 12-months post intervention. The study has three specific aims: (1) to compare the efficacy of HOPE and the psychoeducation control in reducing cardiovascular risk among older adults with HIV with documented risk of cardiovascular disease; (2) to compare the efficacy of HOPE and the psychoeducation control in improving mental health and HIV-related outcomes in older adults with HIV; and (3) to examine mediators whereby HOPE reduces cardiovascular risk and improves mental health and HIV-related outcomes. Aims 1 and 2 will be tested separately using a Generalized Linear Mixed Model for main effects of group, time, and time-by-treatment interaction as the primary analytic strategy. For Aim 3, SEM will be applied to test mediation. As an exploratory aim, our team will explore CHW and decisionmaker perspectives on potential operational barriers and facilitators to the future implementation and dissemination of HOPE. Such data will yield useful information regarding future implementation of HOPE and related health promotion interventions. The proposed study will increase our understanding of the impact of HIV on older adults and has the potential to improve approaches for managing HIV-related comorbidities.

National Institutes of Health

Purpose. The purpose of this program announcement is to encourage applications that evaluate the efficacy of stress management interventions on intermediate outcomes purported to be in the biological or behavioral mechanistic pathway through which mental stress (MS) is thought to influence major adverse cardiac events (MACE) in patients with confirmed coronary artery disease (CAD). These include subclinical measures of atherosclerosis, measures of cardiac or endothelial function, or measures such as cardiovascular reactivity or neurohumoral response to a provocative mental stress test. The ultimate goal is to determine whether stress management interventions can slow progression of CAD or reduce MACE and, if so, to translate effective stress management interventions to clinical practice.

NIDA - National Institute on Drug Abuse

Homelessness and housing instability represent critical public health challenges in the US with more than 650,000 people experiencing homelessness (PEH) nightly. PEH experience differential health effects across various conditions, including chronic disease, substance use, and HIV, compared to their housed counterparts. An astounding 65% of PEH report having used illicit drugs regularly in their lifetime with 37% reporting regular drug use in previous 6 months. Homelessness and illicit substance use, in isolation and in combination, continue to be significant drivers of poor HIV outcomes and are highlighted as key priority targets under the Ending the HIV Epidemic (EHE) Initiative. EHE has identified evidence-based interventions, including rapid HIV testing, antiretroviral therapy (ART), low barrier clinics, and PrEP that need to be implemented, scaled, and sustained within communities most affected by HIV. To maximize the effectiveness of these interventions among PEH who use drugs and to address the HIV, overdose and homelessness syndemic, comprehensive healthcare models need to be developed, tested, and deployed where they are in comfortable environments that simultaneously address a key driver of HIV, namely untreated substance use disorders (SUD). The HIV Medicine Association has called for the scale-up of street medicine (delivering health services directly to unsheltered individuals where they are), counseling and differentiated service delivery to end the HIV epidemic. We developed, refined, and pilot tested Status Neutral Tele-Health ConcieRge (SN-THR), a telehealth-based, multicomponent care model originally designed for people with who inject drugs (PWID) with HIV then adapted it to include PWID without HIV for prevention via PrEP and MOUD. We hypothesize that SN-THR will increase access to HIV care (testing, prevention, treatment), SUD services, and mental health services through telehealth to augment street-based primary care (i.e. street medicine). We propose to test the efficacy, cost-effectiveness, and implementation of an innovative integrated HIV, addiction, and primary care model—SN-THR—in a street-based setting using a hybrid type I effectiveness-implementation approach. The specific aims are 1) Evaluate the efficacy of SN-THR vs. standard of care (patient navigation to off-site clinic) on HIV treatment and prevention adherence; 2) Perform an economic evaluation of SN-THR and estimate the cost-effectiveness of SN-THR; and 3) Assess the drivers of SN-THR implementation and their impact on implementation outcomes. We hypothesize that more participants in the SN-THR intervention condition will be adherent to ART for treatment or prevention than those in the control condition across 12-month follow-up This application is directly responsive to the priorities of NIDA’s RFA-DA-25-072 by testing a novel telehealth-based, status-neutral care model for integrating HIV and SUD services into street-based primary care for PEH who use drugs.

NIMH - National Institute of Mental Health

ABSTRACT Serotonin Type 3 Receptors (5-HT3Rs) are a subfamily of cationic pentameric ligand-gated ion channels (pLGICs) that play a critical role in gut-brain signaling. 5-HT3R pathophysiology is associated with neuropsychiatric conditions, including major depressive disorder (MDD). Previous studies have shown that antagonism of the 5-HT3R family has been implicated in the role of current antidepressant therapies such as mirtazapine (MTZ). The 5-HT3R family has five types of subunits (A-E), which influence the molecular binding and activation properties of the receptor. 5-HT3ABR is the only receptor subtype demonstrating tissue-specific expression within the brain. Animal studies have shown that the inhibition of the 5-HT3ABR has beneficial effects on mood and anxiety disorders. Despite the role that 5-HT3Rs play in MDD, there is little structural information on 5-HT3ABR and how antidepressants modulate 5-HT3Rs. As a result, 5-HT3Rs present an appealing target for novel antidepressant drug development. The overall goal of this study is to characterize the mechanistic details through which antidepressants modulate 5-HT3R activation across different subtypes. The proposal has two aims designed to address this deficit. Aim 1 will focus on determining the molecular mechanism by which MTZ inhibits 5-HT3AR. Utilizing a full-length m5-HT3AR construct, high-resolution MTZ-bound cryogenic electron microscopy (cryo-EM) structures will be determined with and without 5-HT. Based on this structural insight, site-directed mutagenesis and two-electrode voltage clamp (TEVC) electrophysiology will be used to assess the interactions necessary for MTZ binding. Residues involved in 5-HT binding are not present within the 5-HT3B subunit; therefore, aim 2 seeks to determine the key interactions required for MTZ and 5-HT binding. Aim 2 will address this by determining high-resolution cryo-EM structures of apo-5-HT3ABR and MTZ-bound 5-HT3ABR in the presence of 5-HT. Electrophysiology will be used to probe the role of each key amino acid and will be assessed for its effect on 5-HT3ABR activation. The results of this work will elucidate key interactions required for MTZ binding and highlight how antidepressants modulate different 5-HT3R subtypes. Overall, these studies will provide a deeper understanding of the role of 5-HT3R in the treatment of MDD. Finally, this work will lay the foundation for future drug development targeting 5-HT3Rs.

