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NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Cannabis use among parents has increased rapidly in the past 10 years. In 2023, 7.8% of parents in the U.S. used cannabis on the majority of days, 4.9% used cannabis every day, and 5.7% met criteria for Cannabis Use Disorder (CUD). Cannabis use has acute effects on neurocognition, mood, and behavior that would plausibly affect the parenting of young children. However, research on substance use and parenting has focused largely use of alcohol and hard drugs, not cannabis. This project will use an ecological, within-person design to study the acute effects of cannabis on parenting. We will recruit 190 parents who routinely use cannabis (≥4 days per week) and have a child ages 3-6 years old. We focus on parents of young children because parenting a younger child is more demanding, and thus more likely to be affected by acute use. First, the parent will complete a baseline visit to gather data about how they approach cannabis use around their child and characterize the sample. Second, the parent will complete a 21-day ecological momentary assessment (EMA) protocol designed to repeatedly measure parenting behavior when using vs. not using cannabis (5 surveys per day). Within the 21-day EMA period, the parent will also complete a videotaped, in-home, ecologically valid parent-child interaction task on 2 different days, once shortly after using cannabis and once when not having used. Masked coders will use a validated scoring system to measure behavioral and emotional aspects of parenting linked to healthy child adjustment. Ratings of subjective intoxication and measures of products’ putative THC/CBD content will be collected throughout the study to characterize dose-response. Aim 1: Describe how parents who routinely use cannabis approach cannabis use with children Aim 2: Determine the acute effects of cannabis use on parenting behavior Aim 3: Test potential moderators of the acute effects of cannabis use on parenting The team has expertise in cannabis, parenting, & child mental health and experience leading both intensive EMA studies of cannabis use and in-home assessments of parent-child interactions. This project will yield rigorous evidence on the acute effects of cannabis use on parenting. This evidence will be useful for parents, clinicians, and the public health conversation around cannabis.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Early life stress (ELS)—defined as experiences that threaten the fulfillment of an individual's basic needs leading to prolonged stress—is a well-established risk factor for the development of internalizing and externalizing psychopathology symptoms. Yet, the mechanisms through which ELS contributes to later mental health outcomes remain unclear. Guided by a biopsychosocial framework and informed by developmental psychopathology and behavioral genetics, the proposed project aims to clarify how ELS becomes biologically embedded to influence adolescent psychopathology. Research suggests that stress-responsive biological systems—such as the hypothalamic-pituitary-adrenal (HPA) axis, immune system, and epigenetic regulation— may serve as mechanistic pathways linking ELS to mental health outcomes, but these systems are rarely studied together, and genetic confounding is often unaddressed. This study leverages the Arizona Twin Project, an ongoing, longitudinal twin study representative of the southwestern United States, to address these gaps. The specific aims are to: (1) identify distinct dimensions of ELS and test whether they differentially predict internalizing and externalizing symptoms; (2) examine whether biological mechanisms—specifically hair cortisol concentration, inflammatory markers, and DNA methylation— mediate associations between ELS dimensions and adolescent psychopathology; and (3) use biometric twin modeling to estimate genetic and environmental contributions to these biological mechanisms and their associations with psychopathology. By modeling multiple forms of ELS and multiple biological systems in a genetically informed design, this project will enhance specificity in identifying modifiable mechanistic targets for prevention. The proposed training plan will support the applicant's development into an independent clinical scientist with expertise in developmental psychopathology, behavioral genetics, and biobehavioral mechanisms of stress. Under the guidance of an expert, interdisciplinary mentoring team, training goals include: (1) formal instruction and experiential training in biological data analysis (e.g., HPA axis, inflammation, epigenetics); (2) advanced training in quantitative methods, including longitudinal modeling and twin methods; (3) ongoing professional development in research ethics, dissemination and translation of findings, and career advancement. The fellowship will take place within the collaborative and interdisciplinary training environment at Arizona State University, under the mentorship of experts in developmental psychology, health psychology, neuroscience, and behavioral genetics. This NRSA fellowship will prepare the applicant for a research career focused on identifying modifiable biological mechanisms to inform personalized prevention and improve public health outcomes for youth exposed to ELS.

NIDA - National Institute on Drug Abuse

Project Summary This STTR Phase I application brings together a company, Unchained Health, Inc., with the mission of reducing the burden of addiction, and a leading addiction researcher, Dr. Danielle Dick, Director of the Rutgers Addiction Research Center, to develop an interactive, web-based personalized prevention program for addiction for commercialization. Substance use disorders (SUDs) are among the most costly health conditions, creating a tremendous burden on affected individuals, families, and society at large. Because the development of SUD is preceded by a prolonged trajectory of risk related behavior, there should be ample opportunity to intervene early to prevent progression to problems. Based on the current research, we know who is most at risk for SUDs; however, there is no product currently available to bring this information to the public at scale. ~80% of individuals say they would want to receive personalized risk information for SUDs. This proposal would create a novel interactive program that will deliver personalized risk information, followed by tailored evidence-based recommendations and resources to reduce risk. Unchained Health, Inc. plans to bring this interactive feedback program to the public on a scale appropriate to the magnitude of the problem. It capitalizes on Dr. Dick’s 20+ years of NIH funded research on risk prediction for addiction, and how to create engaging prevention programming. Importantly, Dr. Dick’s preliminary work suggests that personalized risk information is more effective at reducing substance use than standard prevention programs. The Phase I Specific Aims focus on feasibility and commercial potential. In Phase I we will (Aim 1) Build the interactive personalized feedback program on Unchained Health, Inc. platform. The program will consist of two primary parts: (Part 1) the delivery of personalized risk estimates, and (Part 2) the provision of tailored resources to reduce risk. (Aim 2) Conduct an initial market survey to gauge interest and evaluate product price points from two primary target audiences: (1) emerging adults, who are entering a high risk period for the onset of SUDs, and (2) parents of emerging adults, who want to assist their children with avoiding problems and promoting well-being as they transition into adulthood. We will also (Aim 3) seek input from the FDA about possible regulatory requirements. Phase 1 Deliverables will be an executed licensing agreement with Rutgers, a minimum viable product, market data on interest and customer acquisition costs to guide direct-to-consumer marketing strategy, and guidance from the FDA. These activities will lay the foundation for a Phase II application, which will focus on customer feedback on the platform for program refinement, an RCT to evaluate and quantify effects on substance use and mental health associated with program engagement, and further refinement of marketing strategies. At the completion of Phases I and II, we aim to have a novel prevention program ready for commercialization, with the ultimate goal of reducing the burden of addiction and promoting healthy outcomes.

