NIMH - National Institute of Mental Health Grants

NIMH - National Institute of Mental Health

The Contractor, Guild Associates, Inc., aims to develop an electrochemical aptamer-based sensor device for simple, rapid, and low-cost detection and quantification of antiretroviral therapy (ART) drugs in urine and blood samples at the point-of-care (POC).

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Specific Aims: This proposal aims to identify opportunities to improve the prevention and mitigation of risks associated with cognitive impairment among people aging with HIV. Aim 1 will estimate the proportion of cognitive impairment cases potentially attributable to psychosocial and behavioral risk factors to prioritize those, which if intervened upon, could hypothetically result in the greatest prevention of cognitive impairment. Aim 2 will determine whether cognitive impairment increases the risk of losing one’s durable (sustained) viral suppression so we may mitigate this adverse outcome. Significance: As people with HIV (PWH) live longer due to treatment advances, they face a growing burden of age-related conditions, including cognitive impairment. PWH experience higher rates of cognitive impairment than people without HIV despite widespread viral suppression, which implicates non-HIV-related factors in their cognitive risk. Focusing on psychosocial and behavioral risk factors, which are prevalent in PWH and causally linked to cognitive impairment, can help to prioritize fruitful prevention strategies. In addition, cognitive impairment may threaten the durability of viral suppression, which could hinder cognitive maintenance and prevention of HIV transmission. Considering these issues in tandem can inform preparations for the long-term healthcare needs of people aging with HIV. Approach: These aims will leverage the Multicenter AIDS Cohort Study (MACS) (Aim 1), which includes 10 years of longitudinal cognitive screening data, and the Johns Hopkins HIV Clinical Cohort (JHHCC) (Aim 2), an urban cohort of PWH with rich clinical data. In Aim 1, we will estimate population attributable fractions for incident cognitive impairment, using longitudinal data and methods to account for time-varying risk factors, censoring, and competing risks. In Aim 2, we will employ a longitudinal closed cohort design to estimate the risk ratio for loss of durable viral suppression in PWH by cognitive impairment status. Training Information: The proposed research encompasses the dissertation of Madeline Brooks, a PhD student in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. The training plan consists of coursework, mentorship, and professional development to support the successful completion of these aims and prepare Ms. Brooks to become an independent research epidemiologist. These aims address priorities of the NIH Office of AIDS Research to address the role of non-infectious comorbidities in central nervous system complications and subsequent implications for HIV transmission.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Bipolar spectrum disorders (BSDs) are associated with major personal and public health burdens. Despite this heavy burden, the etiology of BSD is not fully understood. Further research on risk factors for BSD during adolescence, when likelihood of first onset of a BSD is highest, is needed to understand how BSD onset and symptoms can be better predicted and interventions delivered earlier. Determining the degree of risk for BSD conferred by various predictors is a vital step toward creating intervention and prevention programs that can identify individuals most at risk in order to reduce the likelihood of BSD onset, delay onset, or lessen course severity. Extant research has established several person-level factors that confer risk and influence dysregulation throughout the course of BSDs. The social and circadian rhythm model of BSDs posits that social and circadian rhythm dysregulation can result in mood symptoms and episodes. In another separate line of research, evidence suggests that hypersensitivity to rewards confers risk for BSDs. Researchers have suggested that the reward and circadian models of BSD risk and course can be combined into a joint, bidirectional model, such that disturbance in one of these systems, through a feedback loop, may promote dysregulation in both systems, contributing to mood symptoms and episodes. Additional theoretically and empirically supported predictors can be combined statistically with reward and circadian factors to better predict risk of bipolar symptoms. These factors include family history of BSDs, hypomanic personality, higher trait impulsivity, exposure to childhood adversity, affective lability, and substance use. However, the means by which predictive factors may be combined to better inform risk for bipolar symptoms is poorly understood. Although myriad risk factors for BSDs have been identified, little work has been done to statistically integrate information obtained through a multimodal approach to determine which individuals are most at risk. Thus, the proposed project seeks to evaluate empirically derived risk groups based on multimodal assessment of multiple risk factors for BSD during adolescence, a critical developmental period in which onset of BSDs is most likely. I will use participants from my sponsor's R01 study, which aims to examine the interplay of reward and circadian factors longitudinally to predict first onset of BSDs, add measures of additional risk factors, and statistically integrate these multimodal risk indicators with latent class analysis to evaluate the predictive utility of empirically-derived risk groups. My sponsors and I have designed a training plan involving coursework, workshops, experiential learning, and mentorship that will allow me to develop greater expertise in the development of mood pathology, learn advanced statistical methods required for this project, and gain the skills necessary for my future career as an independent clinical scientist. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists.

