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NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

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

Kaiser Permanente

One of the largest nonprofit health systems, investing $300M+ annually in community health programs addressing health equity, healthy eating, active living, and mental health.

National Institutes of Health

NIMH seeks applications for innovative research projects to test strategies to increase the reach, efficiency, effectiveness, and quality of digital mental health interventions. This NOFO is intended to support the development of digital health test beds that leverage well-established digital mental health platforms,to rapidly refine and optimize existing evidence-based digital health interventions and conduct clinical trials testing digital mental health interventions that are statistically powered to provide a definitive answer regarding the intervention's effectiveness.

National Institutes of Health

NIMH seeks applications for innovative research projects to test strategies to increase the reach, efficiency, effectiveness, and quality of digital mental health interventions. This NOFO is intended to support the development of digital health test beds that leverage well-established digital mental health platforms,to rapidly refine and optimize existing evidence-based digital health interventions and conduct clinical trials testing digital mental health interventions that are statistically powered to provide a definitive answer regarding the intervention's effectiveness.

NIMH - National Institute of Mental Health

Neural circuits are constructed by synapses that connect neurons into vast networks. Although many neural circuits have been characterized, the molecular mechanisms that construct their synaptic architecture remain largely unknown. Synapse formation in neural circuits is thought to be controlled by bi-directional signaling via trans-synaptic adhesion molecules. Strikingly, genetic changes in trans-synaptic adhesion molecules often predispose to neuropsychiatric disorders such as autism and schizophrenia, suggesting that dysfunction of the synaptic architecture of neural circuits contributes to neuropsychiatric disorders, although the nature of the dysfunction is poorly understood. We previously showed that in hippocampal circuits, postsynaptic latrophilins (Lphns) perform a central activity-dependent role in organizing synapses by forming large and diverse trans- synaptic complexes. Surprisingly, Lphn-based complexes include not only presynaptic neurexins, teneurins and FLRTs but also postsynaptic Unc5s, proteins that were previously only known as repulsive axon-guidance cues and not as synapse organizers. Moreover, our previous findings demonstrate that Lphns act as adhesion-GPCRs that organize synapses via two parallel pathways, local cAMP signaling and recruitment of postsynaptic scaffold proteins as phase-separated condensates. However, how Lphn complexes mediate synapse formation in an activity-dependent manner, what the role of Unc5s is in these complexes, and how significant the function of different Lphn-based complexes is for circuit assembly remains largely unknown. To address this knowledge gap, the present application proposes to test the following overall hypotheses in four Specific Aims. Aim 1 will test the hypothesis that Lphns organize synapses by engaging in large trans-synaptic protein complexes that include teneurins, FLRTs, neurexins and Unc5s and that can be reconstituted from purified proteins with associated pre- and postsynaptic specializations; Aim 2 will test the hypothesis that the components of Lphn- based complexes perform distinct essential functions in synapse formation; Aim 3 will test the hypothesis that postsynaptic Lphns and Unc5s utilize diverse signaling pathways to collaboratively organize synapse assembly; and Aim 4 will test the hypothesis that the differential expression and activity-dependent alternative splicing of Lphn-based complex components regulate synapse diversity and circuit plasticity, enabling circuit adaptations critical for learning and memory. Although the Aims of this application are independent of each other, they together form a logical sequence that will advance our understanding of synapse assembly and, given the close genetic association of the pre- and postsynaptic components of Lphn-based complexes with autism and schizophrenia, provide insight into the pathogenesis of neuropsychiatric disorders. In pursuit of these Aims, the application proposes to employ mice as a primary model system and to use an interdisciplinary methodology ranging from reductionist biochemical experiments in order to reconstitute synapses from purified proteins to synaptic function assays in cultured neurons and in vivo to analyses of neural circuits and behavior.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Innovative strategies are needed to address the unique challenges faced by women living with HIV (WLHIV) in West Africa. Among the 5.1 million people living with HIV (PLHIV) in West and Central Africa in 2023, 65% were adolescent girls and women. Among PLHIV in the region, 81% knew their HIV status, 76% were receiving antiretroviral therapy (ART), and 70% had suppressed viral loads. Addressing the social and structural barriers that disproportionally impact women is critical to achieving the 95-95-95 targets and ending the HIV epidemic. Our previous work in Senegal, West Africa has shown that the majority of WLHIV are food insecure and that food insecurity is associated with poor HIV outcomes, including loss to follow-up, poor adherence to ART, and virologic failure. The high prevalence of food insecurity among WLHIV in Senegal and its role as a driver of poor outcomes across the HIV care cascade, suggest that strategies to address food insecurity are essential to interrupting transmission, improving quality of life, and preventing mortality. The Casamance region, located in the south of Senegal, has been the most severely affected by the HIV epidemic and has the highest prevalence of food insecurity in the country. In collaboration with our longstanding partners at the NGO DIG (“Development in Gardening”), the Service des Maladies Infectieuses et Tropical-CHNU de Fann, and the Région Médicale de Ziguinchor, we recently conducted an NIH funded pilot study to evaluate the experience and impact of a multisectoral nutrition-sensitive agricultural intervention among WLHIV in the Casamance. The findings from our pilot study suggest that participation in the intervention is associated with improvements in food security, virologic suppression, and mental health. In the proposed study, we will leverage our longstanding partnerships in Senegal and build upon our findings to conduct a cluster randomized trial to evaluate the impact of a multisectoral nutrition-sensitive agricultural (MNSA) intervention on HIV outcomes among women in the Casamance region. The AIMS of this study are, AIM 1. Determine the impact of a MNSA intervention on HIV outcomes among WLHIV in Senegal, AIM 2. Determine the mechanisms by which the MNSA intervention improves HIV outcomes among WLHIV in Senegal, Aim 2a. Determine the impact of the MNSA intervention on food security, dietary diversity, and nutritional status, Aim 2b. Determine the impact of the MNSA intervention on mental health outcomes and empowerment, and AIM 3. Determine the costs, cost-effectiveness, scalability, and sustainability of the MNSA intervention.