NIH

The proposed Career Development Award (CDA-2) would support Dr. Hannah Grigorian, Advanced Postdoctoral Fellow within the VISN 1 New England Mental Illness Research, Education, and Clinical Center (MIRECC) in her transition to independence as VHA researcher with a focus on transdiagnostic interventions for intimate partner violence (IPV) use. Romantic partnerships greatly impact mental and physical wellness. However, these vital relationships are frequently put at risk by the use of IPV by Veterans. In the past year alone, up to 90% of Veterans endorsed psychological IPV use (e.g., threats) and 30% endorsed physical IPV use (e.g., choking). As a prevalent and detrimental problem, interventions are gravely needed that consider primary drivers of IPV use: internal emotional processes and intimate relationship functioning (e.g., intimacy, communication, conflict resolution). Intervention development holds particular importance for Veterans who have few treatment options and present with distinct risk factors. For instance, co-occurring PTSD and alcohol misuse (i.e., hazardous alcohol use or alcohol use disorder; AUD) exacerbate risk for intimate relationship dysfunction and IPV use among Veterans through overlapping processes (e.g., emotional numbing, social erosion, increased threat perception). Despite high prevalence of co-occurrence and well-defined impact on IPV use risk, Veterans with PTSD and alcohol misuse are not well served by current IPV use interventions or evidence-based practices for co-occurring disorders. Existing VHA IPV use interventions either silo Veterans to alcohol use programming before violence intervention or do not provide tailored, individual programming With these limitations, existing referral lines for IPV increase likelihood for dropout and evidence higher rates of IPV use following treatment. Further, while evidenced based interventions for PTSD and alcohol misuse show distinct promise in symptom reduction, they do not necessarily improve psychosocial functioning. A new intervention is needed which can provide individualized treatment for Veterans with PTSD and alcohol misuse targeting intimate relationship functioning and IPV reduction. Acceptance and Commitment Therapy (ACT) is a promising avenue for intervention development. Increasing "psychological flexibility" via ACT, or value-driven functioning in the presence of challenging internal experiences, addresses a transdiagnostic process spanning across PTSD, alcohol misuse, intimate relationship functioning, and IPV use. The proposed five year RR&D CDA The Development of a Transdiagnostic Intervention to Improve Social Functioning and Intimate will adapt existing ACT treatments to Veterans with PTSD and alcohol misuse who use IPV. Over the course of the award period, the applicant will develop, refine, and pilot this individual, manualized treatment called: ACT for Social Health, Achievement, and Relationship Effectiveness (ACT- SHARE). The three aims of the current proposal are informed by Stage 1A of the Behavioral Therapy Development Model. Phase 1 aims to adapt existing ACT protocols in collaboration with Veteran and provider stakeholder feedback while phases 2 and 3 utilize iterative piloting. Phase 2 will serve as an initial field test of ACT-SHARE with an emphasis on ongoing feedback and the development of therapist rating forms and training programs. Phase 3 will pilot the adapted intervention, full trial procedures, and training and rating procedures. Primary aims include feasibility and acceptability with exploratory aims examining change scores (e.g., IPV use) and candidate processes. This CDA-2 will directly support an RR&D MERIT proposal to conduct a fully-powered RCT (Stage 2) and will provide invaluable training and mentorship in the following areas: IPV intervention development, PTSD and alcohol misuse research, qualitative methodologies, conducting clinical trials, and VA leadership. In sum, the current proposal is well suited to transition Dr. Grigorian into an independent, IPV researcher developing tailored interventions within the VHA.

National Institutes of Health

-Purpose. This Funding Opportunity Announcement (FOA) issued by NIDA and NIMH solicits Research Project Grant (R01) applications from institutions/ organizations that propose to study the development of the frontal and prefrontal cortices, together with the subcortical areas of the limbic system, that play significant roles in mediating emotional and motivated behavior. This initiative is designed to support basic neuroscience research into the fundamental mechanisms of development of the frontal and prefrontal cortices, as well as the midbrain and basal forebrain structures that mediate a number of functions related to drug abuse and psychiatric disorders including: the euphoric properties of drugs, actions of psychotherapeutic agents, and cognitive and emotional functions. A major goal of this initiative is to understand how exposure to drugs of abuse affects the cellular and molecular mechanisms underlying nervous system development of circuits implicated in drug reward and addiction. An additional goal is to understand how alterations in the normal developmental trajectory of cortical and limbic areas might underlie the pathophysiology of psychiatric disorders with putative developmental etiologies. -Mechanism of Support. This FOA will utilize the NIH Research Project Grant (R01) award mechanism. -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.