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

Project Summary/Abstract The goal of the proposed project is to develop to develop an innovative digital health platform to support families who have a teenager diagnosed with attention deficit hyperactivity disorder (ADHD) who is driving (during permit period or post licensure). Parents of teens with ADHD routinely cite that one of the greatest sources of stress and frustration centers on the issue of driving. Teens with ADHD are at significantly increased risk of crash, more likely to have multiple crashes, and more likely to have their driving license suspended. In addition, teens with ADHD are more likely to have challenges in securing a license during the permitting process. We propose the development of an app that will enable joint parent and teen goal setting, monitoring and personalized feedback. Telematics data enables that development of the proposed app. Development will also be guided by evidence-based strategies for engaging with parents and teens with ADHD and iterative feedback that will be collected from the intended user population. The needs of the intended population will be considered throughout the development process and in phase I, a prototype of the platform will be tested with the intended population for usability and acceptability. We have assembled a team with complimentary expertise to develop the methods of engagement, content, user interface and app, and to conduct the needed testing.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Somatic mosaicism, the genomic differences among the billions of cells in the human brain, may explain the incomplete penetrance and variable expressivity in highly heritable neurodevelopmental disorders. Thousands of clonal somatic mosaic variants (SMVs) in subpopulations of neurons have been discovered in brains of schizophrenia and autism patients, necessitating an urgent, unmet demand to determine if these diverse somatic mutations have a causal role in disease. Major challenges include (1) the inability of using conventional statistical methods for common variants to associate disease status with risk variant, (2) the vast space of non-coding candidates with unknown function, and (3) the unresolved relevant cell types and developmental stages linking mutations to phenotypes. Just as integrating high-throughput genomic-, CRISPR, and stem cell-based technologies resulted in significant progress in understanding germline risk variants, they represent a novel approach to uniquely address the major challenges in the field of somatic mosaicism. As a co-mentored computational and experimental biologist, I will leverage state-of-the-art functional genomic technologies and bioinformatic pipelines to systematically characterize all brain non-coding SMVs discovered to date, resolving their causal roles in neurodevelopmental disorders. From all SMVs identified in case and control brains, I will first create a functional catalog of expression-modulated SMVs in a developmental- and cell-type-specific manner by applying massively parallel reporter assays in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and post-mitotic neurons. By doing so, I will be able to interrogate whether differences in patterns of expression-modulated SMVs exist between cases and controls. Second, I will compare the somatic and germline genetic architectures across neurodevelopmental disorders, determining whether somatic mutations act via the same pathways as germline mutations, or affect genes relevant to diseases, indicating a causal role. By simultaneously uncovering the downstream transcriptomic profiles of hundreds of regulatory elements harboring SMVs with CRISPR screen, I will be able to pinpoint putative disease-causal SMVs. Finally, I will validate the phenotypic impact of putative causal SMVs in physiologically complex and relevant models including 3D brain organoids and “mosaicism-in-a-dish”, testing both cell-autonomous and non-autonomous mechanisms of SMVs. Overall, this work, representing a novel application of scalable functional genomic technologies to SMVs, provides a framework to identify SMVs with putative causal effects in neurodevelopmental diseases, advancing our understanding of a poorly understood disease mechanism. This fellowship will provide me with training encompassing computational genomics, stem cell models and broadly applicable phenotyping techniques, setting a foundation for me to launch an independent research program distinct from my mentors', querying somatic mosaicism's impact into novel cell types, contexts and diseases towards discovering novel therapeutic targets.

NIMH - National Institute of Mental Health

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.

