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National Institutes of Health

- This Funding Opportunity Announcement (FOA) is intended to encourage the development of translational research partnerships between scientists who study basic behavioral processes and those who study the etiology, diagnosis, treatment, and prevention of mental and behavioral disorders (including alcohol and drug use disorders) and the delivery of services to those suffering from those disorders. NIMH, NIDA, and NIAAA are issuing this FOA as part of a major, long-term commitment to (a) encourage the systematic translation of basic behavioral theory, methods, and findings into research designed to reduce the burden of mental illness and behavioral disorders, and (b) encourage basic behavioral scientists to seek a further understanding of behavioral processes through an exploration of how those processes are altered by mental and behavioral alcohol and drug use disorders. -The total amount awarded and the number of awards will depend upon the number, scientific merit, overall quality, duration, and costs of the applications received, as well as on the funds available at the participating NIH Institutes/Centers.-This FOA will utilize the R21 mechanism, and runs in parallel with a FOA of identical scientific scope that solicits applications under the NIH Resource-Related Research Project Grant (R24) award mechanism.-The total project period for an application submitted in response to this funding opportunity may not exceed two years. Direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year.-Eligible organizations: Domestic, for-profit organizations, non-profit organizations, public or private institutions, such as universities, colleges, hospitals, and laboratories, units of State government, units of local government, eligible agencies of the Federal government, community-based organizations, Indian/Native American Tribal Government (Federally Recognized); Indian/Native American Tribal Government (Other than Federally Recognized); and Indian/Native American Tribally Designated Organization.-Eligible Project Director/Principal Investigators (PD/PIs): Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.-Applicants may submit more than one application, provided they are scientifically distinct.-All investigator-initiated exploratory/developmental grant applications described in this announcement will be assigned to Institutes and Centers (ICs) according to standard Public Health Service (PHS) referral guidelines and specific program interests.

National Institutes of Health

- The purpose of this Funding Opportunity Announcement (FOA) is to encourage the development of translational research partnerships between scientists who study basic behavioral processes and those who study the etiology, diagnosis, treatment, and prevention of mental and behavioral disorders (including alcohol and drug use disorders) and the delivery of services to those suffering from those disorders. NIMH, NIDA, and NIAAA are issuing this FOA as part of a major, long-term commitment to (a) encourage the systematic translation of basic behavioral theory, methods, and findings into research designed to reduce the burden of mental illness and behavioral disorders, and (b) encourage basic behavioral scientists to seek a further understanding of behavioral processes through an exploration of how those processes are altered by mental and behavioral alcohol and drug use disorders. -The total amount awarded and the number of awards will depend upon the quality, duration, costs, as well as the number of applications received. Funding decisions will reflect the needs, priorities and mission of the funding IC(s).-This funding opportunity will use the R24 mechanism, and will be run in parallel with a funding opportunity announcement of identical scientific scope that will utilize the Exploratory/Developmental (R21) mechanism (PAR-06-355). -Eligible organizations include for-profit organizations, non-profit organizations, public or private institutions, such as universities, colleges, hospitals, and laboratories, units of State government, units of local government, eligible agencies of the Federal government, non-domestic institutions, domestic Institutions, faith-based or community-based organizations, Indian/Native American Tribal Government (Federally Recognized); Indian/Native American Tribal Government (Other than Federally Recognized); and Indian/Native American Tribally Designated Organization..-Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support.-Applicants may submit more than one application, provided they are scientifically distinct.-See Section IV.1 for application materials.-Telecommunications for the hearing impaired is available at: TTY 301-451-0088.-Initial merit review will be convened by the assigned institute

CA Dept of Veterans Affairs

Grants supporting veteran service organizations providing housing, employment, and mental health services.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT Suicide is a leading cause of death among adolescents in the U.S., and increasing youth access to effective interventions is a critical aspect of suicide prevention. To address this public health concern, many schools have adopted suicide prevention and intervention policies that include plans for identifying and responding to adolescents with risk, creating high demand for easily accessible evidence-based treatments for diverse youth with suicide risk in school and community settings. However, the limited implementation of evidence-based suicide interventions outside of specialty psychiatric settings is a major barrier to effective adolescent suicide prevention, especially for youth in areas with mental health professional shortages. As a network of publicly funded integrated health care clinics located on K-12 school campuses, school-based health centers (SBHCs) are well positioned to receive and treat youth whose risk of suicide is identified in schools, regardless of their insurance status or their ability to pay. SBHCs can increase youth access to evidence-based treatments for mental health problems and are crucial partners of comprehensive adolescent suicide prevention and care plans in schools. The Collaborative Assessment and Management of Suicidality for Teens (CAMS-4Teens, C4T), adapted from CAMS for adults, has reduced suicide risk in adolescents in an open trial conducted in clinical settings. The successful implementation of C4T in SBHCs is important for increasing youth access to evidence-based suicide intervention. Thus, we propose a Hybrid 1 implementation-effectiveness trial that will examine the feasibility and potential effectiveness of implementing C4T in Oregon SBHCs. First, we will engage partner perspectives for deploying C4T training and practices in SBHC settings. We will hold formative interviews with personnel from 11 SBHCs, 5 medical sponsor administrators, and 5 school personnel to assess the barriers and drivers of implementing C4T. We will also invite partners to join a Network Improvement Community to monitor and inform the planning and implementation of C4T. Second, we will conduct a case study with one SBHC site to test the acceptability, feasibility and appropriateness of the implementation strategies and iteratively refine C4T implementation over three patients. Third, we will implement a Hybrid 1 trial of C4T in 10 SBHCs to evaluate its potential effectiveness on patient (ages 12-17) outcomes, while also assessing implementation factors and clinician outcomes, targeting suicidal thoughts and behaviors and possible mechanisms of action: hopelessness and suicide cognitions. This mixed methods study will result in a R01 proposal to conduct a fully powered implementation trial of C4T in Oregon SBHCs. Together, this work will help increase youth access to evidence-based suicide interventions in geographically diverse settings.