NIMH - National Institute of Mental Health

Human brain rhythms serve as representations of inner states of the brain for vigilance and behavior. Dysregulation of brain rhythms is implicated in most neuropsychiatric and neurodegenerative disorders. The molecular, cellular, and circuit mechanisms underlying mammal brain rhythms have been mainly elucidated in animal models. However, the lack of tractable model has challenged the investigation in human system. We have developed methods to produce the 3D structures representing the human cortical (hCO, human cortical organoids) and thalamic (hThO, human thalamic organoids) areas by applying stem cell technologies. These organoids reproduce the developing and functional human brain. Most recently, we generated ventralized thalamic organoids (vThOs) that contain interneurons that are specifically present in thalamic reticular nucleus (TRN). The fusion or assembly of two or more neural organoids have shown the possibilities to study the interaction of the brain domains. While many previous studies have successfully demonstrated the utility of human brain organoids in modeling diseases, no studies have developed human brain organoids that reproduce human brain rhythms. The neuronal connection between thalamus and cortex are crucial for the formation of human cortical oscillations commonly observed in scalp EEG. Thus, our established hCOs and ThOs are essential elements to produce the cortical oscillations. Here, we will assemble the organoids to test the hypothesis that assembloid of hThO and vThO together with hCO generate thalamocortical oscillations via a synaptic interaction among these functionally distinct organoids. In Aim 1, we will develop hThO-vThO assembloids to produce intrinsic thalamic network oscillations. We will examine the role of TRN GABAergic cells in intrinsic thalamic network oscillations. In Aim 2. we will develop methods to produce hCOs assembled with hThO-vThO thalamic assembloid to generate thalamocortical network oscillations. Here, we will develop a thalamocortical network oscillation that reproduces human cortical rhythms. In Aim 3, we will test effect of the noradrenaline and acetylcholine on thalamocortical oscillation formation by examining the neural gene regulation, cellular and synaptic properties of thalamic neurons, and development of thalamocortical network activity. The results will define molecular, cellular, and circuit mechanisms of how neuromodulators promote proper thalamocortical network oscillation development. Overall, our project will generate the assembloids of cortical and thalamic organoids to reproduce the human corticothalamic oscillation, and will offer a highly innovative platform to define the molecular and cellular underpinnings of human cortical oscillation and its associated diseases.

NIMH - National Institute of Mental Health

Summary There is an urgent need for objective and robust diagnostic indices related to psychiatric illnesses, including obsessive-compulsive and anxiety disorders. Brain-based indices are particularly suited for this purpose, but many of the available brain-based markers have limited scope, require specialized equipment, or have unknown reliability and validity. The proposed research aims to examine the value of data-based, quantitative, and objective markers of dysfunctional electrocortical processes associated with obsessive-compulsive and anxiety psychopathology. The proposed research aims to establish advanced computational indices based on resting electroencephalogram (EEG) recordings that are capable of (1) discriminating between diagnostic categories but also (2) predict transdiagnostic variables such as severity and comorbidity. Specifically, we use state-of-the- art data transformations to extract mechanistically informative indices of spectral shape and alpha-frequency phenomena inherent in EEG recordings during resting states. We will then establish their reliability and internal consistency—prerequisites for using them as markers of inter-individual differences. The indices will then be related to clinical data collected in a large sample of individuals presenting with symptoms on the obsessive- compulsive and anxiety spectrum. A Bayesian Hierarchical Model will be used to aid in data reduction and to measure and heighten reliability of the EEG-derived variables. Finding reliable and valid biomarkers of electrocortical processes has the potential of transforming diagnostic assessment by providing continuous indices of cortical dysfunction. If the goals of this application are met, then reliable and valid indices of electrocortical (dys)function may help to significantly shift clinical practice: In assessment, objective measures of EEG alpha reactivity could be used, for example, to objectively identify patients with perception/attention dysfunction, versus those with generally delayed oscillatory activity and thus more general cortical dysfunction. These inter-individual differences may in the future guide how patients are assigned to individualized treatment protocols as well as for predicting treatment outcome.

NIMH - National Institute of Mental Health

The right dorsolateral prefrontal cortex (dlPFC) is increasingly being targeted with transcranial magnetic stimulation (TMS) to reduce anxiety expression in anxiety disorders, depression, and posttraumatic stress disorder (PTSD). There seems to be clear mechanistic evidence that right dlPFC downregulation of amygdala activity should reduce fear and anxiety. Despite this mechanistic evidence, the primary approaches to treat anxiety with neuromodulation involve right dlPFC inhibition. Accordingly, there is a critical need to understand the mechanisms of action underlying neuromodulatory right dlPFC TMS protocols, yet there is not a standardized protocol to yield such evidence. Concurrent TMS/fMRI offers a unique translational perspective for understanding psychopathology. By experimentally stimulating a region of the brain and then directly measuring the activity evoked by this stimulation, it is possible to causally determine the downstream targets of this region, facilitating the development of novel TMS treatments for disorders like PTSD and anxiety. The objective of the current project is to develop a protocol using interleaved TMS/fMRI that can assess the effect of neuromodulatory (potentially therapeutic) TMS protocols on neural and behavioral measures related to anxiety expression. As a proof of concept, we will determine the effect of continuous theta burst stimulation (cTBS) to the right dlPFC on TMS-evoked fMRI responses in anxious subjects. Our central hypothesis is that cTBS of the right dlPFC will drive down activity throughout its downstream targets, resulting in reduced anxiety and greater TMS-evoked deactivations in these downstream circuits. Accordingly, our approach will be to measure anxious arousal and TMS-evoked BOLD responses before and immediately after 1800 pulses of cTBS, or sham stimulation in 140 high anxious individuals using a within-subjects crossover design. Our primary outcome will be TMS-evoked BOLD responses in a network of downstream targets involved in emotion expression (i.e. amygdala, BNST, sgACC). Aim 1 will be to examine the effects of right dlPFC cTBS vs. sham on anxious arousal. Aim 2 will be to examine the effects of right dlPFC cTBS vs. sham on TMS-evoked BOLD responses. Our exploratory aim will be to determine the links between anxiety phenotype, anxious arousal, and TMS-evoked BOLD responses. Our study team features Dr. Desmond Oathes, who is a pioneer in the field of TMS/fMRI, Dr. Lily Brown, who is the head of the Center for the Treatment and Study of Anxiety, and is led by Dr. Nicholas Balderston, who is (to our knowledge) the only researcher who has successfully combined threat of shock with interleaved TMS/fMRI. This study is innovative because it is the first to combine these technologies to study the effect of neuromodulatory TMS on threat-related TMS-evoked BOLD responses. This project is significant because it will provide future researchers with a systematic approach for evaluating the effectiveness of neuromodulatory TMS protocols on several neural and behavioral indices of anxiety expression. It will also yield direct evidence that cTBS can modulate brain activity associated with anxiety.