NIMH - National Institute of Mental Health

Project Summary/Abstract Depressive symptoms represent a serious challenge to youth mental health. There is therefore an urgent need for the identification of possible mechanisms underlying risk for youth depressive symptoms. This is especially crucial for certain high-risk populations, such as youth with a history of adversity exposure. Dysregulation of the oral microbiome, the community of microorganisms inhabiting the human oral cavity, may function as a mechanism underlying risk for depressive symptoms in youth. The oral microbiome is a compelling putative mechanism for youth depressive symptoms because it is manipulable via non-invasive interventions, such as probiotic supplementation, while, at the same time, remarkably resilient to insults once it has stabilized in early adulthood. Indeed, oral microbiome dysregulation has been linked to depressive symptoms, experimentally in animal models and observationally in human youth. However, in order for potential mechanisms underlying this link to be elucidated, there is a need for research that examines the oral microbiome and depressive symptoms longitudinally, that examines the microbiome at a functional level, and that incorporates neuroimaging to better understand depressive symptom etiology. The current project will address these gaps by leveraging a 3-year longitudinal study of youth, ages 6-16 at the first timepoint (N=152), with the first 2 timepoints completed and the 3rd underway. This project oversamples for adversity-exposed youth (N=66), a population at increased risk of both depressive symptoms and oral microbiome dysregulation. Oral microbiome composition and depressive symptoms will have been assessed at all three timepoints, and functional Magnetic Resonance Imaging (fMRI) conducted at the final timepoint. We will analyze the relationship between the oral microbiome and depressive symptoms, and the relationship between the oral microbiome and functional brain connectivity. We hypothesize that elevated pathogenic taxa, increased pro-inflammatory functions of the oral microbiome, and decreased aromatic amino acid precursor biosynthesis will be associated with increased depressive symptoms. We further hypothesize these same indicators of oral microbiome dysregulation will also be associated with altered functional brain connectivity, especially within the affective limbic network, reward network, default mode network, and cognitive control network. This project’s findings will yield critical understanding about potential peripheral mechanisms underlying depressive symptoms in both typically developing and high-risk youth.

NIMH - National Institute of Mental Health

Contact PD/PI: lewis, elinor PROJECT SUMMARY Second generation antipsychotics (SGAs) are widely used clinical tools for the treatment of severe mental illness. However, their utility is highly variable, and they take weeks to become effective. The mechanisms behind this time course are not understood. SGAs are thought of as antagonists at the D2 dopamine receptor. Yet our recent work suggests that some SGAs function as arrestin-biased agonists at the less-characterized D3 dopamine receptor (D3R). Activation of the arrestin-3 pathway leads to degradation of D3R, potentially altering response to these drugs over time. I have generated preliminary data that shows mice grow tolerant to preclinical measures of SGA activity after chronic treatment of an arrestin-biased SGA. I hypothesize that D3R neurons are the locus of tolerance to select SGAs, and this tolerance is driven by decreased D3R membrane expression caused by arrestin-3 recruitment to D3R. I will use in vivo optical methods to assess changes in D3-neuron activity after chronic SGA treatment. I will also measure behavioral tolerance to SGA treatment in transgenic mice with altered abilities to degrade D3Rs and compare D3R levels using saturation binding and PET scans. This project will reveal mechanisms of tolerance to select SGAs at gross anatomy, cell- type, and protein levels. Project Summary/Abstract Page 6

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Suicide is the second leading cause of death among young adults ages 15-241, with rates continuing to rise2. While research has identified some broad predictive factors3, our ability to predict who will experience suicidal thoughts and behaviors (STB) and when these crises will occur remains limited4. This challenge stems from the fact that suicide risk fluctuates dramatically in response to emotional and interpersonal distress5,6, with social threats often acting as precipitating events7,8. The tendency to respond impulsively to negative emotions (e.g., negative urgency9) may help explain why some individuals engage in STB as a maladaptive attempt to escape emotional pain following social threat or rejection. Evidence from neuroscience indicates that social- affective circuitry reflects subjective affective sensitivity to social threat10,11, and overlaps with putative neural correlates of negative urgency12,13, suggesting a potential neural profile that may drive associations between social threat and STB. To test this, I will utilize data from an ongoing R01 including 6 months of ecological momentary assessment (EMA), a personalized peer social feedback fMRI task, and self-report questionnaires from 150 young adults (ages 18-30) with chronic STB to examine how function in social-affective systems and real-world experiences of social threat interact to predict STB. The Specific Aims of this study are to: (1) test associations between negative urgency and STB using both baseline and prospective EMA assessments; (2) investigate associations between functional connectivity of social-affective systems during social threat and trait-level negative urgency; and (3) examine whether individual differences in neural response to social threat moderate same-day relationships between social rejection-generated negative affect and suicidal thoughts. This project, and the associated F31 fellowship at the University of Pittsburgh, will provide critical training for the applicant to become an independent researcher investigating how neural and behavioral responses to social contexts influence suicide risk during key developmental periods. To accomplish the proposed research, this application includes a comprehensive training and mentorship plan that builds on the applicant’s prior clinical psychology and developmental neuroscience training. These Training Goals will focus on expanding the applicant’s knowledge and/or skills in: (1) neurodevelopmental pathways to suicide; (2) negative urgency as a mechanism of suicidal thoughts; (3) task-based fMRI methods, with an emphasis on functional connectivity analyses; and (4) implementing mixed-effects modeling for intensive longitudinal data. These goals will be accomplished through mentorship meetings, workshops, conferences, and coursework with a committed interdisciplinary team. Complemented by support from a dedicated research environment at the University of Pittsburgh, this fellowship will accelerate the applicant’s trajectory toward becoming an independent researcher focused on using multimodal research to identify how individual neurobiology interacts with one’s social environment to create enduring risk for STB.