NIH

Significance to VA: Providing care to individuals with serious mental illness (SMI) is challenging, requiring ongoing monitoring, treatment adjustments, and coordination of various medical and social services. Rates of emergency service and hospital use are high due to unexpected social, medical, and mental health crises. A variety of stressors and poor adherence with treatment are common and can lead to rapid worsening in symptoms, job loss, homelessness, incarceration, or suicide. Clinician visits can be infrequent. Patient- clinician contact between visits is challenging and often nonexistent. As such, illness exacerbations usually occur with no clinician awareness in real time, leaving limited opportunity to provide services. This project studies, in Veterans with SMI and high risk for acute care, the effectiveness of an enhanced care coordination mobile intervention (CCM) that uses passive mobile data and support from peer coaches. We hypothesize that CCM will reduce the need for acute care services in comparison to usual care. For the large population of Veterans with SMI, we need efficient interventions that are capable of monitoring and quickly detecting worsening behaviors and illness, to inform care coordination, outreach, treatment, and services. This project responds to the VA Health Systems Research priority topics of Data Science and Systems Science, and to Mental and Behavioral Health. Innovation & Impact: The outcomes of this study inform whether and how to improve care with CCM. The use of passive mobile data to support improvements in behavior and care coordination in mental health is highly innovative, as is peer coaching for this purpose. If CCM is effective, it has the potential to improve routine practice and outcomes. Specific Aims: Among Veterans with SMI: 1. Engage Veterans and clinicians in co-design activities that adapt previously tested protocols and tools to guide implementation of enhanced care coordination with mobile (CCM intervention) that includes passive mobile monitoring of Veterans’ mental health status, technology and behavioral supports from peer coaches, and care coordination within a Behavioral Health Interdisciplinary Program (BHIP). 2. Determine the effectiveness of CCM on acute care use. Implement CCM using protocols and tools from Aim 1 and randomize high-risk patients with SMI to CCM or usual care for 9 months. 3. Evaluate implementation of CCM. 4. Conduct a budget impact analysis of CCM. Methodology: 1. Population: patients with SMI and high risk for acute care use. Intervention: enhanced care coordination within a VA BHIP program using passive mobile monitoring and supports from peer coaches Comparison: effectiveness trial with patient-level randomization to CCM or usual care for 9 months Outcome: reduction in use of urgent care services (emergency visits, hospitalization, or death) 2. Qualitative and quantitative methods Path to Translation/Implementation: The Office of Mental Health, and the Office of Connected Care are partners on this study and oversee issues addressed here for VA: mental health and virtual care. Both offices have provided their strong support and plan to use results from this study to inform delivery of services.

NINR - National Institute of Nursing Research

PROJECT SUMMARY The carework sector is both a fundamental part of our economy and the backbone of our health and social safety net. Whether working in healthcare, education, or social services, 20% of U.S. workers provide essential care for the ill, the elderly, individuals with disabilities, and children. The U.S. care workforce is predominately women, with women from minoritized racial and ethnic groups disproportionately concentrated in the lowest-paying positions and sectors. Despite our dependence on this workforce for our nation’s well-being, we know comparatively little about how care work impacts the health of those who perform it. Research on this question is critical not only for designing interventions to support the health and retention of these workers, but also for elucidating broader mechanisms through which work functions as a social determinant of health (SDOH) for women and minoritized populations. We propose a mixed-methods investigation, combining quantitative analyses of the Panel Study of Income Dynamics (PSID) and National Health Interview Survey (NHIS) with qualitative interviews of care workers. Our approach will test whether care work is associated with a care work health penalty, conceptualize and measure how pathways such as devaluation and workplace conditions drive this penalty, and consider whether these pathways disproportionately impact minoritized groups. To help guide our research and dissemination to reach a wide audience, we will establish a community-based advisory board (CAB) and a policy advisory board (PAB). In Aim 1, we will use the NHIS and PSID to describe the health status of care workers and test whether there is a health penalty for being employed in care work relative to comparable non-care occupations over the life course. This analysis will assess a range of physical and mental health outcomes, including self-rated health and indicators of stress and burnout. Aim 2 will examine the pathways through which care work may lead to negative health outcomes, focusing on our four hypothesized mechanisms described above: intersectional devaluation, risk of injury and illness, a racialized and gendered “ethic of care,” and resource-constrained work environments. Qualitative interviews with 125 low-wage workers and higher- wage health care workers will be used to refine our conceptual model, identifying how these mechanisms manifest in the lived experiences of workers. Insights from these interviews will inform the refinement of quantitative measures in the NHIS and PSID datasets. Quantitative analyses will then test the relative contribution of each mechanism to the health penalty and investigate interactions with race-ethnicity. Finally, in Aim 3, we will measure the relationship between employment in low-wage carework occupations and health over the life course. We will also test interactions between low-wage carework, race-ethnicity, and mental and physical health outcomes. Qualitative interviews will explore how care workers experience these intersectional vulnerabilities in their workplaces, with particular attention to the compounded impacts of racism, sexism, and economic precarity.

