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National Institutes of Health

Full-Scale Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 - Clinical Trial Required)

National Institutes of Health

Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01 Clinical Trial Required). This NOFO is a key element of NIMHs set of NOFOs to support clinical trials research across the intervention development and testing pipeline. The NOFO supports (1) clinical trials to test the effectiveness of optimized therapeutic and preventive interventions for use in community and practice settings; and (2) clinical trials to evaluate the effectiveness of patient-, provider-, organizational-, or systems-level services interventions to improve access, continuity, quality, equity, and/or value of mental health services. This NOFO is intended to support trials that: address a significant problem, such that the findings have potential to inform practice; are adequately powered to definitively answer the primary research question(s), with well-justified hypotheses supported by pilot data; and are designed to examine questions regarding mediators and moderators of effects. Consistent with the NIMH experimental therapeutics approach, this NOFO is intended to support effectiveness trials that explicitly address whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (i.e., the mechanism(s) that accounts for changes in clinical/functional outcomes, changes in provider behavior, improved access or continuity of services, etc.). The collaborative R01 mechanism provides support for multisite trials when two or more sites are necessary for completion of the trial (e.g., to increase sample size, accelerate recruitment, or increase sample diversity and representation).

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT The transition from adolescence to adulthood is a critical stage of development characterized by significant changes in social-emotional behavior. One of the central brain structures modulating this transition is the amygdala. The development of the amygdala continues through adolescence, undergoing an expansion in size and neuron number into early adulthood. These changes enable healthy social and emotional development, and perturbations in amygdala development and maturation are linked a host of mental health disorders, most notably autism spectrum disorders (ASD) and the long-term behavioral consequences as a result of early life stress (ELS). However, the amygdala neuronal and circuit substrates underlying changes coincident with this major life transition remain little understood. In our published studies in humans and mice, we identified and characterized a unique population of immature neurons in the paralaminar nucleus of the amygdala (PL). While these neurons are born embryonically, they interestingly delay their maturation until adolescence when they differentiate into excitatory neurons. Thus, our discovery and characterization of PL neurons that undergo maturation coincident with adolescence revealed a novel mechanism of brain plasticity during a critical stage of post-natal development. Using the mouse as a model, the goal of our proposed studies is to understand the function of amygdala late-maturing neurons from adolescence to early adulthood and what drives their maturation. To test this, we will examine how PL neuronal responses change over time (Aim 1), the necessity and sufficiency of PL neurons in this transition (Aim 2), and the role inhibitory neurotransmission plays in their maturation and later function (Aim 3). Our proposed studies are also an essential step to understanding the role late maturing PL neurons play in neuro-atypical brain function associated with disorders of social cognition to which the PL has previously been linked, such as ASD and the long-term consequences of ELS.

NIMH - National Institute of Mental Health

Project Summary Schizophrenia (SCZ) is a severe psychiatric disorder with a complex genetic component. Genetic studies have identified a strong link between genetic risk and the neurodevelopmental processes of the brain, contributing to SCZ etiology. Notably, neurogenesis is especially vulnerable to disruption by SCZ genetic factors. However, which SCZ-associated risk genes and variants affect neurogenesis and how non-coding risk variants influence risk gene expression remains largely unknown. The overarching goal of this K99/R00 project is to systematically delineate the direct connection among SCZ-associated variants, risk genes, and neurogenesis by developing and applying advanced functional genomic screening platforms in cerebral organoids. During the K99 phase, I will elucidate the roles of SCZ risk genes in neurogenesis by conducting pooled high throughput CRISPR interference screens in key neurogenic cell types derived from cerebral organoids. During the K99/R00 phase, I will employ prime editing screens in cerebral organoids to assess the effects of individual SCZ-associated variants on neurogenesis. Finally, during the R00 phase, I will investigate the regulatory impact of non-coding SCZ variants on gene expression using single-cell prime editing screens in cerebral organoids. The successful completion of these aims will provide novel insights into which and how SCZ-associated genes and variants disrupt neurogenesis, advancing our understanding of the neurodevelopmental basis of SCZ and aiding in identifying novel therapeutic targets. Additionally, this research will enhance our ability to interpret the broader role of genetic factors in neurogenesis and will generate essential training data for machine learning models focused on neurogenesis, with potential implications for other neurodevelopmental disorders. During the K99 phase, I will further improve my expertise in functional genomics, organoid models, statistical analysis, machine learning, and neurobiology of SCZ, as well as other essential professional skills, including leadership, mentoring, writing, and presentation. To achieve my training and research objectives, I have assembled an exceptional and interdisciplinary team of mentors and collaborators including Dr. Yin Shen (primary mentor, functional genomics and gene regulation), Dr. Arnold Kriegstein (co-mentor, brain organoid), Dr. Katherine Pollard (co-mentor, statistics and machine learning), Dr. Hongjun Song (co-mentor, SCZ neurobiology), and Dr. Xin Jin (collaborator, complex in vivo screening methodologies). This comprehensive mentorship and collaborative research environment will foster my transition to an independent research career, with a long-term goal of elucidating the genomic mechanisms underpinning neurological disorders, ultimately enabling the identification of novel therapeutic targets for prevention and treatment.