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

Reducing the age at autism diagnosis is a crucial public health priority, as early diagnosis is associated with better developmental and mental health outcomes. Though autism can be reliably diagnosed in children as young as fourteen months, the average age at diagnosis in the United States is around four to five years. Documented differences in diagnostic timeliness exist by sociodemographic features. However, more research is needed on the modifiable, or scalable, aspects of the service system that can facilitate earlier access to autism diagnosis. Autism screening in primary care holds promise to reduce the average age at diagnosis, as autism-specific screening and attendance at well-child visits are associated with earlier age at diagnosis. Yet, to date, no comparative studies have been conducted to understand the differences in diagnostic timeliness between those screened versus those not screened for autism in primary care. Optimizing early identification of autism in primary care is crucial, as primary care is often children’s entry point on their pathway to a diagnosis. Of parallel importance, more research is needed on children’s complete pathway through services to the receipt of a diagnosis so that optimal pathways that facilitate earlier diagnosis can be identified. Therefore, the present study aims to understand what services work and in what context to lower the age at autism diagnosis, with a particular focus on autism screening in primary care. Prior studies of age at diagnosis have been limited by an over-reliance on Medicaid claims data, retrospective caregiver-report, and analysis of discrete variables in relation to age at diagnosis (e.g., number of appointments). The present study leverages the MarketScan Commercial Claims Database—a national claims database comprised of over 10 billion records from 70 million privately insured individuals. The present study is the first to examine autism screening in primary care using claims data. Analyzing data from a sample of children diagnosed with autism in early childhood, we aim to: 1) evaluate the effect of autism screening in primary care on child age at autism diagnosis using propensity score matched samples, 2) compare the effect of autism screening in primary care on child age at diagnosis in resource-poor or resource-rich areas, and 3) discover service pathways to a formal autism diagnosis using discrete sequence clustering analysis. A highly experienced mentorship team of investigators will support the principal investigator’s research and training plan to further her independence as a behavioral health services researcher, with a focus on autism-related services. Through a combination of carefully curated training activities, the principal investigator will: 1) deepen her understanding of autism-specific service disparities in early childhood and identify targets for intervention, 2) develop expertise in behavioral health services research methodology, 3) build mastery in administrative claims data management, 4) gain knowledge in rigorous analytic approaches for use in observational data, and 5) strengthen skills in scientific writing and related skills to bolster her independence as a scientist.

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

PROJECT SUMMARY A major advance for treating depression, the leading cause of disability worldwide, has been the non- pharmacological development of repetitive transcranial magnetic stimulation (rTMS). While rTMS is effective for some, only about half of patients demonstrate a sustained clinical response. This is partly due to stimulation parameters not being fully optimized. While recent research has focused on personalizing where to stimulate, a critical gap remains in optimizing how to stimulate for each patient. This study aims to improve rTMS treatment for depression by using prefrontal electrophysiological biomarkers to personalize stimulation. We seek to enhance target engagement and better understand how brain changes relate to clinical response. Our method centers on early local TMS-evoked potentials (EL-TEPs), which provide reliable measurements of prefrontal excitability at the individual level. Prefrontal EL-TEPs are altered in depression, correlate with treatment outcomes, and respond to neuroplastic interventions like intermittent theta-burst stimulation (iTBS). Our team has pioneered a novel method to optimize EL-TEP acquisition, significantly improving signal quality and reliability. We hypothesize that personalizing iTBS pulse count and intensity to maximize EL-TEP suppression will optimize neural effects and improve clinical outcomes. We propose a R61/R33 study to develop and validate a personalized iTBS protocol. The R61 phase will demonstrate target engagement based on prefrontal excitability changes in 80 patients with treatment-resistant depression (TRD). We will characterize how iTBS parameters affect EL-TEPs in an abbreviated protocol, focusing on acute neurophysiological effects. The R33 phase will confirm target engagement and relate brain changes to clinical response in 106 new patients with TRD, comparing EL-TEP-guided personalized iTBS treatment to non-personalized iTBS treatment. This phase will involve a randomized, triple-blind design with comprehensive neurophysiological, clinical, cognitive, and functional assessments at multiple timepoints. This research is innovative as it uses prefrontal electrophysiology to deliver personalized iTBS treatment. The significance lies in its potential to select treatment parameters based on brain changes. Impact: This project aims to improve iTBS treatment through neurophysiology-guided personalization. By demonstrating target engagement and relating brain changes to clinical outcomes of personalized iTBS treatment, we seek to advance our understanding of the neural mechanisms of depression. If successful, this research could lead to more effective and efficient personalized treatments for depression.