NIMH - National Institute of Mental Health

Project Summary/Abstract The ability to reduce fear responses through extinction when threats are no longer present is essential for mental health. Deficits in extinction underlie fear-related disorders such as post-traumatic stress disorder (PTSD). A critical gap remains in understanding the neural mechanisms underlying fear extinction, which poses a major barrier to developing more effective therapeutic interventions. The amygdala (AMY)-prefrontal circuits are critical in fear extinction. In animal models, the lateral nucleus of AMY (LA) receives sensory inputs and initiates fear learning, while the basal nucleus of AMY (BA) integrates regulatory inputs from the ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) for appropriate fear response. However, due to species-specific differences between animal and human neurobiology, the nucleus-specific contributions of the AMY and their interactions with vmPFC/dACC in human fear extinction and regulation remain poorly understood. Clinically indicated stereoelectroencephalography (SEEG) electrodes, which allow direct recording and stimulation of AMY-prefrontal circuits, provide a unique opportunity to address this critical gap. The long-term goal of the candidate is to uncover the neural mechanisms underlying fear processing through intracranial electrophysiology and neuromodulation in humans, and to bridge systems and affective neuroscience with the development of targeted therapeutic interventions. The objective here is to determine the causal dynamics of the AMY-prefrontal circuits involved in fear extinction learning in epilepsy patients undergoing SEEG monitoring. Specifically, this proposal will address three Aims: (1) Determine the intrinsic and stimulation-induced dynamics of human AMY-prefrontal circuits (K99). The study will create an unambiguous delineation of cause-effect relationships in AMY-vmPFC-dACC circuits by delivering single-pulse and high-frequency electrical stimulation to the circuits. (2) Characterize nucleus-specific and lateralized dynamics of AMY-prefrontal circuits during fear extinction (K99/R00). The study will reveal the neural dynamics of LA, BA, and left/right AMY-prefrontal circuits in fear extinction and regulation. (3) Determine the modulatory effects of theta-burst stimulation of AMY nuclei on fear extinction (R00). Theta-burst stimulation will be applied to the LA and BA during extinction learning. Dr. Xie will conduct this research and training through the Epilepsy and Human Brain Mapping Program (one of the highest-rated epilepsy programs in the United States) at WashU Medicine, the Grady Trauma Project (the largest civilian research project on the effects of trauma and PTSD in the world) at Emory University, and the National Center for Adaptive Neurotechnologies (the only neurotechnology center in the United States that is funded by NIH). In the K99 phase, Dr. Xie will receive training in five key areas to lead successful intracranial electrophysiology and brain stimulation studies: psychophysiology, neuromodulation, neural analytics & modeling, clinical research, and career development. The training gained from pursuing the proposed aims will be essential for Dr. Xie to attain his independence as a researcher in systems/affective neuroscience and neuromodulation.

NIMH - National Institute of Mental Health

Project Summary Neuropsychiatric disorders frequently fail to respond to first-line treatments, highlighting the urgent need for innovative therapeutic approaches targeting underlying neural mechanisms. A common feature across neuropsychiatric disorders is pathological expectation states, including both pathologically negative expectations (e.g., major depression: pessimistic future outlook, social anxiety: anticipated rejection, generalized anxiety: catastrophic forecasting) and positive expectations (e.g., gambling disorder: anticipation of unlikely wins, substance use disorder: overvaluation of drug rewards, bipolar mania: unrealistic optimism about risky behaviors). The proposed project will examine the causal role of frontal cortical circuits in generating and updating affective expectations. Leveraging cutting-edge neuromodulatory and high-density recording techniques, this research will determine how non-human primate orbitofrontal cortex (OFC) influences behavior through outcome expectation signals and how these signals can be modulated with precisely targeted electrical stimulation. The experimental approach centers on a novel behavioral paradigm that captures the dynamic nature of expectation-guided behavior in macaque monkeys. By monitoring continuous behavior following expectation violations, this paradigm provides unprecedented sensitivity to detect both the persistence of expectation bias and the temporal dynamics of behavioral updating. This investigation will: (1) Establish the causal relationship between OFC activity and expectation-driven behavior through temporally specific microstimulation; and (2) Elucidate the functional network dynamics between three interconnected cortical regions integral to expectation bias and error signaling—OFC, anterior insula, and anterior cingulate cortex— during expectation generation, violation detection, and behavioral adjustment processes. By simultaneously recording from multiple cortical regions with high-density electrode arrays while delivering targeted neuromodulation, this work will reveal how expectation and error signals propagate through frontal cortical networks and how this propagation can be influenced by exogenous stimulation. The basic and translational implications of this work are significant. From a basic science perspective, the proposed work will elucidate the network effects of targeted microstimulation and the causal contributions of OFC activity to motivated behavior. Translational significance lies in identifying specific neural circuit mechanisms that could be targeted to disrupt pathological expectation patterns in clinical populations. These findings will inform the development of next generation neuromodulatory therapies with enhanced spatial, temporal, and computational specificity for treating conditions characterized by persistent maladaptive expectations.