NIMH - National Institute of Mental Health

PROJECT SUMMARY: Cognitive flexibility is disrupted in many neuropsychiatric diseases, but how the brain generates flexible behavior is not fully understood. Learning from recent actions requires neural mechanisms that maintain information about relevant decision variables to influence future decisions. Persistent activity in cortical areas required for cognitive flexibility, such as prefrontal cortex (PFC), connect an animal’s choices and recent outcomes. Neural mechanisms for generating and maintaining this persistent activity involve excitatory loops between the neocortex and subcortical structures. Recent studies suggest that the claustrum, a poorly understood subcortical nucleus that forms reciprocal connections with the neocortex, is particularly highly interconnected with cortical areas strongly implicated in behavioral flexibility. We propose to test whether the claustrum contributes to generating flexible behaviors using two tasks, dynamic foraging and reversal learning. These tasks require medial prefrontal cortex (mPFC) and lateral orbitofrontal cortex (lOFC) function respectively, two areas likely influenced by claustrum activity based on recent studies of claustro-cortical- claustral loops. First, we will test the hypothesis that the activity of claustrum neurons encodes decision variables in these two tasks. Second, we will test whether claustrocortical projections contribute to generating persistent cortical activity and influence the encoding of decision variables by cortical neurons. We will further test whether claustrocortical neurons with projections biased to two different cortical areas, Cla→mPFC and Cla→lOFC neurons, form distinct functional modules within the claustrum and whether the claustrocortical projections to mPFC and lOFC influence cortical activity using similar cellular mechanisms. In addition, we will determine whether claustrocortical neuron activity is required for dynamic decision making and reversal learning, respectively. Third, we will test whether claustrocortical projections are required for learning at different timescales, both during and after the acquisition of a reversal learning task. We predict that claustrocortical loops contribute to generating and maintaining persistent cortical activity required for task performance and learning at multiple timescales. Together, these data will represent the first studies of claustrum neurons in well established, carefully controlled, decision-making tasks combined with quantitative models using normative theory. Furthermore, these experiments will directly test effects of claustrocortical inputs on cortical activity during flexible behavior and on an animal’s behavioral responses, enabling the integration of the claustrocortical system into models of flexible decision making and cognitive control in health and disease.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT The Community-Academic Scholars Illinois-Substance Use and Mental Health Mentored Experience and Research (I-SUMMER) program supports undergraduate students in addressing substance use disorders and mental health comorbidity through intensive community-engaged summer research experiences at the University of Illinois Urbana-Champaign (Illinois). This program supports undergraduates who want to make a difference in their local community while developing key research skills. The overall goal of the program is to foster collaborations and drive new initiatives that shape the direction of health research in the state of Illinois, particularly in areas seen as critical to our community, such as the negative health outcomes related to substance use. The participants in this program will be drivers of change as we strive toward community collaboration as the foundation for improving public health. The Community-Academic Scholars I-SUMMER Program is focused on three pillars: research, community engagement, and collaboration. Our goals are to: 1) support and encourage all students to obtain community- driven research experience in the health sciences; 2) motivate learning to address the societal challenge of substance use and mental health disorders; 3) integrate research early in the college experience to encourage critical thinking and analytical skills; and 4) provide hands-on real-world experience in the community that highlights the importance of addressing substance use/misuse. The program pairs undergraduate researchers with an academic- and community-mentor to facilitate meaningful research deemed beneficial to the University of Illinois’ academic, local, and regional communities. Through this 10-week engaged research experience, scholars will participate in hands-on research in the community while working as part of an established community-academic research team. In addition to conducting research, scholars will meet as a cohort for weekly “coffee hours” to learn about a variety of topics including data privacy, leveraging research to create public policy, effective research dissemination, planning for a career in research, and building mutually beneficial and ongoing community-academic research partnerships. This research experience culminates in a poster session where the participants present their findings to campus and community leaders. These scholars will have the opportunity to improve the health and wellbeing of others, while participating in a supportive community of other scholars and receive mentoring from both their academic and community supervisors. By increasing the number of students participating in community-engaged research at Illinois, the Illinois- Substance Use and Mental Health Mentored Experience and Research (I-SUMMER) Program will build long- term partnerships within the local community that endure long after the individual scholars have graduated.