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.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) often result from mutations in genes essential for brain development and function. Recent advances in gene replacement therapy have shown promise for rescuing molecular and behavioral deficits in mouse models, even when gene restoration occurs postnatally. However, the context and feasibility of gene replacement for specific disorders remain unclear. This project focuses on Tatton Brown Rahman Syndrome (TBRS), a rare NDD caused by mutations in DNMT3A, a gene critical for DNA methylation and neuronal development. TBRS patients exhibit intellectual disability, overgrowth, joint hypermobility, and seizures. In mice, loss of DNMT3A leads to altered neuronal differentiation and synaptic function, emphasizing its importance in early brain development. Kim will explore the potential for restoring DNMT3A function using innovative mouse models and gene therapy approaches. In Aim 1, Kim will employ spatial transcriptomics and single-nucleus RNA sequencing to assess how DNMT3A loss impacts cell type distributions and gene expression in the cerebral cortex and whether these changes can be reversed by restoring DNMT3A expression. In Aim 2, she will evaluate the feasibility of gene replacement therapy for TBRS using adeno-associated viruses (AAVs). These studies will address timing, delivery methods, and baseline efficacy of DNMT3A reinstatement in both tamoxifen-inducible and disease-relevant mouse models. This work will determine whether postnatal DNMT3A restoration can rescue molecular, cellular, and behavioral deficits associated with TBRS and provide a foundation for gene therapy strategies targeting NDDs. The findings will contribute to understanding the therapeutic potential of gene replacement, with implications for improving outcomes and quality of life for patients and families affected by TBRS and related conditions. This project will be conducted at Washington University in St. Louis, a phenomenal research environment that integrates cutting-edge genomic technologies, advanced imaging platforms, and expertise in neurodevelopmental disorders. The lab is supported by collaborations with leading researchers in mouse behavior, epigenetics, and computational biology, ensuring access to unparalleled resources and mentorship. This environment fosters innovation, collaboration, and rigorous scientific inquiry, creating the ideal setting to achieve the goals set forth by this proposal.

NIMH - National Institute of Mental Health

Project Summary Fragile X syndrome (FXS) stands as a prominent contributor to intellectual disability and autism spectrum disorders, stemming from mutations within the FMR1 gene. These mutations lead to severe reduction or absence of the FMRP protein. Despite extensive research, effective medical interventions for FXS remain elusive, hindered by a limited understanding of its underlying mechanisms. Biochemical investigations have consistently highlighted FMRP's role in modulating mRNA translation, with its absence correlating with increased translation levels of select FMRP- interacting mRNA targets. However, emerging evidence suggests broader dysregulation, as FXS neurons exhibit heightened overall protein synthesis, hinting at elevated translation of non-FMRP interacting mRNAs. This intriguing phenomenon underscores the need for a deeper exploration into the cellular dysfunctions characterizing FXS. This research initiative aims to unravel a novel facet of FXS pathology—nucleolar hyper-function. We propose that this hyper-function contributes to aberrant ribosome biogenesis, thus augmenting the cellular capacity for translation and driving the observed global increase in protein synthesis in FXS. Aim 1 will assess neuronal and glial nucleolar function in wild-type (WT) and Fmr1 knockout (KO) mice. Aim 2 will conduct a comparative analysis of genome-wide proteomic data encompassing nucleolar proteins in WT and Fmr1 KO samples, discerning molecular alterations integral to ribosome biogenesis and assembly. Aim 3 will assess nucleolar function in the peripheral tissue in Fmr1 KO mice, establishing the hyper-functional pathological outcome as a potential clinical biomarker. The successful execution of this exploratory R21 project promises to unveil previously unexplored cellular mechanisms underlying FXS pathology. This study will also suggest nucleolus-associated abnormalities as novel molecular/cellular measures and potential biomarkers.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Human subjects research with novel neural devices raises unique ethical issues, such as post-trial responsibilities, privacy of brain data, and atypical risks such as changes to personality. To manage the discrepancy between research practices and ethics oversight, in 2018 the NIH added a mandatory neuroethics section to a subset of neuroscience grants in addition to the standard protection of human subjects component. However, despite the unique nature of this requirement, to date there have been no systematic efforts to assess stakeholders’ experiences with and attitudes toward these mandates. This represents both a critical gap and opportunity. Without empirical research evaluating the impact of neuroethics mandates, we risk implementing ineffective requirements, lack the information needed to make useful modifications, and remain unaware of their strengths and weaknesses. Furthermore, given that there is no established pathway nor guidance for investigators to address neuroethics requirements, examining researchers’ experiences offers a valuable opportunity to understand how they devise neuroethics plans as well as barriers they might encounter when implementing them. The overall objective of this short-term R21 exploratory proposal is to assess the impact of mandatory NIH neuroethics guidelines on the ethical design and conduct of brain-related research and to identify effective strategies that investigators have utilized to address neuroethics in their research. This will be achieved through two complementary aims that involve interviewing researchers who have been funded through NIH grants requiring neuroethics sections (Aim 1) and surveying those who review neuroethics components of grant applications (Aim 2). This project directly addresses the broad area of RFA-MH-25-171 (“enhance integration of neuroethics and neuroscience”). The expected outcomes of this two-year exploratory R21 project are a set of multistakeholder perspectives on the impact of neuroethics mandates and recommendations for improving them, an identification of strategies that researchers have utilized to address neuroethics mandates, and a determination of areas of unmet needs regarding resources for addressing neuroethics requirements. Our findings will benefit funders, by providing insights into the impact of neuroethics requirements and recommendations for improving them; researchers, by providing a set of effective strategies that have been used to address neuroethics sections; neuroethicists, by determining areas of unmet need regarding neuroethics resources; and the public, by identifying pathways for enhancing the ethical conduct of neurotechnology research. This project is significant because it has the potential to impact the way that the ethics is integrated and assessed across BRAIN Initiative research and in other scientific endeavors.