NCIPC - National Center for Injury Prevention and Control

The Family Violence Prevention and Services Act (FVPSA)-funded Promising Futures initiative strengthens organizational capacity among community agencies to support families impacted by intimate partner violence (IPV). This proposed study will evaluate the impact of adding training and technical assistance (TTA) in healing- centered systems integration (All In For Kids model, AIFK) on reducing child abuse and neglect (CAN), IPV, and parental mental health conditions. This proposal responds to the call for rigorous evaluation of community- level primary prevention approaches to prevent adverse childhood experiences (RFA-CE-25-025), specifically, existing primary prevention approaches that address community-level conditions and strengthen economic supports to families (Research Objective 3). Since 2016, Promising Futures, a project of Futures Without Violence (FUTURES, national non-profit violence prevention organization), has provided support to a network of IPV state coalitions, local community-based programs, and other child-serving systems on enhancing services for families impacted by IPV. Opportunity to drive systemic change is hampered by siloing of systems, few incentives for cross-sector collaboration, limited involvement of community members in designing solutions, and challenges in collating and using shared data and metrics to monitor progress. To address these challenges, All In For Kids (AIFK), also a project of FUTURES, focuses on healing-centered systems integration to design responsive healing and caring early childhood ecosystems across health, education, and community sectors. AIFK promotes systems-level changes to sustain services, policies, and practices that result in holistic well-being across generations including strengthening economic supports to families. The proposed study will evaluate addition of AIFK healing-centered systems-transformation TTA with existing Promising Futures sites as a primary prevention approach to prevent ACEs. The research team has expertise in cross-sector collaboration, implementation science, community-partnered evaluation, healing-centered engagement, and science of thriving. This team will lead evaluation of the effectiveness of adding systems integration training via the AIFK model with Promising Futures grantees compared to matched grantees receiving usual support on CAN, IPV, parent mental health conditions, child thriving, and connectivity of early childhood ecosystems (Aim 1). The team will document implementation processes using qualitative and quantitative methods (Aim 2). With site leads and community partners, the team will disseminate lessons learned about use of community-led systems design to envision ideal structures, implement cross-sector solutions with measurable results, and improve prevention of ACEs (Aim 3).

NCIPC - National Center for Injury Prevention and Control

This K01 award application is for Dr. Lindsey Palmer, a PhD-trained social worker whose overarching career goal is to become an independent violence prevention scientist, focused on promoting child health and well- being by advancing data-driven, evidence-based strategies to prevent maltreatment and its long-term consequences. This K01 will support three key areas of career development: 1) the application of machine learning approaches on violence prevention research, 2) cross-cutting violence prevention strategies, and 3) professional development and leadership. Dr. Palmer has assembled an interdisciplinary mentoring team comprised of Kristine Campbell, MD, MSc, a nationally recognized expert in pediatric child maltreatment with extensive experience collaborating with public agencies to develop cross-system prevention efforts; Fernando Wilson, PhD, an expert in the application of machine learning techniques on large-scale databases to examine health services and policy; Brooks Keeshin, MD, an internationally recognized expert in trauma assessment and suicide prevention; and Angela Fagerlin, PhD an expert in faculty enhancement, leadership and representation. Over the past decade, rates of self-directed violence (SDV) have risen sharply, particularly among 10- to 17-year-olds, with children and adolescents who have experienced maltreatment being at particularly heightened risk. A staggering 57% of children and adolescents who die by SDV have a history of alleged child maltreatment, which encompasses physical abuse, sexual abuse, emotional abuse, physical neglect, and exposure to intimate partner violence. These youths often face the compounded challenges of trauma, family dysfunction, and mental health issues. While child welfare system (CWS) involvement frequently signals heightened vulnerability, the pathways linking child maltreatment to SDV remain poorly understood. Contributing factors such as parental mental illness, substance use, overlapping forms of maltreatment, family instability are not well defined or understood. Additionally, there is limited evidence on the effectiveness of CWS interventions in reducing the risk of SDV for these children. This study’s Specific Aims include: 1) Determine the relationship between child maltreatment and SDV, specifically: Establish how the timing, type, and frequency of child maltreatment indicators are associated with SDV; and characterize the association between child maltreatment intervention and SDV; and 2) Leverage machine learning based approaches to identify direct and indirect pathways between child maltreatment and SDV, focusing on the progression of suicidal thoughts and behaviors over time. This study is significant and innovative because it will clarify the relationship between child maltreatment and SDV, identify high-risk subgroups, and examine if existing CWS interventions mitigate or exacerbate SDV risk, providing critical insights into the strengths and limitations of current maltreatment practices in reducing other forms of violence.