NIMH - National Institute of Mental Health

ABSTRACT Adolescent girls and young women (AGYW, age 15-24) in Africa face disproportionately high risks of HIV acquisition and unintended pregnancy. These risks are compounded by social and cultural challenges that hinder the uptake and retention of preventative care, including pre-exposure prophylaxis (PrEP). Despite PrEP's effectiveness, current uptake among AGYW is limited due to low awareness, cultural barriers, and dissatisfaction with existing PrEP modalities. Newer biomedical HIV prevention options, such as long-acting injectables, hold promise, but their real-world impact remains uncertain due to low awareness, gaps in provision, and inattention to user needs. Ascertaining the scale of need for PrEP while concurrently centering user desires is critical for sustainable prevention efforts and for effectively addressing the burden of HIV faced by AGYW. My long-term objective is to develop an independent research career aimed at reducing the disproportionate burden of HIV on AGYW by bridging data and implementation science. This specific research seeks to address gaps in measuring unmet need for PrEP, project the impact of newer biomedical HIV prevention products on addressing that need, and develop targeted interventions to bridge the evidence-to-action gap. This innovative proposal is complemented by an integrated training plan that includes four training objectives (TO) supervised and supported by a distinguished mentorship team of experts in each of the respective areas: TO1) learning methods for sampling harder-to-reach populations, TO2) applied training in infectious disease modeling, TO3) gaining expertise in implementation science, and TO4) topical training in biomedical HIV prevention products. My project aims to rigorously quantify the unmet need for PrEP using Demographic and Health Survey data from 21 countries, specifically leveraging sexual behavior questions that parallel in-country PrEP eligibility criteria to conduct a proxy PrEP screening (Aim 1). I will use infectious disease modeling to model the impact of newer biomedical HIV products and estimate person-years of protection offered by each PrEP product among AGYW with unmet need (Aim 2). Aim 3 builds on the success of the previously evaluated Malkia Klabu intervention, which increased the distribution of sexual and reproductive health (SRH) and HIV prevention products through community drug shops. I propose to pilot an enhanced version that includes community-based promotion of PrEP demand, screening, and referrals. The pilot will evaluate the acceptability, feasibility, and appropriateness of the intervention among 100 AGYW across two pharmacies in Kisumu, Kenya. (Aim 3). Upon completion of the TOs and Aims, I will have the necessary training and preliminary data to conduct a scaled R01 to evaluate the PrEP-enhanced Malkia Klabu's impact on PrEP adoption, effective use, and persistence. This work will generate critical insights and establish a foundation for my independent research career, aiming to reduce the disproportionate burden of HIV and unintended pregnancy faced by AGYW via data and implementation science.