NIMH - National Institute of Mental Health

PROJECT SUMMARY ABSTRACT Effective interventions to reduce the functional impact of core features of autism spectrum disorder (ASD) in school-aged children are critically needed. This R61/R33 application proposes to test whether in-person computer training delivered individually by a coach engages an electroencephalographic (EEG) biomarker of cognitive control (N2 event-related potential [ERP] amplitude) and whether changes in the target neural response mediate the reduction of restricted and repetitive behaviors and interests. An extensive clinical and cognitive neuroscience literature documents reduced cognitive control among autistic children compared to neurotypical children and a relation between cognitive control and repetitive features of autism––providing a solid rationale for our training program. Based on this work, we predict that developing more effective cognitive control, metacognition, and working memory will enhance neural responses to conflicting information (i.e., a neural marker of effective cognitive control) and changes will correspond with decreases in restricted and repetitive behaviors and interests. The R61 study will randomly assign 95 autistic children (ages 8-11yrs) to a novel computer-based Cognitive Control Training combined with Metacognition Coaching or to a waitlist control group. Before and after intervention, EEG will be used to examine engagement of the target neural responses. We expect the group assigned to Cognitive Control Training + Metacognition Coaching to exhibit significantly larger changes in N2 ERP amplitude in incongruent relative to congruent trials than the waitlist group. If this hypothesis is supported, the R33 will be implemented and 140 autistic children (8-11yrs) will be randomly assigned to either: 1) Cognitive Control Training + Metacognition Coaching; or 2) MentalUP Educational Games, an active control condition that provides computer-based cognitive training. Both Cognitive Control Training + Metacognition Coaching and MentalUP will be delivered individually during 15 in-person sessions. Before and after intervention, we will collect neural responses and behavioral measures of cognitive control and working memory. We expect target engagement (greater differentiation of N2 amplitude) to be associated with reduced restricted and repetitive behaviors and interests. This study is innovative in several ways and has the potential for large clinical and scientific impact. It is the first study to examine a cost-effective computer-based cognitive control intervention for ASD that provides in-person metacognition coaching. This could increase functioning for autistic children at a time when intensive intervention delivery is waning. The study will use biomarkers and validated behavioral measures of cognitive control and metacognition in the context of an ASD clinical trial. Finally, the study will provide critical information about the relation between cognitive control and clinically relevant ASD outcomes, thereby providing insight into the mechanisms underlying behavioral challenges for autistic children. Promising results from this study would provide the basis for a larger clinical trial to investigate the efficacy of cognitive control training and mediators and moderators of its effects.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Background. In Eswatini, adult HIV prevalence is over 31%, and national adult HIV incidence is the highest in the world at 7.77 new infections per 1,000 persons annually. While the country has almost met UNAIDS’ 95-95- 95 goals for epidemic control, HIV incidence is declining at a glacial pace, pointing to the need for comprehensive HIV prevention programs. Eswatini’s scale-up of HIV pre-exposure prophylaxis (PrEP) began in 2018, with nearly 100,000 individuals initiating PrEP in-country since. The proposed study will develop better methods to determine who could most benefit from PrEP (i.e., PrEP need) in Eswatini, and whether that need is being met at programmatic and individual levels, to inform future implementation of HIV prevention programs. Aims. In line with the NIMH Division of AIDS Research’s strategic priorities, this study will 1) compare models for predicting who could most benefit from PrEP in Eswatini; 2) compare novel PrEP-to-Need Ratios (PnRs) to original PnRs at the facility level; and 3) examine individual-level prevention-effective persistence and trajectories over time. Approach. This research will use data from the 2021 Eswatini Population-based HIV Impact Assessment (N=11,199) and Eswatini’s HIV-1 Recent Infection Surveillance (N~32,780) to build machine learning models to predict both recent and long-term but newly diagnosed HIV infections, providing insight into vulnerable subpopulations most in need of PrEP. Using routinely collected health facility data (N=150 facilities), PnRs will be created that account for heterogeneity in infection timing (i.e., recent vs. long-term), as well as subpopulation variability. Facilities will be compared over time. Lastly, using data from the DYnamics of Contraception in Eswatini (DYCE) Study (N=321), changes in PrEP need over time, relative to changes in use of PrEP and other prevention methods, will be assessed using an operationalization of prevention-effective persistence. Latent class analysis will be used to detect actionable differences between classes of prevention-effective persistence trajectories. Each aim is designed to identify gaps in HIV prevention efforts and guide the continued scale-up of PrEP in Eswatini to ultimately reduce HIV incidence. Training. Ms. Wallach’s training plan leverages her quantitative analysis and HIV research experience to advance her skills and launch her career as an independent HIV investigator. Her training goals are to develop a deep, nuanced understanding of PrEP need, gain experience working with and triangulating various data sources, gain skills in machine learning methods and latent class analysis, gain experience with longitudinal data analysis, and build capacity for effective research communication and dissemination. Under the guidance of her Primary Sponsor, Ms. Wallach will receive tailored mentorship from a team of experienced HIV researchers who work with the included data sources, conduct PrEP-related research, and have expertise in the advanced epidemiologic methods herein. Training will occur at Columbia University, a high-caliber institution with specialized research programs, including in infectious disease epidemiology, and that houses ICAP, a global health and HIV implementation and research organization.