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.

Administration for Children & Families - ACYF/FYSB

The Basic Center Program (BCP) provides temporary, emergency shelter; and counseling services to youth who have left home without permission of their parents or guardians, have been forced to leave home, or other homeless youth who might otherwise end up in the law enforcement or in the child welfare, mental health, or juvenile justice systems. BCPs work to establish or strengthen community-based programs that meet the immediate needs of runaway and homeless youth and their families. BCPs provide youth under 18 years of age with food, clothing, counseling and referrals for health care. BCPs can provide up to 21 days of shelter for youth and seeks to reunite young people with their families, whenever possible, or to locate appropriate alternative placements.

Administration for Children & Families - ACYF/FYSB

<p>The Basic Center Program (BCP) provides temporary, emergency shelter; and counseling services to youth who have left home without permission of their parents or guardians, have been forced to leave home, or other homeless youth who might otherwise end up in the law enforcement or in the child welfare, mental health, or juvenile justice systems. BCPs work to establish or strengthen community-based programs that meet the immediate needs of runaway and homeless youth and their families. BCPs provide youth under 18 years of age with food, clothing, counseling and referrals for health care. BCPs can provide up to 21 days of shelter for youth and seeks to reunite young people with their families, whenever possible, or to locate appropriate alternative placements.</p>

Substance Abuse and Mental Health Services Adminis

The purpose of the 988 Tribal response program is to improve connection and response to 988 contacts (including calls, chats, and texts) originating in Tribal communities and/or activated by American Indians/Alaska Natives. American Indian and Alaska Native communities experience a significantly higher suicide risk compared to the general population. CDC reports that in 2022 non-Hispanic Al/AN people had a suicide rate 91% greater than the general population.

Substance Abuse and Mental Health Services Adminis

FY2026 Support for 988 Tribal Response Cooperative Agreements

Substance Abuse and Mental Health Services Adminis

<p>The purpose of the 988 Tribal response program is to improve connection and response to 988 contacts (including calls, chats, and texts) originating in Tribal communities and/or activated by American Indians/Alaska Natives. American Indian and Alaska Native communities experience a significantly higher suicide risk compared to the general population. CDC reports that in 2022 non-Hispanic Al/AN people had a suicide rate 91% greater than the general population.</p>