NIMH - National Institute of Mental Health

Abstract Behavioral health crises are periods of extreme suicide risk, yet rigorous causal evidence on the effectiveness and mechanisms of mobile crisis response for suicide prevention remains a critical gap. Existing research largely lacks the study designs needed to definitively establish the added value of in-person mobile response services over telephone-only support. Our proposed project will rigorously evaluate the real-world effectiveness and implementation of mobile crisis services, studying the A3 Crisis Response program in Contra Costa County, CA. This large-scale program includes a crisis call center and 30+ mobile crisis teams, providing 24/7 service to all county residents. With a population of 1.2 million across 19 cities and 700 square miles, the county encompasses a range of communities and socioeconomic variation, positioning this research to be relevant to all Americans. Using a convergent mixed-methods design, we will concurrently and iteratively pursue two integrated aims. Aim 1 will use a quasi-experimental Instrumental Variables (IV) study design to determine the causal impact of mobile crisis response (vs. telephone support only) on suicide, self-harm, and service use and identify mechanisms of effect. Service use outcomes include: involuntary psychiatric holds, psychiatric emergency services and general Emergency Department visits, inpatient hospitalizations, jail intake, outpatient mental health visits, substance use disorder (SUD) treatment visits, and primary care visits. We will then use IV-based mediation analyses to test whether increased engagement with community-based follow-up care (outpatient mental health, SUD treatment, primary care) mediates reductions in suicide, self-harm, and use of acute services/ jail intake. Aim 2 will qualitatively identify effective mechanisms and implementation strategies of mobile crisis response using implementation science-guided ethnography. We will use an ethnographic approach combining multi-sited observations (call center, dispatch, field response, linkages to care, follow-up) and in-depth interviews with crisis response staff, cross-sector partners, and clients to generate qualitative evidence on implementation determinants and mechanisms. Analyses will be guided by the Consolidated Framework for Implementation Research (CFIR). Qualitative findings will be integrated iteratively with Aim 1 to contextualize and explain findings, refine mediators, and guide subsequent analyses. This application directly addresses RFA-MH-25-135 by rigorously evaluating effectiveness and implementation of crisis response for suicide prevention in a real-world system. Building on a 6-year research-practice partnership, this study was co-designed with Contra Costa Health and a community Advisory Board, ensuring strong stakeholder alignment. The integrated mixed-methods design will provide actionable evidence to help policymakers, payers, health system leaders, service users, and families make informed decisions about investing in, implementing, and accessing crisis response services.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY – Cambridge Health Alliance (CHA) Over the last decade, there has been a dramatic increase in the frequent and high-intensity use of nicotine vaping, cannabis, and alcohol use among adolescents and young adults (AYA), with increasing rates of days and times per month of vaping nicotine, cannabis and consuming alcohol. Remarkably, among adolescents with last month cannabis use, there has been a doubling of cannabis use disorder diagnoses from 29.2% in 2019 to 59.4% in 2022. Adolescents and young adults (AYA) with mental illness are particularly vulnerable to initiation of cannabis, nicotine, and alcohol (CNA) use and have more difficulty quitting, making this population an especially high priority for public health promotion. There have been massive shifts in public policy approaches to substance use in recent years, most notably recreational cannabis legalization (RCL). Emerging evidence shows RCL is linked to increases in cannabis, vaping nicotine and co-use of alcohol and cannabis among youth, but there remains a major gap in understanding of the effects of RCL among AYA with mental illness. This proposal seeks to fill that gap by utilizing a rigorous convergent parallel mixed methods design to a) assess the causal effects of RCL on CNA prevalence, intensity, risk perception, and disorder, and b) to contextualize results with qualitative interviews among AYA aged 12-25 with mental illness. In Aim 1a, we will analyze the 2010-2025 National Survey on Drug Use and Health (NSDUH) providing detailed information on CNA use and risk perception. In Aim 1b, we will analyze the 2018-2025 Population Assessment of Tobacco and Health (PATH) studies, capitalizing on longitudinal data to estimate highly controlled longitudinal causal inference methods (individual fixed effects models) and longitudinal outcomes (time from initiation to disorder). In Aim 2, we analyze comprehensive 50 state Medicaid claims data to assess the effect of RCL on hospitalizations related to CNA misuse and intoxication. In Aim 3, we will conduct qualitative interviews with AYA to gather more nuanced data on the use and co-use of these substances as well as inform and contextualize our quantitative results to inform public policy. The research proposal was developed and will be carried out with intensive collaboration and engagement from AYA with mental illness, caregivers, the Cannabis Regulators Association (CANNRA), and leaders in cannabis and tobacco control and addiction medicine, and will provide actionable information for youth and caregiver groups, and state cannabis control and tobacco control managers.

European Commission - HORIZON

The impact of the use of digital tools outside school and for communication on educational outcomes and mental health. Call: Culture, Creativity and Inclusive Society 2026. Programme: HORIZON. Keywords: Education, general (including training, pedagogy, didactics). Open call from the EU Funding & Tenders Portal.

NIH

Background. Eating disorders (EDs) remain understudied in U.S. military Veterans. However, recent studies have found high rates of EDs in Veteran men and women, which did not differ by race or ethnicity, and which persisted into middle age. EDs are associated with myriad debilitating physical and mental health comorbidities, and high rates of EDs are of concern from a healthcare costs perspective. The minority of people with EDs receive treatment for them. EDs are often undetected in medical settings, and men and people of color are especially unlikely to seek or be referred for treatment. There are critical barriers to care, including availability of providers and the cost of treatment. The Veterans Health Administration (VHA) began training provider teams, which include at least one physician, therapist, and dietician, in 2017; 89 teams have been trained to date. Significance. The inception of these provider teams trained in ED treatment presents an unprecedented and timely opportunity to investigate the impact of training providers on reducing disparities and healthcare costs associated with EDs in VHA. Our aims directly address the Health Systems Research priorities of mental health, women’s health, and health equity. Innovation and Impact. No previous study has investigated whether training providers to treat EDs results in improved detection and treatment of EDs in a large healthcare system or evaluated the impact of ED provider training on racial/ethnic disparities or the total cost of treatment. Our methods capitalize on strengths of real-world observational studies, including greater generalizability, very large sample size, and inclusion of diverse groups that make it possible to evaluate racial and ethnic disparities. Our results will likely reveal that training providers in assessment and treatment of EDs will have a critical impact on detection of EDs, which will greatly improve patient health and well-being and reduce long-term costs to the healthcare system. There is a severe unmet treatment need with respect to EDs across the globe. Our findings will underscore the importance of training providers and providing resources for providers to treat EDs in large healthcare systems, in order to improve the care of men and women with EDs. Specific Aims: 1) Evaluate the effect of implementing VA provider training in ED treatment on the rates of ED diagnosis and treatment among Veterans by (a) modeling within-site change and (b) comparing sites with versus without ED provider teams from one year pre- to post-training. 2) Investigate whether racial and ethnic disparities in ED diagnoses and treatment are reduced following the provider training. 3) Evaluate the effect of implementing VA provider training in ED treatment on the rates, patterns, and costs of healthcare utilization among Veterans with diagnosed EDs. 4) Qualitatively examine a) factors associated with high/low rates of ED diagnosis and treatment following provider training and b) Veterans’ and providers’ experience with ED service delivery. Methodology. The proposed study will use a quasi-experimental design to investigate the impact of the trained provider teams. We will use data from the VHA electronic health record (EHR) to achieve Aims 1-3. For Aim 4, we will conduct qualitative interviews with ED providers and Veteran patients to investigate barriers and facilitators to implementation and sustainability of the training. Next Steps/Implementation: We have identified Dr. Jennifer Strauss, National Director, Women and Gender-Related Mental Health for the Office of Mental Health and Suicide Prevention (OMHSP), as an Operational Partner for this project. Our findings regarding the impact of the ED provider teams on ED diagnosis and treatment, as well as health disparities and healthcare costs, will be shared with OMHSP to inform ongoing training efforts and allocation of resources for these efforts. Results from the qualitative interviews also will provide opportunities for Dr. Strauss to work with individual teams to enhance their productivity and effectiveness. Our findings will underscore the importance of training clinical teams and providing resources for providers to treat EDs in large healthcare systems, in order to improve the care of men and women with EDs.