NCIPC - National Center for Injury Prevention and Control

PROJECT SUMMARY/ABSTRACT People involved in the criminal legal system (CLS) face a disproportionately high burden of substance and opioid use disorders (SUD/OUD), which upon release from jail or prison is compounded by lack of access to care and results in extremely elevated post-release drug overdose mortality. Few interventions have been able to reduce overdose risk among CLS-involved people. A number of ongoing studies are testing strategies for linking CLS-involved people to medications for OUD (MOUD) in the community. However, lack of insurance for many CLS-involved people makes these care linkages unsustainable after study completion. Medicaid expansion provides an avenue to address healthcare needs for many CLS-involved people. Recent studies show that pre-release Medicaid enrollment increases post-release MOUD and reduces overdoses for CLS-involved people. However, benefits appear to accrue to white individuals and not to black individuals – a concerning inequity because overdose deaths are rapidly increasing among racially minoritized people in the US. Research to date, which has been ecological, has not been able to identify the mechanisms by which Medicaid enrollment may improve MOUD and overdose outcomes and why these benefits may differ across racialized groups. Large, longitudinal, individual level data can map the pathways through which Medicaid expansion benefits some groups but not others. While overdose prevention work among CLS-involved people deservedly focuses on MOUD access, the role of mental health treatment is also critical. Two-thirds of people with OUD have co-occurring mental health needs, a burden that is likely even higher among CLS-involved individuals. Hence, MOUD without mental health care may fall short in MOUD engagement and overdose prevention for CLS-involved individuals. In this application, we propose to conduct a quasi-experimental study, by leveraging the 2023 Medicaid expansion in North Carolina (NC), to examine racialized inequities in enrollment in Medicaid among CLS- involved individuals, as well as post-release MOUD and mental health care access. We will further examine the impact of enrollment in Medicaid and MOUD and mental health care access on fatal and non-fatal drug and opioid overdoses. We will use 13 years of Big Data (2013-2025) on all formerly incarcerated people in NC linked with Medicaid and death records, which our team already has access to through two ongoing studies focused on suicide and polydrug overdose prevention. Our study is aligned with RFA-CE-25-149’s Funding Option A. This study will be the first to examine the individual-level impact of Medicaid enrollment, MOUD access, and mental health services on drug and opioid overdoses among CLS-involved people. This study will further identify mechanistic factors that contribute to racialized inequities among CLS-involved people to help enhance and sustain linkage to care for all CLS-involved people, but especially racially minoritized individuals, thereby enhancing the impact of Medicaid expansion for all people.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Major depression impacts >350 million lives worldwide and contributes to 1 million suicides each year. Although depression is treatable, approximately one-third of patients are classified as having treatment-resistant depression (TRD) due to inadequate response to first-line pharmacotherapies, despite appropriate dosing and duration. Among the alternative treatment options, the FDA-approved neuromodulation therapy of electroconvulsive therapy (ECT), is widely regarded as the most effective acute intervention. ECT is a safe, fast- acting and highly effective treatment for TRD though stigma and risk of short-term cognitive side effects can dissuade eligible patients from treatment. Furthermore, whether mechanisms accounting for ECT’s antidepressant and adverse cognitive effects engage different physiological pathways remain unclear Understanding the therapeutic mechanisms of ECT thus remains a priority for guiding maximally effective ECT treatment with minimal cognitive risks. Existing evidence indicates that the physiological effects of ECT include an initial inflammatory response and at the same time, ECT is shown to induce neurotrophic processes in animal models that appear consistent with findings of neuro-structural and functional changes in human imaging studies of ECT. To address this more specifically, we propose a high-risk/high-reward R21 proposal, in which we will examine the dynamics of circulating cell-free DNA (cfDNA) in the context of ECT in TRD using the infrastructure of an ongoing longitudinal NIMH funded study of ECT in subjects with TRD. cfDNA are short fragments of DNA that are released into the bloodstream from cells throughout the body. These DNA fragments originate from normal cell turnover and can also come from diseased cells. There is evidence that cfDNA can pass the blood- brain barrier which provides opportunity to also examine brain-specific cellular events. DNA methylation patterns of cfDNA are used to identify their tissue and cell-type origins. cfDNA’s ability to provide real-time insights into the dynamics of molecular/cellular processes occurring with ECT holds substantial promise for understanding the temporal mechanisms underlying its therapeutic and cognitive risk effects. Together with biomarkers of inflammatory response collected from blood samples longitudinally at the same time points, and MRI measures of structural and functional connectivity allow empirical evaluation of the disrupt, potentiate and rewire hypothesis, which has been proposed for the mechanism underlying ECT. cfDNA profiling may elucidate whether ECT-induced changes occur at the cellular level and relate to observed patterns of inflammatory response and/or the reorganization of neural networks, all measured in-vivo. This approach has the potential to significantly advance our understanding of ECT's mechanisms and guide improved personalized treatment.