Community Oriented Policing Services

The Office of Community Oriented Policing Services (COPS) is the component of the U.S. Department of Justice responsible for advancing the practice of community policing and the Administration s priority of Making America Safe Again by supporting the nation s state, local, territorial and Tribal law enforcement agencies through information and grant resources. This is a notice of funding opportunity (NOFO) for the FY26 Law Enforcement Mental Health and Wellness Act (LEMHWA) Program. The mental health and wellness of law enforcement officers and their families is a priority of the Administration. Through the LEMHWA program, the Department of Justice supports this priority by providing funding directly to state, local, tribal, and territorial (SLTT) law enforcement agencies to implement new or enhance existing programs that offer training and services to support officers emotional and mental health including, counseling programs, peer mentoring, suicide prevention, stress reduction, and police officer family services. As community policing is common sense policing, throughout the FY26 LEMHWA program NOFO materials, the terms community policing and common sense policing are used interchangeably, unless otherwise specified. The COPS Office seeks to increase the delivery of and access to mental health and wellness services through this NOFO in the following three funding categories: Category 1: FY26 Start-up LEMHWA Implementation Projects The purpose of this program is to provide funding to law enforcement agencies that do not have established law-enforcement specific mental health and wellness programming. These funds will serve as start-up funding to support the development of new mental health and wellness services and programming for employees of law enforcement agencies and their families. This program also serves to increase grant funding accessibility for small and understaffed departments, especially those in rural communities, to implement mental health and wellness programs. Implementation of peer support, training, family resources, suicide prevention, stress reduction, clinical support, and other promising practices for wellness programs are highly encouraged. Agencies that currently offer rudimentary or limited wellness services and are seeking to develop a comprehensive wellness program for their department are encouraged to apply. Category 2: FY26 Enhanced LEMHWA Implementation Projects The purpose of this program is to provide funding to law enforcement agencies who have current wellness programs in place and are seeking to enhance or expand upon those existing wellness programs. Category 3: FY26 LEMHWA Community of Practice Initiative The purpose of this initiative is to provide support to current and future LEMHWA grantees, that include peer support and technical assistance through the development and facilitation of an innovative forum where grantees can learn from their peers and share promising practices.

Community Oriented Policing Services

The Office of Community Oriented Policing Services (COPS) is the component of the U.S. Department of Justice responsible for advancing the practice of community policing and the Administration’s priority of Making America Safe Again by supporting the nation’s state, local, territorial and Tribal law enforcement agencies through information and grant resources. This is a notice of funding opportunity (NOFO) for the FY26 Law Enforcement Mental Health and Wellness Act (LEMHWA) Program. The mental health and wellness of law enforcement officers and their families is a priority of the Administration. Through the LEMHWA program, the Department of Justice supports this priority by providing funding directly to state, local, tribal, and territorial (SLTT) law enforcement agencies to implement new or enhance existing programs that offer training and services to support officers emotional and mental health including, counseling programs, peer mentoring, suicide prevention, stress reduction, and police officer family services. As community policing is common sense policing, throughout the FY26 LEMHWA program NOFO materials, the terms “community policing” and “common sense policing” are used interchangeably, unless otherwise specified. The COPS Office seeks to increase the delivery of and access to mental health and wellness services through this NOFO in the following three funding categories: Category 1: FY26 Start-up LEMHWA Implementation Projects • The purpose of this program is to provide funding to law enforcement agencies that do not have established law-enforcement specific mental health and wellness programming. These funds will serve as start-up funding to support the development of new mental health and wellness services and programming for employees of law enforcement agencies and their families. This program also serves to increase grant funding accessibility for small and understaffed departments, especially those in rural communities, to implement mental health and wellness programs. • Implementation of peer support, training, family resources, suicide prevention, stress reduction, clinical support, and other promising practices for wellness programs are highly encouraged. • Agencies that currently offer rudimentary or limited wellness services and are seeking to develop a comprehensive wellness program for their department are encouraged to apply. Category 2: FY26 Enhanced LEMHWA Implementation Projects • The purpose of this program is to provide funding to law enforcement agencies who have current wellness programs in place and are seeking to enhance or expand upon those existing wellness programs. Category 3: FY26 LEMHWA Community of Practice Initiative The purpose of this initiative is to provide support to current and future LEMHWA grantees, that include peer support and technical assistance through the development and facilitation of an innovative forum where grantees can learn from their peers and share promising practices.