NIMH - National Institute of Mental Health

Project Summary This project seeks to elucidate sex-specific mechanisms by which maternal immune activation (MIA) during pregnancy impacts cortical development and elevates the risk for neurodevelopmental disorders (NDDs), focusing specifically on the CXCR7 (Ackr3)/CXCL12 chemokine signaling axis. MIA, triggered by maternal infection or inflammation, is a known risk factor for conditions such as autism spectrum disorder and schizophrenia, with male offspring often showing increased vulnerability and differing symptom profiles compared to females. The molecular basis of these sex differences remains poorly understood, representing a critical knowledge gap in both developmental neurobiology and translational medicine. Aim 1 will investigate the physiological role of the CXCR7/CXCL12 axis in corticogenesis, examining how sex-specific regulation of CXCR7 affects neural progenitor cell (NPC) differentiation and migration. By employing Ackr3 knockout models and epigenetic profiling, we will determine how CXCR7 signaling is modulated in male and female NPCs, which may underlie differences in cortical organization between the sexes. Aim 2 will examine the pathophysiological role of CXCR7/CXCL12 in response to MIA, testing the hypothesis that MIA induces a male-specific upregulation of CXCR7 that leads to aberrant cortical development and behaviors associated with NDDs. We will use advanced molecular techniques to assess how CXCR7 activation in males contributes to cortical disorganization, precocious NPC maturation, and behavioral changes, as well as to evaluate the dependency of these effects on maternal IL-17 signaling. Together, these aims will provide mechanistic insights into how intrinsic sex differences interact with environmental factors like MIA to shape brain development and vulnerability to NDDs. This work is significant because it addresses an urgent need to understand how intrinsic sex differences and external maternal immune influences jointly shape neurodevelopmental trajectories. This research ultimately aims to bridge a gap in neurodevelopmental disorder research by providing a clearer understanding of how male and female brains respond differently to environmental stressors during critical periods of development, which may have lasting implications for public health and clinical care.

NIMH - National Institute of Mental Health

Project Summary We live in an ever-constant Ʋuctuation of sensory input, and navigating this can be easily overwhelming. To remedy this, our brains have devised sensory sampling behaviors to rhythmically parse out this input and optimize sensory processing by weighting sensory experiences time-locked to behavior while dampening behaviorally unrelated neural activity. Such “active sensing” is commonly achieved through rhythmic behaviors such as sniffing and saccadic eye movements and can be mechanistically explained by the combination of neural entrainment and phase-amplitude coupling (PAC). Neural entrainment describes the alignment of peak neural excitability to the phase of self-generated sensory input, allowing the brain to better predict and process incoming information. This entrainment can further improve sensory processing through PAC, in which the timing of lower-frequency oscillations (e.g., delta) modulates more localized higher-frequency oscillations (e.g., gamma) associated with sensory processing, enhancing coordination across different brain regions and frequencies. Rhythmic behaviors exist in many forms, with some being less obvious in sensory function, such as motor stereotypies (STY). STY are highly rhythmic and stereotyped behaviors prevalent in autism but also observed in the neurotypical (NT) population, albeit less frequently. Traditionally presumed purposeless, flrst-person accounts by autistics and NTs suggest STY serve as coping behaviors to reduce sensory under/overstimulation from the environment. Our flrst aim probes the relationship between rhythmic behavior and environmental sensory stimulation across diagnosis. We will collect motion-tracking data and ambulatory EEG from autistic and non-autistic children and adolescents (5–17 years) while they explore augmented reality environments of low, medium, and high sensory stimulation. In pursuit of this goal, we will use video recordings and motion-tracking data to build a database for the automated classiflcation of motor stereotypies. We hypothesize motor rhythmicity differences across diagnostic groups and environmental conditions, expecting increased rhythmic movement in autistics compared to neurotypicals, and increased motor rhythmicity during low- and high-sensory stimulation conditions. Our second aim explores the neural mechanisms underlying the sensory processing beneflts of STY. We hypothesize that STY serve an active sensing role in both autistics and NTs by entraining low-frequency neural oscillations, with reduced entrainment and delta-gamma PAC in autistic participants. This novel framework of STY may inform how we design sensory environments to tailor individual sensory needs and assist autistics in developing more efficient sensing behaviors.

NIMH - National Institute of Mental Health

Major Depressive Disorder (MDD) is a serious problem that keeps aggravating yearly. Its pathophysiology remains unclear despite vast amounts of research and the advancements in diagnostics. Common antidepressants have delayed onsets and are unsuccessful in 30% of patients, suggesting other factors play a role. Indeed, a very strong link exists between neuroinflammation and treatment resistant depression (TRD). Hallmarks of depression, like disruption of monoaminergic activity and neural structural/functional abnormalities within mesolimbic regions, have been observed to occur after inflammatory response. However, it remains unclear how inflammation affects circuits dysfunction and MDD development. Our long-term goal is to elucidate the neurobiological correlates of MDD by enabling the investigation of the core neural circuits that underpin its pathomechanisms in humans in vivo. The goal of this project is to elucidate the circuits connecting limbic regions with the nucleus tract solitarii (NTS) in the brainstem. Converging evidence from clinical and preclinical studies points to this circuitry as a major neural route through which inflammatory processes affect limbic regions involved in MDD. We will leverage multi-modal data in non-human primates (NHPs) and humans to: 1. map ground truth anatomy of the limbic-NTS circuits using tracer in NHPs and guide in vivo reconstructions of these connections from high-resolution diffusion MRI (dMRI) in healthy volunteers; 2. map the glia populations of the limbic-NTS circuits using immunohistochemistry in NHPs and guide the interpretation of changes in dMRI measures of glia processes in subjects with TRD in relation to changes in depression severity. DMRI allows to noninvasively delineate neural circuits and detect microstructure changes along them, making it a promising tool to elucidate the relationship between neuroinflammation and depression. However, the study of neural circuitries in depression has been largely limited to major cortical pathways, due to the resolution limits of conventional dMRI and the lack of anatomical ground truth for finer subcortical circuits. Here, we propose a multi-modal approach to generate a novel, validated atlas of the circuits involved in neuroimmune communication between visceral and limbic regions, that will allow accessing the anatomical substrates of neuroinflammation in vivo at unprecedented resolution and accuracy. We will use this atlas to perform retrospective analyses of high- resolution longitudinal dMRI from TRD patients undergoing long-term ketamine treatment. In TRD, ketamine has a rapid antidepressant effect that has been linked to anti-inflammatory mechanisms. The evaluation of advanced dMRI measures of neuroinflammation along these circuits in relation to changes in depression severity will provide novel insights into the interplay between depression and inflammation. By providing a validated atlas for the in vivo investigation of the NTS circuits and candidate imaging biomarkers of neuroinflammation we will unlock more specific approaches to probe the mechanisms of MDD in relation to neuroinflammation, monitor progression, and evaluate treatment response.