NIMH - National Institute of Mental Health

Project Summary/Abstract Most sensory stimuli acquire value through learning and experience. While progress has been made in deline- ating the circuits involved in sensory value-guided behaviors, the cellular and circuit mechanisms that underlie how distinct value representations are formed during learning, regulated during behavior, and modified to ac- commodate changes in cue-outcome contingencies remain unclear. Resolving these open questions is a funda- mental challenge in neuroscience and will advance our understanding of how synaptic plasticity induced by reinforcement learning is maintained, yet behaviors remain adaptive. The overarching goal of this proposal is to seek a mechanistic understanding of the circuits underlying value-guided learning and action in the mouse me- dial prefrontal cortex (mPFC), a region essential for the imposition of value on sensory stimuli to guide behavior. Using an olfactory-based appetitive classical trace conditioning task in combination with high-density electro- physiological recordings and optogenetics, I will focus on how functionally distinct yet spatially intermingled pop- ulations of neurons encoding rewarded (conditioned stimuli, CS+) and unrewarded (CS-) odors interact within the local network to drive stable yet flexible reward-seeking behaviors. I will test the hypothesis that the CS+ and CS- populations form a mutually inhibitory circuit that underlies their behaviorally-opposing roles in reward-seek- ing (Aim 1, K99). I will investigate how the existence of a CS- population may represent a circuit mechanism to permit the maintenance of prior reinforcement despite the extinction of learned behavior, thus uncovering a pre- viously unappreciated role for the CS- ensemble in reinforcement learning (Aim 2, K99). In my R00 phase, I will interrogate the mechanisms by which CS+ and CS- representations arise during learning, testing the hypothesis that distinct inputs to the mPFC drive the reinforcement of odors predicting the presence or absence of reward (Aim 3a,b). Further, I will study how the CS+ and CS- representations are updated when cue-outcome contin- gencies are reversed (Aim 3c). Finally, I will model the mPFC circuit to reveal fundamental principles on value- guided learning, which will inform future experiments and also extend the insights that could be gained beyond that which is feasible by experimentation (Aim 3d). This work will have broad implications for various neuropsy- chiatric conditions in which adaptive value-guided learning is disrupted, including addiction and depression. Can- didate and Career Goals. I aim to establish an independent research program investigating the neural basis by which value representations are generated and flexibly regulated to support context-dependent behaviors. I have extensive experience in molecular and systems neuroscience and have developed foundational tools and in- sights for studying value learning. Career Development Plan. I will be trained by my mentors Drs. Richard Axel and Larry Abbott. Dr. Axel is a foremost leader in sensory neuroscience, who will guide me on all aspects of experimental design. Dr. Abbott is a world-renowned theorist who will provide training in the analysis and mod- eling of complex datasets. All mentors will provide career development training for my transition to independence.

NIMH - National Institute of Mental Health

PROJECT ABSTRACT There is a paucity of interventions targeted to changing developmental trajectories for young children with disabilities. As we face a continuing youth mental health crisis (currently estimated to affect 13% of youth, with a 35% increase between 2016-2023), there is an urgent need for evidence-based, early intervention that can address skill deficits and improve outcomes. Executive function has been identified as a transdiagnostic, underlying driver of mental health outcomes, and deficits are present across childhood disabilities. Executive function deficits in early childhood predict later aggression, anxiety, and mood challenges, as well as emotional, academic, and adaptive functioning in neurodevelopmental conditions such as autism and ADHD. Children with disabilities and associated early executive function challenges are at elevated risk for preschool expulsion and a subsequent cascade of poor mental health and academic outcomes. Universal (Tier 1) programs for early childhood executive functioning have mixed outcomes and do not adequately meet the needs of children with disabilities and identified challenges with executive function. This project proposes to test a novel executive function intervention, Unstuck and On Target for Early Childhood (Unstuck-EC), compared to a services-as-usual control, implemented by preschool classroom teachers of children with disabilities, as the first Tier 2 (selective) executive function intervention for young children. Unstuck-EC is adapted from the evidence-based Unstuck and On Target: 8-11, which is designed to be implemented in schools as a Tier 2 intervention for executive function challenges in neurodivergent youth. Unstuck-EC has been developed with input from early childhood providers and shown promise of efficacy in a preliminary development trial, when implemented by behavioral and development specialists. Grounded in the PRISM framework, we will collaborate with an advisory board to adapt Unstuck-EC for implementation by preschool teachers. We will partner with local public preschools to conduct a hybrid (Type 1) effectiveness-implementation trial (N=100 Unstuck-EC, N=60 Services as Usual Control), over the course of two school years. We predict that children in Unstuck-EC will show gains in executive function, and teachers will show improved knowledge and use of executive-function supporting strategies. We will also explore potential improvements in child mental health and expulsion risk, as well as in teacher strain and self-efficacy. Finally, we will assess factors related to reach, adoption, and implementation of Unstuck-EC, preparing for a future, larger randomized comparative effectiveness trial.