Community Oriented Policing Services

FY26 Law Enforcement Mental Health and Wellness Act Program

Community Oriented Policing Services

The Office of Community Oriented Policing Services (COPS) is the component of the U.S. Department of Justice responsible for advancing the practice of community policing and the Administration’s priority of Making America Safe Again by supporting the nation’s state, local, territorial and Tribal law enforcement agencies through information and grant resources. This is a notice of funding opportunity (NOFO) for the FY26 Preparing for Active Shooter Situations (PASS) Program. The preparedness of law enforcement to respond to active shooter incidents is a priority of the Administration. Through the PASS program, the Department of Justice supports this priority by providing funding to deliver nationally recognized, scenario-based training that prepares officers, first responders, and mental health and social service providers on how best to prepare their communities for an active shooter threat or act of terrorism. PASS program funds are used to increase public and law enforcement safety nationwide by training first responders—including law enforcement, fire, emergency medical services (EMS), dispatchers, medical personnel, facility security, emergency management, and any other professionals who may reasonably be key to a successful integrated response—to handle an active shooter threat or act of terrorism. In addition, this program will provide priority access to training for School Resource Officers funded under the COPS Hiring Program, to support active shooter preparedness and response in primary and secondary schools. Training provided under the PASS program will advance the goal of the 2016 Protecting Our Lives by Initiating COPS Expansion (POLICE) Act in offering scenario-based, integrated response courses designed to counter active shooter threats or acts of terrorism against individuals or facilities.

Community Oriented Policing Services

The Office of Community Oriented Policing Services (COPS) is the component of the U.S. Department of Justice responsible for advancing the practice of community policing and the Administration s priority of Making America Safe Again by supporting the nation s state, local, territorial and Tribal law enforcement agencies through information and grant resources. This is a notice of funding opportunity (NOFO) for the FY26 Preparing for Active Shooter Situations (PASS) Program. The preparedness of law enforcement to respond to active shooter incidents is a priority of the Administration. Through the PASS program, the Department of Justice supports this priority by providing funding to deliver nationally recognized, scenario-based training that prepares officers, first responders, and mental health and social service providers on how best to prepare their communities for an active shooter threat or act of terrorism. PASS program funds are used to increase public and law enforcement safety nationwide by training first responders including law enforcement, fire, emergency medical services (EMS), dispatchers, medical personnel, facility security, emergency management, and any other professionals who may reasonably be key to a successful integrated response to handle an active shooter threat or act of terrorism. In addition, this program will provide priority access to training for School Resource Officers funded under the COPS Hiring Program, to support active shooter preparedness and response in primary and secondary schools. Training provided under the PASS program will advance the goal of the 2016 Protecting Our Lives by Initiating COPS Expansion (POLICE) Act in offering scenario-based, integrated response courses designed to counter active shooter threats or acts of terrorism against individuals or facilities.

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

PROJECT SUMMARY/ABSTRACT The proposed project for a K23 Career Development Award will enable Dr. Camilia Kamoun to become an independent physician-scientist expert in patient-centered research on psychosocial health in early female puberty. Early female puberty is increasingly common, yet there is a lack of patient-centered tools to assess its psychosocial impact and guide treatment decisions. The proposed research aims to develop a patient-oriented outcomes (PROs) measure for early puberty, addressing a critical gap in evidence-based, patient-centered care. This research would positively impact public health given high rates of early puberty. Dr. Kamoun’s long- term goal is to become an expert in researching psychosocial health in pediatric patients with endocrine conditions, integrating bioethical inquiry to advance just, patient-centered care. Her strong research background, as well as bioethics training, make her an ideal candidate. The research has the following specific aims: 1) To characterize parental health concerns related to early female puberty, as well as parental experiences of its social and mental health impacts; 2) To understand parental prioritization of patient-reported health outcomes for early female puberty and explore their association with parental and child traits; and 3) To assess early female puberty-related PROs using adapted existing relevant PROMIS® measures. These aims will be accomplished through integrated mixed methods. They will lead to the development of a patient- oriented outcomes measure to use in a clinical trial to assess the effect of pubertal suppression treatment on psychosocial health in early female puberty, which will constitute the next steps in the research. In the last two years of the K23, Dr. Kamoun will develop an R01 or equivalent proposal to secure funding for this follow-up research. An interdisciplinary team of mentors and collaborators will guide Dr. Kamoun in accomplishing the following training goals: 1) To acquire advanced theoretical and practical knowledge of research methodologies used in patient-centered research; 2) To gain skills and knowledge in patient-oriented health outcomes research; 3) To acquire knowledge in peripubertal psychoneuroendocrinology and developmental psychology; 4) To deepen her bioethics expertise with a focus on pediatric, research, women’s health ethics, and the relationship between risks, values and ethical care. This training will include survey science coursework through the Odum Institute for Research in Social Science at UNC-CH and advanced bioethics training through the Children's Mercy Bioethics Center's Certificate Program in Pediatric Bioethics. Dr. Kamoun’s mentorship team will meet regularly with her to monitor progress, as well as to provide guidance in writing manuscripts and R01 and equivalent grant proposals. This K23 Career Development Award will provide Dr. Kamoun with the necessary training, mentorship, and research foundation to launch an innovative patient- centered research program that aligns with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s mission to improve child and adolescent health and the transition to adulthood.