NIMH - National Institute of Mental Health

ABSTRACT HIV treatment is an essential pillar of the End the HIV Epidemic (EHE) strategy. Yet, in 2021, of the 1.2 million people living with HIV (PLWH) in the US, only 50% were retained in care, 58% achieved viral suppression and significant racial inequities persisted for Black Americans. HIV treatment outcomes are driven by poor access to HIV clinics; and for those who are on treatment, many forget to take their daily oral antiretroviral therapy (ART). Long acting injectable (LAI) ART, approved for every 1- or 2-month administration, can combat memory barriers related to taking a pill every day, but HIV clinic access remains a challenge, especially for Black Americans who are less likely to live near an HIV clinic. To increase equitable LAI ART access and viral suppression, we propose integrating LAI ART in pharmacies. Despite promising evidence that pharmacies with specialized HIV training can increase ART adherence and viral suppression, pharmacies with specialized HIV training are uncommon, likely because no free, widely available HIV treatment pharmacy trainings exist. Our work has shown that expanding HIV services in pharmacies could drastically increase access, but training is critically needed to develop a model for integrating LAI ART specifically into pharmacy workflow. Thus, we propose the Pharmacy- based LAI ART versus Clinic Effectiveness (PLACE) study to evaluate administration of LAI ART within pharmacies versus HIV clinics. We aim to 1) Examine the policy- and pharmacy staff-level barriers and facilitators of adopting LAI ART services in pharmacies among key stakeholders (policy members, pharmacy staff, HIV- clinic staff, and PLWH), 2) Develop and evaluate a pharmacy-based LAI ART training, and 3) Test the integration of pharmacy-based LAI ART delivery in pharmacies compared to HIV clinics on effectiveness, implementation, and clinical outcomes. Guided by the Exploration, Preparation, Implementation, Sustainment framework, this study will include three phases. An exploration phase of 300 online pharmacy staff surveys, and in-depth interviews of 10 Board of pharmacy members who shape pharmacy policy, 40 pharmacy staff, 10 HIV clinic staff (clinicians and nurses) and 40 diverse PLWH that examine the barriers and facilitators to pharmacy-based LAI ART provision. These data will inform the preparation phase which will develop a hybrid (virtual/in-person) LAI ART pharmacy training that will be tested among 100 community pharmacy staff. Finally, an implementation and sustainment phase, will evaluate the acceptability, feasibility, reach by race and ethnicity, uptake, costs, viral suppression and visit adherence of LAI ART service integration in 5 community pharmacies compared with 2 Ryan White funded HIV clinics among 222 LAI ART patients. Findings will inform a model that could be implemented across Ryan White funded clinics to scale pharmacy-based LAI ART services in the US Southeast where efforts to improve equitable HIV treatment and reduce HIV transmission are desperately needed to EHE.

Administration for Children & Families - ACYF/FYSB

The Primary Prevention Youth Homelessness Demonstration Program provides funding to identify and implement strategies and services for youth and young adults between ages 12 and 26 in order to prevent homelessness, including strategies designed to serve youth and young adult populations with a high likelihood of experiencing homelessness, housing instability, particularly among youth at risk of human trafficking; struggling with substance abuse or mental health concerns; or transitioning out of foster care, the juvenile justice system, or a residential behavioral health system. Primary prevention efforts should focus on reasons youth become homeless, such as a lack of affordable housing, poverty, and family dynamics.Grant recipients must also work with youth who have experienced homelessness, are self-sufficient, and can assist with helping design and implement their projects. This includes establishing local youth advisory boards. In addition, grant recipients awarded under this funding opportunity must participate in a federally sponsored evaluation.