NIMH - National Institute of Mental Health

HIV persists in central nervous system (CNS) reservoirs despite effective combination antiretroviral therapy (ART), contributing to chronic neuroinflammation and neuropathogenesis. While macrophages and microglia are known cellular reservoirs in the CNS, recent evidence suggests that infiltrating T cells also play a critical role in sustaining viral persistence. Limited access to human CNS tissues hampers our understanding of contributions of the CNS T cell reservoir in HIV neuropathogenesis. To closely examine the effects of HIV infection in the CNS, we will leverage a unique barcoded HIV system in a novel humanized mouse model to study CNS-resident viral reservoirs. Our preliminary data demonstrate that this barcoded HIV, which allows us to track and characterize virus that is being produced from different anatomic reservoirs, establishes a robust infection in both peripheral and CNS tissues, with RNA sequencing revealing upregulated type I interferon signaling and microglial activation, indicating HIV driven chronic neuroinflammation in vivo. Additionally, we have previously demonstrated in non-human primate (NHP) studies that HIV-specific chimeric antigen receptor (CAR) T cells that developed from gene modified hematopoietic stem/progenitor cells (HSPCs) can traffic to the CNS and reduce viral burden, indicating that there are ways to specifically deliver therapeutic antiviral T cells to the CNS. These findings highlight a need to define the mechanisms underlying T cell-mediated viral persistence in the CNS and to optimize CNS reservoir-targeted therapies. In these studies, we propose an integrated approach using barcoded HIV tracking, spatial transcriptomics, single-cell RNA sequencing, and integration site analysis to investigate the contributions of T cell populations in HIV persistence and inflammation in the CNS. Our central hypothesis is that T cells serve as key latent reservoirs in the CNS, promoting chronic immune activation, and that HSPC-derived CAR T cell therapy can effectively target and reduce these reservoirs. To test this hypothesis, we will: 1) Assess T cell reservoirs in the CNS during acute and chronic phase of HIV infection in humanized mice infected with barcoded HIV. 2) Investigate the contributions of T cell populations on CNS inflammation and neuropathogenesis during HIV infection. 3) Evaluate the antigen-specific T cell responses and therapeutic effects of CAR T cells on viral reservoir clearance and neuropathogenesis in the CNS. This study will provide critical insights into the role and consequences of T cell-mediated HIV persistence in the CNS and assess CAR T cells as a novel strategy for reservoir clearance and neuroinflammation reduction, advancing HIV cure strategies.

NIMH - National Institute of Mental Health

SUMMARY Alternative splicing generates isoform diversity and plays an important role in disease. We previously profiled postmortem prefrontal cortices of individuals with major psychiatric disorders and found substantial dysregulation of isoform expression at the bulk tissue level in ASD compared to neurotypical controls. Moreover, changes in isoform expression, rather than overall changes in gene expression, showed the largest effect sizes and genetic enrichments. Our understanding of the contribution of isoform dysregulation to psychiatric disorders remains incomplete because they cannot be fully resolved at the cell type-level by commonly used short-read RNAseq technologies. To address this deficit, we will profile the postnatal development dynamics and cellular context of isoform dysregulation by generating genome-wide high- resolution maps at cellular resolution across the lifespan. We will further integrate these data with existing genotypes for the same subjects to conduct allelic-isoform analyses to map regulatory genetic effects on isoform expression. In Aim 1 we will profile splicing changes in high-quality postmortem prefrontal cortex (PFC) brain tissues of 74 ASD and 74 neurotypical controls at single-nucleus (sn) resolution from childhood to adulthood, using long-read multiplexed arrays isoform sequencing (MAS-Seq) and our IsoPropeller analysis framework to resolve their complete isoform structure and quantitate cell-type specific isoform expression. We will then use these data to identify significant changes in isoform abundance and usage between ASD and controls, and fully delineate cell type and age-dependent expression patterns. In Aim 2 we will leverage our existing cell-type isoform abundance datasets, and further cto deconvolute cell-type specific expression patterns and with the newly generated data in our aim 1 combine analyze dysregulated isoforms across RNA-Seq datasets from >1k ASD and control PFC samples, and to further construct isoform-level co-expression networks. Available genotyping data for the same set of ASD and neurotypical controls will be used to examine cis-regulatory genetic effects on expression by splicing and allelic isoform analyses of expression patterns and to perform functional characterization. Finally, in Aim 3, we will validate selected isoform changes by RNA fluorescent in situ hybridization (FISH) and quantitative isoform-specific PCR in FANS-sorted neuronal and non-neuronal cell types. We will also perform mechanistic assessments of cis-regulatory SNP:isoform associations by introducing SNPs into isogenic iPSCs, and study their effects in isogenic iPSC-derived neural cells. The quantitative isoform maps generated here will allow us to address major outstanding questions regarding control of isoform expression in the brain, and in ASD cases in particular, which is instrumental in unravelling the neurobiological mechanisms of genetic risk for ASD. Our data and results will provide an invaluable resource to the community, and widely applicable to other neurodevelopmental and psychiatric disorders.