NIMH - National Institute of Mental Health

ABSTRACT Less than half of people with HIV (PWH) in the US are retained in outpatient HIV care, impeding access to life- saving antiretroviral therapy and increasing transmission risk. Hospitalizations are common among PWH, particularly PWH not engaged in care. An inpatient admission is an opportunity to link hospitalized PWH, either newly diagnosed or previously diagnosed but not in care, to outpatient HIV care following discharge. However, interventions to improve linkage to outpatient HIV care have been largely unsuccessful. Prior studies have been limited by fragmented data sources, often restricted to a single health system, cross-sectional data, or with insufficient variables to comprehensively examine complex risk factors influencing post-discharge care engagement. We propose to integrate complementary data sources that capture the full HIV care continuum among hospitalized PWH and collect qualitative data from key informants to investigate individual-, hospital-, community-, and policy-level determinants of post-discharge HIV care engagement. We will conduct this study in North Carolina (NC), where academic-public health partnerships have a proven track-record of using HIV surveillance data to inform public health interventions, improving care outcomes and interrupting transmissions. We will combine electronic health records (EHRs) from three of the largest health systems in NC with HIV surveillance data, including statewide viral loads, for the years 2018-2024. PWH will be matched across the data sources using highly accurate novel techniques that do not require sharing sensitive identifying data. Our study will include 34 hospitals that care for 80% of hospitalized PWH in NC. Care continuum outcomes and differences across hospitals will inform sampling for our qualitative work, engaging PWH, healthcare providers and administrators, and staff from community-based organizations involved in supporting engagement in HIV care for PWH. Our specific aims for this three-year grant are: 1) Characterize HIV care engagement pre- and post-discharge among hospitalized PWH; 2) Identify patient- and hospital-level predictors of post-discharge linkage to care; and 3) Explore key informants’ perceptions of factors that influence post-discharge linkage to care. In Aims 1-2, integrated EHRs capturing >600 in- and outpatient sites in all 100 NC counties and statewide HIV surveillance viral load data enables us to examine the full HIV care continuum among hospitalized PWH – diagnosis, linkage, retention, and viral suppression. Our collaboration capitalizes on clinical, epidemiological, and public health expertise at three academic institutions and the NC Division of Public Health, and leverages established partnerships with community-based organizations, local health jurisdictions, and community advisory boards. Combining HIV care continuum outcomes, predictors of care engagement following hospitalization, and a comprehensive examination of contextual determinants at individual, community, organization, and policy levels, we will identify modifiable targets from which we can develop tailored, multi-level interventions for subsequent testing.

NIMH - National Institute of Mental Health

Project Summary Retrieving memories of emotional events can result in (re)experiencing subjective feelings. Importantly, the feelings elicited by memories can influence current emotional states. For example, recalling positive events can both reduce current negative affect and diminish acute physiological stress responses. Similarly, recalling negative events can lead to current negative feelings and moods. The feelings of memories have also been linked to subjective clinical symptoms. The frequency of reported negative intrusive memories is related to both the severity of clinical symptoms in a treatment-seeking population and the likelihood of reporting clinical symptoms in a typical undergraduate population. Because of the impact of the feelings elicited by memories on current emotional health and well-being, understanding how the feelings of memories might change over time has to potential to suggest novel treatment innovations. The proposed research investigates techniques intended to alter the feelings associated with memories. Specifically, we take advantage of reactivation induced memory change (RIMC) to determine factors that may reduce or enhance the negative feelings elicited by memories. To explore how RIMC can modify the feelings of memories, the proposed studies examine three kinds of memories and two techniques to alter subjective feelings. There are three specific aims: Aim 1 examines whether RIMC interventions can be used to diminish the negative feelings elicited by memories for negative events. Aim 2 examines how RIMC mechanisms may enhance the negative feelings elicited by memories for negative events. Aim 3 examines if RIMC techniques can infuse negative feelings into previously neutral memories. In addition to examining the feelings elicited by memories, we will also examine the impact of these interventions on changes in physiological stress reactions and the pattern of blood oxygen level dependent (BOLD) signals when retrieving these memories. It is hypothesized interventions following the reactivation of a previous acquired memory will change the later expression of subjective feelings elicited by that memory more than interventions without reactivation. It is further hypothesized that the reactivation of a previously acquired negative memory without any intervention will result in strengthening the memory and enhancing negative feelings. We expect these changes will also be reflected in physiological stress reactions and BOLD response patterns during retrieval.