Pritchard Beach Waterfront Center Project

Demand for water-dependent programming in SE Seattle is strong. This diverse community deserves safe ACCESS to the unique asset at its back door: Lake Washington. Current Pritchard Beach bathhouse facilities located at 8400 55th Ave S Seattle WA are little used but offer excellent potential as a site for a waterfront center like those at Green Lake or Mt. Baker. This project seeks to create a welcoming, inclusive, fully ADA accessible community boating center that will allow more people, but in particular youth, to experience the mental and physical benefits of recreating & competing in the outdoors, safe access for all, and a variety of programs with material health and academic benefits for youth. Phase I of the project will focus on a community engagement process to document the demand for repurposing the bathhouse and prepare proposals for Phase II. The anticipated project completion date is January 31, 2026.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Adolescence is a postnatal developmental period observed across many species, marked by large changes in behavior driven by extensive remodeling of neural circuitry. It is critical to elucidate how the brain changes in this transient period between childhood and adulthood: the adolescent brain is powerfully dynamic, but this plasticity induces high sensitivity to both beneficial and adverse alterations, including onset of neuropsychiatric disorder. Despite this necessity for scientific understanding to improve neuropsychiatric health outcomes, the biological drivers of adolescent behavior are only partially understood, in part due to limits of human neuroimaging studies and the short duration of adolescence in model species. A plethora of behavioral work emphasizes adolescent hypersensitivity to rewards, resulting in heightened risk-taking and novelty-seeking; a smaller body of evidence suggests adolescents also show altered sensitivity to aversive outcomes. These studies are often limited in interpretation due to risk/reward tradeoff task designs, from which it is difficult to parse out pure reward versus aversion signals. The neural circuitry that underlies sensitivity to both reward and aversion outcomes critically includes the nucleus accumbens (NAc), a region necessary for motivation and decision-making. Two vital regions sending glutamatergic projections to the NAc are the amygdala, known to receive and send signals for affective processing and fear encoding, and the prefrontal cortex (PFC), which is critically involved in executive function and decision-making. High level changes to these systems are well-characterized in the context of adolescent development; however, these changes are most certainly driven mechanistically by alterations at the level of individual synapses. Mechanistic studies at high resolution are necessary to build an accurate model of adolescent behavior and understand how synaptic development drives the transition from childhood to adulthood in both typical and atypical states. With the goal of uncovering the synaptic developmental mechanisms that define adolescent sensitivity to aversive behavioral outcomes, this proposal will use a combination of superresolution histology, ex vivo electrophysiology, behavior, fiber photometry, and optogenetic approaches. The proposed study will test the central hypothesis that different developmental timeframes of synaptic connectivity from two glutamatergic inputs to NAc neurons, the amygdala and the PFC, underlie age-specific sensitivities to aversive outcomes. In addition to providing description of the exceptional training environment and resources available to complete this work, the fellowship training plan in this proposal details specific scientific training goals in histological interrogation of synaptic biology, ex vivo whole-cell patch clamp electrophysiology to quantify functional connectivity, and in vivo studies of synaptic function using fiber photometry. Additionally, the training goals include development of mentorship and pedagogical skills in the laboratory.

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 Epidemiological data consistently show that exposure to chronic stress precedes the onset of several psychiatric disorders. However, there are profound individual differences, with some people demonstrating resilience to the deleterious effects of chronic stress. The biological underpinnings of this individual difference remain poorly understood, hindering efforts to develop new and improved therapeutics. Emerging evidence suggests that long non-coding RNAs (lncRNAs), epigenetic regulators enriched in the human brain, contribute to individual differences in stress responses. LncRNAs comprise a large portion of the human genome and give rise to a comparable number of transcripts as protein-coding genes, yet our understanding of their contribution to human brain function is in its infancy. Several studies profiling the genomic and transcriptomic landscape of depression, a disorder associated with susceptibility to chronic stress, highlighted the regulation of lncRNAs. However, the role of lncRNAs in brain function, including those associated with chronic stress, remains uncharacterized, limiting mechanistic insight and translational potential. We hypothesize that lncRNAs play a key role in individual differences in responses to chronic stress. To test this hypothesis, we propose this study with the overarching objective to expand our knowledge of lncRNAs associated with the response to chronic stress. Bioinformatic integration of genetic, transcriptional, and epigenetic datasets offers a powerful strategy to pinpoint lncRNAs that mediate stress susceptibility and resilience. Specifically, we would harness published genetic analyses of depression to conduct extensive bioinformatic analyses to identify a subset of candidate lncRNA for future experimental analysis (Aim 1). As a proof of concept, we will experimentally explore LINC02977, identified through a multi-omics analysis (Aim 2). These aims will be addressed by: A. further bioinformatic analysis of genome-wide association studies (GWAS) results for depression, focusing on lncRNA and overlaying with data sets from transcriptional and epigenetic studies. B. Combination of genetic expression of LINC02977 in the medial prefrontal cortex of mice of both sexes, with a chronic stress model, followed by behavioral, molecular, and morphological analysis. In summary, this research program is poised to generate critical insights into the contribution of lncRNAs to the molecular basis of individual differences in response to chronic stress. Our application has potential implications for mental health as it may catalyze the development of therapeutic interventions for stress-induced mental health disorders.

NIMH - National Institute of Mental Health

Project Summary The mechanistic target of rapamycin (mTOR) is a serine/threonine-protein kinase that regulates cell growth, proliferation, and synaptic plasticity. Dysfunction in mTOR signaling has been implicated in several neurological disorders, including seizures, autism, and attention deficit hyperactivity disorder. However, there is limited understanding of how abnormal mTOR signaling in specific cell types leads to neuropsychiatric and behavioral disorders. The mTOR controls protein synthesis by sensing nutrient and energy levels. Midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have large somata and widespread axonal arborizations rich in mitochondria. Their high energy demands make dopamine neurons highly sensitive to the status of mTOR signaling. To investigate the role of mTOR signaling in midbrain dopamine neurons, we generated dopamine neuron-specific mTOR conditional knockout (mTOR-cKO) mice by crossing mTOR-floxed mice with DAT-Cre mice. We made the serendipitous discovery that mTOR-cKO mice exhibited a pronounced increase in basal locomotor activity in an open field compared with that of wild-type mice, and a low dose of the stimulant amphetamine increased locomotor activity in wildtype mice but produced a paradoxical calming effect on locomotor activity in mTOR-cKO mice. In addition, mTOR-cKO mice exhibited impulsive behavior and attention deficits. Although mTOR-cKO mice share a striking resemblance to the distinct behavioral endophenotypes of hyperactivity, impulsivity, and inattention, this proposal does not seek to create a mouse model of a human neurodevelopmental illness. Instead, the long-term goal of this application is to investigate cellular and circuit mechanisms underlying the hyperactive and impulsive behavioral phenotypes. Three Specific Aims are proposed. In Aim I, we will examine how mTOR-cKO alters dopamine neuron physiology. In Aim II, we will investigate the mechanisms that underlie differential locomotor responses to amphetamine between the two genotypes. In Aim III, we will investigate the molecular and circuit mechanisms underlying impulsive behavior and attention deficits in mTOR-cKO mice. Together, these studies will elucidate mechanisms that govern hyperactive and impulsive behavior and provide novel insight into the role of mTOR signaling in regulating the function of dopamine neurons.