NIMH - National Institute of Mental Health

Abstract Despite antiretroviral therapy (ART), HIV-associated brain injury (HABI) persists in over half of people with HIV (PWH), manifesting as chronic cognitive impairment. While HIV-1 primarily infects microglia, driving central nervous system (CNS) neuroinflammation, current preclinical models do not recapitulate the chronic, suppressed infection characteristic of the ART era. Furthermore, they do not capture complex patient genetics and multicellular, glial and neuronal, interactions in a scalable and efficient manner. To address this need for more physiologically relevant models, we propose the development of an AI-guided triculture platform comprising major CNS cell types. This platform will use induced pluripotent stem cell (iPSC)-derived microglia, astrocytes, and neurons, using both morphological profiling and other omics-based profiling to model HABI under ART suppression. AI/machine learning (ML)-driven analysis of cellular morphology, combined with multi-omic data integration, will facilitate rapid classification and prediction of microglial functional states and their impact on neuronal health. Leveraging Modulo's established triculture system, previously successful in yielding therapeutic candidates for amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) currently in Investigational New Drug (IND)-enabling studies, we will construct a scalable HABI model under ART suppression. Our objectives are to (1) develop and validate an HIV-infected, ART-suppressed triculture platform, utilizing AI/ML-driven morphological profiling to classify HABI-specific microglial states; and (2) comprehensively characterize this model through neuroinflammatory profiling, behavioral correlates, and integration with publicly available HABI patient datasets. We hypothesize that our combined computational lab-based triculture system can effectively model HABI pathophysiology under ART conditions, enabling both rapid disease state classification and identification of therapeutic targets. Through the integration of experimental and computational approaches, this platform will provide insights into HABI mechanisms and accelerate therapeutic development. We will disseminate this model to the scientific community through publication and collaboration. Connecting in vitro modeling with patient outcomes offers a powerful tool for investigating neuroimmune dysfunction in HIV and related neurological disorders. Successful implementation will yield a platform for modeling neuroHIV under ART suppression, advancing our understanding of disease mechanisms and facilitating the discovery of novel therapeutic strategies for PWH with cognitive impairment.