NIMH - National Institute of Mental Health

Mental health challenges among young adults in the U.S. are rising, with 36% of individuals aged 18–25 reporting anxiety and 29% reporting depression, underscoring the need for effective interventions. Socially disconnected youth (SDY)-young adults who experience limited dependable support and disconnection from outpatient mental health services due to social, interpersonal, and contextual barriers—may face additional daily stressors that elevate risks for mental health disorders, suicidality, and substance use. In rural regions known to be underserved by outpatient mental health services, documented provider shortages and geographic isolation further limit access to care and create documented gaps in support. This study will assess mental health needs and outpatient service access among SDY aged 18–25 living in rural areas of the Southern United States. We will leverage Geosocial Network Applications (GSNA) to engage young adults not currently receiving outpatient mental health care. Ecological Momentary Assessment (EMA), a real-time data collection method, will examine daily stressors, coping behaviors, and mental health fluctuations. This mixed-methods approach will provide critical insights into access barriers and identify scalable strategies for improving outpatient mental health engagement. Aim 1: Identify measurable barriers to outpatient mental health service utilization and optimize GSNA-based recruitment strategies through 20 semi-structured interviews examining digital engagement pat terns, prior service use, and perceived barriers to care. Aim 2: Assess the feasibility of smartphone-delivered EMA to monitor mental health in real time. We will recruit 150 participants via GSNA and collect both active (validated symptom scales) and passive (device-based behavioral indicators) data on stress, anxiety, depression, substance use, and coping behaviors to gain a dynamic understanding of how environmental and community-level factors influence mental health. This study will refine GSNA-based engagement methods to improve outreach and service access for rural young adults. Real-time tracking through EMA will provide insights into daily stressors, informing adaptive intervention strategies. Findings will guide evidence-based recommendations for providers and contribute to service delivery models addressing documented gaps in rural outpatient mental health care.