NIMH - National Institute of Mental Health

Dysregulation of basal ganglia and cortical development in the forebrain is central to epilepsy, mental deficiency, autism and schizophrenia. During forebrain development, the medial ganglionic eminence (MGE) generates GABAergic projection neurons in the basal ganglia and GABAergic interneurons in the cortex and hippocampus. We aim to identify transcriptional and epigenetic mechanisms that control cell fate specification and neuronal differentiation of these forebrain GABAergic neurons - information that will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders.

NIMH - National Institute of Mental Health

Summary One of the major problems in human genetics is understanding the genetic causes underlying complex phenotypes, including neuropsychiatric traits such as autism spectrum disorders, bipolar and schizophrenia. Despite tremendous work over the past few decades, it has been frustratingly difficult to get a good understanding of the underlying biological mechanisms in most cases. Nonetheless, large psychiatric genetic studies are beginning to deliver fundamental knowledge about genetic architecture, disease pathways and specific genetic loci for follow-up. Most psychiatric genetic studies to date have focused on individuals of European origin, leading to profound difference in genetic discoveries with limited transferability of results across populations, but also limiting our knowledge about disease pathophysiology in general. Recently, several large projects in neuropsychiatric genetics have focused on collecting and assembling genetic and deep phenotype data in admixed and populations of different geographic origins. Such projects include the Latin American Genomics Consortium (LAGC), the Genomics of Autism in Latino Ancestries (GALA), the Ancestral Population Network (APN), and PsycheMERGE. Most approaches for causal variant discovery fail to account for key complexities that arise in studies of varying geographic origin, including heterogeneity across populations in terms of effect sizes and linkage disequilibrium (LD) structure, and correlations across geographic origins. Furthermore, with meta-analyses with external LD from reference panels being commonly used in genome-wide association studies, certain types of inconsistencies are inevitable. Therefore, existing methods tend to have suboptimal power and can even produce invalid results, i.e., they prioritize non-causal variants. We propose to develop robust fine-mapping tools that model heterogeneity across populations and are robust to inconsistencies in the data. We also propose to leverage a possibly large number of genetically related traits available in electronic health record systems, including diagnoses, lab results and biomarkers with the goal to refine phenotypes and improve power of genetic association studies for psychiatric phenotypes. We further propose to apply these methods to the largest available collections of datasets from various geographic origins for autism, bipolar, schizophrenia and other neuropsychiatric traits, including data from several psychiatric genetics consortia and electronic health record systems. We believe that the proposed research is very timely and leverages modern datasets with the potential to substantially improve our understanding of the biological mechanisms underlying risk to neuropsychiatric diseases, including schizophrenia, autism and related disorders.