NIMH - National Institute of Mental Health

Project Summary As life expectancy increases in people living with HIV (PLWH), the probability of developing other chronic conditions such as type 2 diabetes (T2DM), hypertension, and cardiovascular disease also increases. PLWH live longer, develop multiple chronic conditions (MCCs), and experience polypharmacy, reinforcing a need to evaluate composite medication adherence across all chronic medications. Suboptimal medication adherence to essential treatments may limit treatment effectiveness, shorten survival, decrease overall population health, and increase health-system costs. Positioned at the nexus of therapeutic intent and success, medication adherence is influenced by myriad system, provider, and person-related factors that cannot be evaluated using claims-based studies alone. Therefore, the overarching goal of this research is to identify a taxonomy of composite medication adherence trajectories (MATs) over a 36-month observation period in older (50-99 years of age) PLWH and MCCs. The taxonomies will inform future research involving development and testing of comprehensive medication adherence interventions and clinical decision support strategies with the highest probability to positively impact medication adherence-related clinical outcomes in older PLWH and MCCs. We propose a mixed-methods explanatory sequential design by combining group-based trajectory modeling (GBTM) of medication refill data followed by 75 semi-structured interviews to fully understand the clinical, social, behavioral, cultural, structural, and economic perspectives that may influence medication adherence decision-making in PLWH and MCCs (i.e., T2DM, hypertension, and/or hyperlipidemia). We propose the following aims: 1. Apply group-based trajectory modeling of medication refill data to identify dynamic profiles of medication adherence behavior over time for older PLWH and MCCs. 2. Use qualitative, semi-structured interviews of older PLWH and MCCs to obtain in-depth understanding of social, behavioral, cultural, structural, and economic perspectives that align with each MAT profile. In contrast to disease-specific (intra-disease), dichotomous summary measures focused on antiretroviral therapy alone, this study uniquely identifies longitudinal MATs across MCCs (inter-disease). Qualitative assessment of lived medication use experiences and array of social, behavioral, cultural, structural, and economic perspectives contributing to MAT profiles advances understanding of needs for PLWH and MCCs to inform optimal, tailored interventions for unique MATs unachievable with claims-only studies.

NIMH - National Institute of Mental Health

Identifying the Specific Reward Processes Underlying the Maintenance of Binge-Eating Disorder using EEG and EMA ABSTRACT Binge-eating disorder (BED) is the most common and most expensive eating disorder in the United States. Further, BED is associated with significant medical complications (e.g., obesity) and premature death. Treatments for BED have demonstrated limited effectiveness, signaling a critical need for improved understanding of the mechanisms underlying BED maintenance to help guide novel or enhanced interventions. Reward-related processes (e.g., wanting, liking, learning) are highlighted within the National Institute of Mental Health’s Research Domain Criteria (RDoC), and have been increasingly implicated in BED persistence. However, the specific reward processes that maintain BED are currently unknown. The incentive-sensitization theory suggests that food reward wanting, in particular, may serve as the primary maintenance factor underlying BED. Although preliminary data from our group indicate that food reward wanting may indeed play a critical role in BED maintenance, these data suggest that food reward liking and learning processes may also contribute to binge-eating persistence, highlighting their potential as novel targets for clinical intervention. Given this, research is critically needed to systematically evaluate the relative roles of food reward wanting, liking, and learning using both neural and naturalistic assessment approaches in BED, in order to pinpoint the specific reward mechanisms underlying BED persistence and guide treatment development. To address this need, the current proposal seeks to 1) evaluate the concurrent associations between binge-eating symptoms and food reward processes (i.e., wanting, liking, and learning) assessed at the neural level in the laboratory using electroencephalography (EEG); 2) evaluate the momentary prospective relationships between binge- eating symptoms and food reward processes (i.e., wanting, liking, and learning) assessed in the natural environment using ecological momentary assessment (EMA); and 3) evaluate the longer-term prospective associations between food reward processes (i.e., wanting, liking, and learning) assessed in the laboratory (via EEG) and the natural environment (via EMA), with change in binge-eating symptoms over 6-month follow-up. The research team includes experts in eating disorders, EMA, EEG, multilevel statistical modeling, and the neural basis of reward. Data from this study will clarify the specific neural and behavioral reward-related processes that contribute to binge-eating maintenance within BED. Knowledge gained from this study will help guide the development of targeted therapeutic approaches (e.g., neuromodulation, pharmaceutical, psychotherapy) that are designed to directly engage empirically-identified disorder-maintaining mechanisms, which will enhance the efficacy and efficiency of treatments for BED.

NIMH - National Institute of Mental Health

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