NIMH - National Institute of Mental Health

Abstract: Functional variants in GRIN2A, which encodes the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), have been found in patients with Schizophrenia (Scz) and have been linked to impaired working memory (WM). The consequences of GluN2A dysfunction on neural activity and behavior are poorly understood and there are no methods to restore impaired GluN2A function in Scz. Sarcoma Tyrosine Kinase (Src) regulates NMDAR current via GluN2A phosphorylation. Src serves as a hub upon which several proteins dysregulated in Scz interact to influence NMDAR function, including dysbindin-1 (dys-1), suggesting that a Src pathway influences glutamate function via GluN2A. Src activity is reduced in prefrontal cortex (PFC), a region critical for WM, in Scz patients. Indeed, reduction of Src activity in mice impairs trace fear conditioning (TFC), which relies on retention of a cue for 20 seconds, indicative of WM. Thus, the Src pathway is a promising mechanism to explain WM deficits across multiple etiologies, and a provides a means to restore GluN2A function across a range of molecular and genetic conditions. The current proposal will assess the role of the dys-1à Srcà GluN2A pathway on molecular (synaptosomal NMDAR co-immunoprecipitation), single cell (patch clamp), in vivo network function (multi-electrode arrays) and WM (TFC), using a cell-circuit-behavior approach to determine how dysfunctions at each level interact to impair outcomes. The synapse specific activator of Src (TAT-SAPIP), which increases Src availability, will be used to assess the extent to which increasing Src activity restores GluN2A function. Aim 1 will assess the effects of dys-1 removal on cellular, circuit, and behavioral measures related to WM. Dys-1 knockout (KO) increases NMDAR channel decay constant, gamma excitatory/inhibitory (E/I) balance, and TFC. Further, dys-1 KO reduces NMDAR EPSCs, which is restored by increasing Src activity. We propose that decreased dys-1 in KO mice impairs NMDAR activity by reducing GluN2A phosphorylation via Src, and that administration of TAT-SAPIP will restore GluN2A function, thereby restoring cellular, circuit, and behavioral outcomes. Aim 2 will assess the effects of reduced Src on cellular, circuit, and behavioral measures related to WM. Reduction of Src impairs TFC and reduces TFC-dependent GluN2A phosphorylation, reduces NMDAR EPSCs and disrupts E/I balance. Preliminary data indicate that TAT- SAPIP selectively enhances Src in the synapse, facilitates NMDAR EPSCs in wild type (WT) but not Src KO mice, and that chronic TAT-SAPIP restores TFC in Src het mice. We hypothesize that enhancing Src activity will restore normal GluN2A phosphorylation and function, thereby restoring each outcome. Aim 3 will assess the effects of reduced GluN2A availability on cellular, circuit, and behavioral measures related to WM. Reduction of GluN2A function (Grin2A het mice) slows receptor kinetics, will disrupt network gamma E/I balance, and TFC. TAT-SAPIP is expected to restore GluN2A function. This proposal advances a novel mechanistic approach to treating Scz that builds upon previous genetic, post-mortem and preclinical studies.

NIA - National Institute on Aging

ABSTRACT Career Goal: My career goal is to become a leading independent investigator contributing rigorous social science research to understand cognitive health differences among the growing population of older immigrants in the US. With the immigrant population 65 and older expected to double to 20 million by 2050, investigating the ways modifiable risk factors for Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) operate for immigrant populations is an imperative area of research. Training towards content area and methodological expertise will enable me to contribute to scholarship aimed at reducing the public burden of AD/ADRD in a growing US population. Career Development: I will undertake four training aims to enhance my knowledge and skills in (1) the biological and social pathways shaping AD/ADRD, (2) geriatric mental health and social relationships, (3) epidemiological causal inference, and (4) professional development for becoming an independent investigator. Research Project: Mexican immigrants, the largest group of immigrants in the US, are rapidly aging, but current research often