NIMH - National Institute of Mental Health

Although the rate of suicide death across the U.S. has risen dramatically over the past two decades, prevention of mortality remains challenging. This proposal will continue discovery efforts leveraging unique genetic data, comprehensive health records, and deep genealogical records. The variation in responses to environmental and social risks due to underlying genetic vulnerabilities creates an opportunity for discovery of subtypes of individuals at particularly high risk for mortality to lead to future clinical translation. Thus far, genetic discoveries associated with suicidality remain largely removed from translational utility, and are additionally primarily focused on the outcome of suicide attempt. Among individuals with evident suicidality, fewer than 10% go on to die by suicide, and roughly half of suicide deaths occur with no prior evidence of suicide attempts, suggesting that suicide attempt may be a poor proxy for determining risks leading to mortality. Data resources in the Utah Suicide Mortality Risk Study (USMRS) offer much needed opportunities to bridge this knowledge gap, including >12,000 suicide deaths linked to statewide electronic health records; ~9,000 with genotyping, and 1,053 selected for high extended familial risk with whole genome sequencing. All data linkage, subsequent de-identification, and analyses are possible via the Utah Population Database (UPDB); this comprehensive statewide resource also includes unique knowledge of familial risk through genealogical records that go back to the 1700s. In the previous award period, we used the WGS resource, prioritizing genomic regions using 43 very extended families at high risk of suicide death. We pursued non- synonymous variants in the NRXN1 gene which is important for synaptic function, demonstrating the utility of the familial approach. We more broadly characterized suicide deaths with significant extended familiality, finding significant reduction in age at death and significant increase in polygenic risk specific to suicide. We expanded our sequencing sample from N=281 to N=1,053, prioritizing suicide deaths in extended high-risk families. In addition to familial prioritization, we prioritized brain-related expression quantitative trait loci in the deaths with WGS, finding significance associated with RFPL3S (a gene important for arousal), in addition to implicating other gene pathways. We characterized non-transmitted genomic deletions using a conservative strategy of internal replication and rigorous bench validation. Our large sample of genotyped suicides provides information regarding background common genetic risks of hundreds of diagnoses and traits via polygenic scores. Additional ongoing work has also strongly implicated underlying transdiagnostic risks above and beyond psychiatric risks, driving new research directions. We propose to target discovery of mechanistic genomic change within homogeneous subtypes. Extended families provide one method of reducing heterogeneity. We also propose complementary strategies of risk discovery within extreme subtypes of physiological stress response and of brain-related function.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY Early initiation of cannabis use (<16 years of age) increases risk for cannabis use disorder (CUD), mental illness, cognitive impairment, later unemployment, and poor social relationships. Prevention of early initiation is critical for improving social and health outcomes. Precision prevention programs have reduced youth substance use, but no approaches have specifically targeted cannabis use. Furthermore, no studies have comprehensively considered risk factors for early cannabis initiation (genetic, social, behavioral, environmental, and cognitive) to enhance the prediction of early use and inform precision prevention approaches. Comprehensive multivariable prediction models for early cannabis initiation that include genetics and social/environmental factors are needed. Cannabis use is polygenic, influenced by multiple genetic variants with weak-to-moderate effects, and polygenicity makes it difficult to translate genetics for clinical application. One method for clinically applying genetics is through the development of polygenic risk scores (PRS) that are composite scores representative of overall genetic risk. Prior PRS have typically lacked portability to non-European populations; however, a state- of-the-art method has been developed to build PRS with significantly improved risk prediction (34% improvement) across ancestries. There is a need to apply this method to develop cross-ancestry PRS for cannabis use for inclusion of overall genetic risk in comprehensive prediction models. Furthermore, given the complex interplay between genetics and social/environmental factors, research is needed to understand gene by environment (GxE) interactions in which social/environmental factors synergistically impact the risk conferred by genetics. Research into GxE interactions is statistically and computationally challenging, and traditional single-variant and more recent polygenic approaches focus on lower order 2-way interactions. Our logic forest (LF) algorithm efficiently searches all possible interactions up to 8 variables without a priori specification. This study will apply these state-of-the-art computational methods to the Adolescent Brain Cognitive Development (ABCD) Study, which examines childhood risk factors and initiation of substance use from ages 9-10 years to early adulthood in a population demographically reflective of the U.S. Nearly all youth had not used cannabis at recruitment, enabling the prospective measurement of initiation and the development of prediction models integrating genetics with pre-substance use measurements of cognitive, social, and environmental factors. This research will 1) develop cross-ancestry PRS for inclusion in prediction models that comprehensively consider genetic, sociodemographic, behavioral, cognitive, and environmental factors, and 2) apply LF to gene-sets within known biological pathways across the whole genome to identify pathway-specific GxE interactions. Comprehensive models coupled with a more complete understanding of GxE factors influencing early cannabis initiation can identify 1) high risk youth populations for targeted prevention, 2) targetable factors present among high-risk clusters for tailored interventions, and 3) biological pathways for therapeutic development.