NINR - National Institute of Nursing Research

Project Summary In the United States, women are twice as likely to report depression and anxiety than men, and face stressors related to interlocking systems of oppression such as racism, sexism, and xenophobia. Interlocking systems of oppression can exacerbate inequalities in mental health by manifesting an unequal distribution of women’s resources and result in symptoms of depression and anxiety like exhaustion, hopelessness, and loss of interest. Despite the growing recognition of the mental health impacts of systems of oppression, several studies have analyzed this relationship at the individual-level, and not the structural or policy-level. Political intersectionality focuses on how policies and laws enact unfair practices against intersectional groups and subdue their rights. Policies related to structural gendered racism may shape the inequitable allocation of women’s social, economic, and political resources across racial, ethnic, and nativity groups, which may put racially and ethnically minoritized women at risk for depression and anxiety. The objective of this R01 grant proposal is to use novel theoretical frameworks and methodologies to examine how structural gendered racism-related policies impact depression and anxiety through intersectional social-structural factors among US- and foreign-born Black, Latina, and white women. This proposal will also aim to identify the best strategies to enhance adoption of supportive policies, and de-implement harmful policies that perpetuate systemic inequities. Informed by Intersectionality, Constrained Choice theory, and a policy implementation science, we propose a sequential explanatory mixed methods study with US- and foreign-born Black, Latina, and white women, and policy stakeholders. Aim 1 examines the direct and indirect relationships between structural gendered racism-related policies, intersectional social-structural factors, depression and anxiety among US- and foreign-born Black, Latina, and white women. Population-based data of adult women’s depression and anxiety from the National Health Interview Survey will be linked to state structural gendered racism-related policies, and an existing structural sexism and racism index of state social, economic, and political data from publicly available administrative sources. Aim 2 includes conducting focus groups with US- and foreign-born Black, Latina, and white women to explicate quantitative findings and identifying unanticipated themes. Aim 3 includes integrating findings from Aims 1 and 2 to systematically develop policy implementation strategies using a three-round Delphi method approach with US- and foreign-born Black, Latina, and white women, and policy stakeholders. This proposal responds to RFA-NR-25-004 by analyzing “relevant policies that reinforce intersectional social-structural factors and identify social-structural interventions to improve mental health.”

NIMH - National Institute of Mental Health

The overarching goal of this collaborative program is to understand how circuits in the mammalian brain are reorganized to encode new memories. We address this problem through detailed reconstruction of neuronal connectomes, single synapses, and glia at nanometer resolution using 3D Electron Microscopy (3D-EM). We combine 3D-EM with chemogenetic techniques for labeling cellular ensembles recruited for specific cognitive tasks and Artificial Intelligence (AI)-based computational tools for image segmentation. Using this interdisciplinary approach, we began to identify the morphological hallmarks of long-term associative memory in the mouse hippocampus. Our recent studies of the canonical CA3-CA1 pathway revealed principles by which pyramidal glutamatergic neurons (PNs) engaged during fear learning modify their local wiring diagrams, synaptic weights, and membrane organelles essential for energy metabolism and intracellular calcium buffering. Despite their broad physiological implications, these structural correlates of information storage share three features: (1) Their induction requires presynaptic activity elicited by sensory stimuli with negative valence; (2) Their manifestation transcends co-activated neurons; and (3) They involve multi-synaptic boutons (MSBs), atypical connections capable of simultaneously relaying neurotransmitter signals from one axonal terminal to several independent dendritic spines. Contrary to common dogma, we found that the initial cellular substrates of memory traces expand their connectivity via MSBs, thereby recruiting new neurons into the network while preserving the stable arrangements of individual synaptic sites on axons and dendrites. Taken together, these observations support the hypothesis that MSBs are pivotal for memory storage and that the structural plasticity of neural ensembles representing engrams does not adhere to traditional Hebbian rules. Our studies provide the first mechanistic explanation for representational drifts, a non-Hebbian phenomenon suggesting that population coding of a particular experience is not fixed over time. We will test out central hypotheses in the following specific aims: Aim 1. Investigate the spatiotemporal dynamics of non-Hebbian network remodeling via MSBs. We will determine if the synaptic architectures of an associative memory engram are reconfigured through MSBs globally or in a circuit-specific manner and will investigate the temporal dynamics of this process. Aim 2. Explore the physiological mechanisms of MSB morphogenesis. We will determine how the organization of MSBs reflects memory strength and will test if MSB morphogenesis is regulated by de novo protein synthesis, transcription, and synaptic activity. Aim 3. Define the composition of MSBs and their local microenvironment. We will comprehensively dissect the fine-scale architecture of MSBs and their postsynaptic partners. These analyses will involve reconstructions of active zones, PSDs, vesicles, other intracellular membrane organelles, astrocytes, and microglia.