aggregates US Latinos, overlooking origin- and nativity-specific social, structural, and migration-related factors that influence AD/ADRD risk. Attention to specific immigrant populations is necessary to address heterogeneity in cognitive risk factors. To address this gap, the proposed research focuses on loneliness, a risk factor for AD/ADRD that may be heightened in the older Mexican immigrant population. Using data from a nationally representative panel survey, complemented by data from a Rutgers-based cohort that collects advanced biomarkers, the proposed project uses causal inference to analyze the inter-relationship between loneliness, social relationships, inflammation, and cognition for Mexican immigrants in the US compared to non-migrants, advancing understandings of modifiable risk factors for AD/ADRD. Specific Aims: (1/K99) Determine loneliness trajectories, social relationship risk factors for loneliness, and the contribution of loneliness to cognitive functioning in the Mexican immigrant population compared to non-migrants. (2/R00) Quantify inflammation as a mediator in the loneliness-cognition pathway in the Mexican immigrant population compared to non-migrants. (3/R00) Characterize the loneliness- inflammation and loneliness-AD/ADRD relationships in the Mexican immigrant population compared to non- migrants using advanced biomarker data. Mentorship: A complementary set of accomplished experts in AD/ADRD, geriatric mental health, social networks, immigrant health, biomarker analysis, and causal inference will provide training and professional mentorship to ensure my successful transition to independent investigator. Future Directions: With the proposed training and research experience, I will have a unique combination of substantive expertise and methodological skills to become an independent scientist and submit successful R01 proposals to examine AD/ADRD social determinants among high-risk subpopulations.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Chronic loneliness is a pervasive issue in persons with schizophrenia and can lead to downstream consequences of worsening symptoms (e.g., paranoia, cognitive and functional impairments), social withdrawal, and diminished quality of life. Central to these challenges are deficits in social motivation, encompassing both positive motivation (i.e., desire for connection) and negative motivation (i.e., avoidance due to anxiety). High rates of anxiety and depressive symptoms further exacerbate these motivation deficits, hindering social engagement and intensifying chronic loneliness. Despite the critical role of social motivation in shaping social interactions and mental health outcomes, existing research has primarily relied on static, retrospective assessments, which fail to capture the real-time fluctuations and bidirectional relationships between social motivation, mood, social interactions, and loneliness. The proposed F31 project will use ecological momentary assessment (EMA) to examine these dynamic processes as they unfold in daily life. By leveraging data from an NIMH-funded R01 study on loneliness and aging in schizophrenia, this study will evaluate moment-to-moment fluctuations in positive and negative social motivation, and their associations with mood, loneliness, and social interactions. Advanced statistical techniques, including linear mixed effects models and mediation analyses, will identify mechanisms linking social motivation to loneliness and mood over time. These insights aim to advance understanding of how momentary changes in social motivation shape real-world experiences in schizophrenia, with the goal of identifying modifiable targets for intervention. Through the training opportunities afforded by the F31 fellowship, the candidate will gain expertise in EMA methodologies, advanced statistical modeling, and translational research approaches. These skills will support the candidate’s long-term goals of becoming an independent investigator specializing in the social and psychological mechanisms of serious mental illness (SMI) and the development of technology-based interventions. The proposal aligns with the NIMH Strategic Plans by advancing the understanding of dynamic, modifiable processes underlying social motivation deficits in schizophrenia, and informing innovative, targeted intervention strategies.