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Gastrointestinal motility disorders in childhood include rare but life-threatening conditions of Hirschsprung's disease and pediatric intestinal pseudo-obstruction and common conditions termed disorders of gut-brain interaction, including irritable bowel syndrome, functional abdominal pain, constipation, and dyspepsia. These conditions create a substantial burden through chronic health issues and lower quality of life. Hirschsprung and pediatric intestinal pseudo-obstruction are well-understood to be due to abnormalities in the enteric nervous system (ENS), which controls motility, secretion, absorption, and blood flow. Mounting evidence suggests that unrecognized abnormalities in ENS and nervous system development may also predispose to disorders of gut- brain interaction. It follows that disruption of fetal development of the ENS could result in a range of motility disorders and identification of potential disruptors could lead to novel opportunities for prevention. The objective of this proposal is to determine whether antidepressant exposure in pregnancy increases the risk of various pediatric gastrointestinal motility disorders and disorders of gut-brain interaction. We hypothesize that modulation of serotonin, norepinephrine, and dopamine through antidepressant exposure during fetal development, essential for development of the ENS and for maintaining daily functioning of the GI tract, will have long-term effects on ENS function. Animal data has demonstrated this potential, but limited human data exist. To fill this substantial gap in knowledge, we will assess the association between antidepressant use in pregnancy and pediatric motility and disorders of gut-brain interaction using three large healthcare utilization databases in the US and the UK. Specifically, we will estimate the association between in utero exposure to antidepressants and life-threatening GI motility disorders (Aim 1), and common disorders of gut-brain interaction (Aim 2). In both aims, associations of each antidepressant class and individual medications will be explore, as well as gestational timing of exposure. Multiple sources of confounding by indication, familial susceptibility, and environment will be addressed using propensity score methods and through design techniques, including use of various comparator groups, sibling comparisons, and negative control exposures. Acknowledging the complex etiology of disorders of gut-brain interaction, Aims 2.1-2.3 will assess whether various early life stressors (neonatal factors, childhood mental health, and maternal mental health in childhood) are causal mediators or modifiers of the association between antidepressant exposure and disorders of gut- brain interaction. These sub-aims will provide critical insight into causal pathways and interventions. This work will produce generalizable and actionable results that will lead to improvements in preventing these debilitating pediatric GI conditions.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Serotonin is an important growth factor during gestation. Animal studies have shown that in early gestation, before the fetus’ own ability to synthesize serotonin develops, the mother’s serotonin system plays an important role in the fetus’ brain development in ways that impact future cognition and behavior. In mice, for example, we found that manipulation of the maternal serotonin system alters placental gene expression, fetal brain serotonin levels, and neuronal projections from the thalamus to the somatosensory cortex. When we initially tested these pathways in humans, we saw a similar initial relationship between maternal whole blood serotonin and offspring symptom severity; however, that study was retrospective, and restricted to a clinical population with autism spectrum disorder, and no study has examined the role of the placenta. Recognizing these limitations, it would be premature to develop a large new study without first testing whether and how the pathways identified in the animal models are conserved in humans. Thus, we propose an Exploratory/Developmental R21 project harnassing the strengths of an ongoing study of 375 mother-infants being followed from early pregnancy to offspring 30-36 months of life (R01MH119510). Because the parent study has already collected the maternal blood in early pregnancy, placenta and cordblood, infant neuroimaging at 2-4 weeks of age, and prospective offspring cognitive and behavioral assessments, there is no data collection in this proposal, and we will be able to test our questions immediately and cost-effectively. Our central hypothesis that lower maternal (but not paternal) whole blood serotonin levels in early (14-18 weeks) pregnancy will be associated with changes in placental transcriptome and diminished cord blood serotonin, reduced infant thalamocortical connectivity (using existing structural connectivity measures) at 2-4 weeks of life, and, ultimately, difficulties in neurocognitive and social functioning at 30-36 months of age. Preliminary analyses of the first twenty maternal blood samples we collected support feasibility and demonstrate a range of serotonin levels consistent with those in the population. This developmental proposal will dissect, for the first time, the effects of maternal and placental serotonergic systems on offspring brain and neurodevelopment. Anchoring this proposal to an established study further provides a rigorous and cost-effective infrastructure. Data from this study can fuel future studies to confirm and test generalizability of mechanisms in larger samples, and test promising interventions. Importantly, serotonin function is modifiable, e.g., through diet, micribiome and pharmacological changes, potentially opening up opportunities for maternal screening and prevention.

NIMH - National Institute of Mental Health

Project Summary/Abstract Our daily lives require constant decision-making in which we pursue potential rewards at the expense of potential costs. The integration of costs and benefits is an essential component of decision-making. Abnormal decision- making, including increased pursuit of high cost/ high reward options, is a transdiagnostic symptom of multiple psychiatric and neurological disorders including depression, post-traumatic stress disorder, addiction and many others. Stress exposure can induce these disorders and lead to long-term alterations in decision-making. Here, we will explore interactions between neural circuits and endocrine mechanisms that contribute to the pursuit of high cost/high reward options in mouse models of chronic stress exposure. Our previous work showed that the striosomal patches of the dorsomedial striatum are essential for integration of cost and benefit and that dysregulated activity in striosomal inputs contributes to persistent pursuit of high cost-high reward options in previously stressed rodents. Our previous work also showed that ghrelin receptor activity contributes to processing of reward and cost, and that the ghrelin receptor is present within the striatum. Here, we hypothesize that striosomal projection neuron hyperactivity is a key factor in stress-induced cost insensitivity, and activation of ghrelin receptor in the striosomes plays a causal role in this shift in decision- making. Using a naturalistic cost-benefit decision-making task that does not require food deprivation as motivation, we will examine decisions to pursue high costs paired with rewards and lower costs paired with rewards. We will record from striosomal projection neurons within and following different types of chronic stressor exposures to identify the “tipping point” at which abnormal striosomal activity and altered decision-making first emerge. We will use optogenetics to manipulate activity patterns in stress-exposed mice to “correct” stress- induced changes in decision-making and to “mimic” stress-induced striosomal firing patterns in unstressed mice to induce cost insensitivity. We will pharmacologically activate ghrelin receptors and determine whether this is sufficient to induce cost insensitivity and striosomal hyperactivity in unstressed mice. We will perform virus- mediated knockdown of the ghrelin receptor in striosomes and determine whether this is sufficient to prevent stress-induced changes in decision-making in stress-exposed mice. The goal of our proposed work is to identify a mechanistic basis for the shift in circuit activity and decision-making after repeated exposure to stressors, thereby advancing towards our long-term goals of predicting individuals who are at-risk for altered decision- making, and providing new peripheral and central targets for intervention to restore normal decision-making in the face of trauma and psychiatric illness.

Substance Abuse and Mental Health Services Adminis

The purpose of this program is to support a comprehensive, public health, and evidence-based approach for colleges and universities that: improves access to behavioral health services for all college students, including those at risk for suicide, depression, serious mental illness, and substance use disorders that can lead to school failure; prevents and reduces suicide, mental health and substance use disorders; promotes student help-seeking behaviors and reduces stigma; improves the identification and treatment of at-risk college students.Note: At least six awards will be made to junior/community colleges pending adequate application volume.