NINR - National Institute of Nursing Research

PROJECT SUMMARY The period of emerging adulthood (ages 18-24) is a particularly critical developmental period in which significant decisions are made that set a life course towards adulthood, including training/education, employment/career, residential independence, relationships, and parenthood. The substantial physical, emotional, and developmental changes that occur during this developmental period put young people at risk for increased mood disorders, increased risk-taking behaviors, and decreased health seeking behaviors. Further, emerging adults experience the highest poverty rates of any group, contributing to their disproportionately adverse mental and physical health outcomes. Economic interventions have demonstrated improvements in economic stability and health for low-income communities. For young people transitioning to adulthood, an economic intervention could provide the support needed to develop healthy educational and employment trajectories before financial strain instills deepening disparities. The BEEM study (U01OD033266/ U01MD019398) is an NIH-supported randomized wait-list-controlled trial to determine the impact of an economic intervention including cash payments and opt- in financial mentoring on the physical, emotional, and financial well-being of low-income emerging adults. Since 2022, we have recruited and delivered the economic intervention to 300 emerging adults residing in low-income neighborhoods. We later began recruitment of a comparison cohort with 150 young adults from the same communities who were offered only tailored financial mentoring, without the cash payments, to work towards their financial goals. The current BEEM study is providing critical data on the short-term impact of cash on mental health and economic well-being. We have found that anxiety and depression were significantly lower after one year for participants receiving the cash compared to those who did not. However, the long-term sustainability of the health and wellbeing outcomes in BEEM needs to be established. Further, identifying the pathways and malleable targets for adjunctive interventions for those participants with suboptimal response can maximize the impact of economic interventions. We propose to follow these 450 low-income emerging adults, 300 who received cash and 150 who have not for an additional 3 years, collecting extensive information on psychosocial, economic, household, and neighborhood characteristics to : 1) assess longer term impacts of the economic intervention on mental health, 2) explore three mediating pathways (economic, psychosocial, and physical/behavioral) through which the economic intervention impacts mental health outcomes, and 3) identify malleable moderators operating at multiple levels (individual, household, neighborhood) that could be intervened on to maximize the impact of the economic intervention. This study will provide a roadmap to develop future economic interventions that are optimized to effectively address mental health in emerging adults.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Poor social-emotional development in early childhood is associated with negative short- and long-term outcomes, such as childhood psychopathology, poor school achievement, and economic consequences for families and society. Therefore, improving social-emotional development during early life may prevent adverse outcomes for children and families. Insomnia experienced by mothers during pregnancy or the postpartum period (i.e., perinatal insomnia) is a common, modifiable, and promising risk factor for poor social-emotional development in offspring, but extant observational data preclude causal inference. The current proposal capitalizes on the unique, cost-effective opportunity to follow an established cohort of mother-offspring dyads in order to provide causal evidence of whether and how an insomnia intervention delivered during pregnancy promotes offspring social-emotional development in humans. Specifically, the current proposal leverages the ongoing NIMH-funded PRISM Study. Participants are pregnant people with insomnia disorder (target N=498), randomized to a digital intervention proven effective for improving perinatal insomnia (cognitive behavioral therapy for insomnia) or to a clinically relevant but inert control condition (sleep hygiene education) and followed through one year postpartum. The proposed Growing Offspring Wellness Study (GROW Study) will follow the PRISM Study mother-offspring dyads longitudinally from ages 2-4 years to investigate a distinct, non-overlapping set of aims. Specifically, the PRISM Study provides the experimental manipulation required to achieve the following GROW Study aims: 1) Examine the impact of an efficacious perinatal insomnia intervention on offspring social-emotional outcomes measured via maternal report and objectively coded behavioral observation; and 2) Investigate postpartum depression and observed parenting behavior as potential mediators. If successful, the proposed project will show that a scalable, effective insomnia intervention delivered to mothers during pregnancy improves the social-emotional outcomes of their offspring. Findings regarding mediators may assist with intervention refinement to further amplify the impact on offspring social-emotional outcomes. Improving social-emotional outcomes in early life has high public health significance considering the high individual, familial, and societal costs of poor social-emotional outcomes and their sequelae.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT. Rates of anxiety disorders in childhood are increasing and anxiety in childhood often predates other diagnoses. Early identification of trait-based markers associated with anxiety disorder risk, and their neural correlates, is needed to develop childhood interventions that reduce later illness burden in adolescence and adulthood. High trait anxiety is one such behavioral marker that is present in children and is stable over the lifetime. High trait anxiety is characterized by misattribution of threat, such that nonthreatening stimuli are perceived as threatening. Given the developmental importance of social stimuli, faces are a particularly salient source of potential threat in those with high trait anxiety. Indeed, anxious adults tend to perceive threatening emotional expressions at a lower intensity, misattribute threat to neutral expressions, and perceive novel faces as threatening. While threat misattribution in anxiety disorders is often thought to involve reduced prefrontal regulation of limbic regions such as the amygdala, this model alone cannot account for differences in visual discrimination in anxiety, which are present at an early latency following stimulus onset and associated with differences in visual cortical networks. For example, in anxious adults, threat misattribution is associated with altered function of the ventral visual stream and limbic regions, particularly the fusiform gyrus and the amygdala. However, the function of this network and its relationship to anxiety has not been studied developmentally. Given the earlier development of visual cortices relative to prefrontal cortices, visual- limbic networks also likely play a role in high trait anxiety and anxiety disorder risk. Therefore, understanding the development of ventral visual stream regions associated with threat misattribution offers a potential novel target for early intervention. This longitudinal functional magnetic resonance imaging (fMRI) study seeks to characterize the development of the neurofunctional correlates of social threat perception in children ranging in trait anxiety. Children ages 8-12 (n=120) will be scanned, with a subset (n=60, ages 8 to 10 at baseline) scanned a second time two years later. We will collect measures of mood and anxiety symptoms at 3-month intervals following the baseline visit for all participants. The aims of this study are to assess the function of social threat perceptual networks in high trait anxiety. Specifically, we aim to understand the neural correlates of face identity discrimination (novel vs. familiar) and visual discrimination of subtle emotional expressions in children with high trait anxiety using a series of fMRI tasks. We also will explore the development of these circuits over time, and the predictive utility of the function of these regions for understanding the later development of anxiety symptoms and prefrontal regulation of the amygdala in anxiety.

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT An unprecedented and increasing number of Americans are living to old age. As a result, the economic and societal benefits of maintaining physical function in older ages are significant and far-reaching. Importantly, while the prevalence of disabilities among older adults has been declining in recent decades, these declines have not extended to all segments of the population. Successful interventions to improve physical function and reduce disability for older Americans will require understanding and targeting contributing factors within highrisk groups across different regions of the US. Longitudinal, multi-site studies are necessary to identify the relative role of modifiable risk factors at the individual-level (e.g. lifestyle, social circumstances) and contextuallevel (e.g. neighborhood supports) across the life course across population subgroups. In this study, we propose to leverage over 30 years of extensive longitudinal data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort to address major gaps in research on modifiable individual- and neighborhood-factors influencing differences in physical function as participants age. In addition to leveraging decades of data on individual lifestyle and social factors, we propose four complementary, large-scale data collection processes (i.e. GIS, virtual systematic audits, participant surveys, community-informant surveys) to expand neighborhood contextual data. Paired with performance-based objective physical function (i.e. Short Physical Performance Battery, SPPB) and self-reported physical function and disability, this study builds an unprecedented dataset that will enable us to understand and identify intervention strategies for maintaining physical function for all Americans and among high-risk groups in different regions of the US. This project is poised to provide robust new evidence links between individual life experiences, neighborhood environments, and physical function outcomes, with important implications for built environment science, disability research, and policies to support healthy aging. Aim 1 will better assess the role of individual modifiable factors (e.g. physical activity, sleep, substance use, mental health, social connection, work, stress) in functional decline within previously unexamined populations using longstanding lifestyle, behavior, and social data. Aim 2 will estimate the role of multifaceted, longitudinal neighborhood characteristics (e.g. in-home supports, walkability, access to resources, disorder, support for aging in place) to later life physical function and provide evidence to guide the design of neighborhood for healthy aging. Finally, in Aim 3 we combine these novel and rich datasets to investigate the relative contributions of these multi-level factors to differences in physical function outcomes among population subgroups. We anticipate this research will identify actionable community interventions to address and remediate aging inequalities derived from the unequal distribution of environmental supports for healthy aging. We expect this evidence to support and amplify efforts to effectively reduce age-related declines for all Americans.

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

Project Abstract Adverse mental health conditions are the most common complication of pregnancy and childbirth, affecting 1 in 5 birthing people in the US each year. Sexual and gender minority (SGM) individuals, including lesbian, bisexual, and queer women as well as transgender and gender nonconforming individuals, face increasing social stigma, animosity, and conflicts. Preliminary data suggests that these negative societal factors contribute to significant disparities in mental health outcomes among SGM birthing people. Two modifiable protective factors—access to quality healthcare and social support—are crucial for reducing the risk of pregnancy-related complications and mitigating adverse mental health effects. Unfortunately, SGM individuals often encounter unaffirming and inappropriate care, leading to elevated stress levels, non-compliance, and delays in seeking essential healthcare services. Additionally, the nature of support needed by SGM individuals often differs from that required by heterosexual cisgender women. Therefore, there is a pressing need for a deeper examination of SGM birthing people's experiences with medical care and social support to inform culturally sensitive interventions tailored specifically for SGM people, alongside comprehensive training for healthcare providers to deliver appropriate care. The main objective of Mx. Ezra's project is to elucidate how social support and medical care contribute to the mental health trajectories of SGM birthing people throughout the perinatal period. They will accomplish this objective by conducting a longitudinal mixed methods study to address three aims: (Aim 1) visualize and describe the trajectories of psychological distress and social support across the perinatal period among SGM birthing people; (Aim 2) explore mental health, support, and healthcare experiences of SGM birthing people during the perinatal period using qualitative longitudinal trajectory analyses; and (Aim 3) integrate the findings from Aims 1 and 2 to illuminate how psychological distress, social support, and healthcare experiences coalesce across the perinatal period for SGM birthing people. To accomplish the objective and aims of their proposed research plan, Mx. Ezra will seek out additional training to increase their conceptual, methodological, and dissemination skillsets which will augment their core training in Family Science. Their training plan combines formal coursework in family and maternal and child health, statistics, one-on-one mentoring, conference presentations, and publishing research to prepare them for a career as an independent researcher.