NIMH - National Institute of Mental Health

Abstract Autism spectrum disorders (ASD) are neurodevelopmental conditions marked by early-emerging deficits in social behavior, restricted interests, and motor abnormalities. Converging genetic and clinical evidence implicates dysfunction of the dopaminergic (DA) system as a core feature of ASD pathophysiology. DA signaling is essential for the maturation of striatal circuits, which govern reward processing, motor learning, and emotional regulation. However, the developmental origins of dopaminergic dysfunction in ASD, and how genetic risk factors affect striatal DA signaling in vivo during early life, remain unknown. Mutations in SHANK3 are among the most penetrant genetic causes of ASD, and Shank3-deficient mice exhibit early striatal circuit abnormalities, impaired social behavior, and DA neuron dysfunction. Preliminary evidence suggests that loss of Shank3 disrupts DA neuron excitability and alters dopamine release dynamics in the nucleus accumbens (NAc) during ethologically relevant behaviors. However, technical challenges have historically limited in vivo monitoring of DA signaling in developing mouse pups, preventing direct investigation of this hypothesis. To address this gap, we have developed a novel fiber photometry platform optimized for postnatal mice (~P15) using tapered optical fibers, enabling stable, high-resolution recordings of striatal DA dynamics and neural activity during maternal and social interactions. We will combine this in vivo imaging approach with whole-cell electrophysiology and genetic tools to define the impact of Shank3 loss on the maturation of dopaminergic circuits. Aim 1 will quantify in vivo DA signaling in the NAc of P15 Shank3-/- and conditional DA neuron-specific Shank3 knockout mice during maternal and social interaction paradigms. Aim 2 will assess intrinsic excitability and HCN channel function in VTA DA neurons projecting to the NAc, comparing global and DA neuron-specific Shank3 knockouts to isolate cell- autonomous mechanisms of dysfunction. Together, these studies will provide the first real-time characterization of postnatal DA circuit dynamics in a genetically validated ASD model and identify a mechanistic link between Shank3 loss, HCN channel dysfunction, and DA signaling abnormalities. The proposed work will not only establish an innovative platform for studying DA function in early development but also define therapeutic targets for SHANK3-related disorders and other forms of ASD with disrupted striatal dopamine signaling.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Autism spectrum disorder (ASD) affects 1 in 36 children in the U.S. and is characterized by substantial heterogeneity in core symptom severity and co-occurring conditions. These variations complicate diagnosis, intervention, and treatment planning, highlighting the need for characterizing ASD clinical traits that better reflect real-world support needs While ASD has a strong genetic basis with heritability of 0.83, specific prenatal environmental exposures also contribute to risk. However, most existing ASD genetics studies rely on binary ASD case definitions and overlook the role of prenatal risk factors. We propose to use a novel unsupervised machine learning method, discriminative dimensionality reduction tree (DDRTree), to construct ASD subtypes categories, continuous ASD subtype scores and severity based on ASD clinical traits. This approach offers a clear visualization of heterogeneous ASD clinical traits. It also helps identify ASD subtypes and severity based on the natural order of the symptom scores represented in the tree structure. By applying DDRTree model in diabetes, researchers identified patterns of differential drug responses among heterogeneous diabetes patients. In a preliminary analysis of 6,356 autistic individuals from the Simons Foundation Powering Autism Research for Knowledge (SPARK), we identified three clinically relevant subtypes with varying support needs in language, social functioning, and medication use. The proposed study will expand this work using multiple ASD cohorts (N=~55,000) and link subtype variation to genetic and prenatal risk factors. In Aim 1, we will construct ASD subtypes and severity scores using ML models based on symptom and comorbidity data from ~45,000 autistic individuals in SPARK, and validate them in external cohorts (N=~10,000). We will also examine differential use of educational and therapeutic services across subtypes. In Aim 2, we will identify common and rare genetic variants associated with the subtypes and severity using GWAS and whole exome/genome sequencing data. We will map common variant effects to neuronal cell types using public single- cell brain atlases, and assess the contribution of rare inherited and de novo variants using family-based analyses. In Aim 3, we will assess prenatal exposures (e.g., maternal complications and exposures) associated with ASD clinical profiles and build risk prediction models that integrate genetic and environmental data. This project will be led by a multidisciplinary team of genetic epidemiologists, ASD clinicians and statisticians. We aim to improve our understanding of ASD heterogeneity by linking symptom profiles to underlying genetics and early-life exposures. The proposed work will support development of individualized risk prediction tools and inform early screening and intervention. By identifying distinct ASD subtypes with unique genetic and prenatal risk factors, we aim to advance personalized medicine approaches in ASD research and care.

NIMH - National Institute of Mental Health

Project Summary Autism spectrum disorder (ASD) is a neurodevelopmental disorder long associated with functional connectivity abnormalities that are widespread throughout the brain. Despite countless studies on the topic, no single unifying model of functional connectivity abnormalities in ASD has emerged to date. Enthusiasm for studying functional connectivity differences in ASD has subsided in light of evidence of alterations that are more heterogeneous than some of the earlier hypotheses suggested, and because the links of these alterations to neural mechanisms of ASD have been challenging to map. Yet, one related theme that has garnered support has been that functional connectivity in ASD is increased in the bottom-up (or "feedforward") direction and decreased in the top-down (or "feedback) direction. Here, we propose to test a hypothesis that the functional characteristics of ASD are rooted in a fundamental imbalance between feedforward and feedback influences. This hypothesis stems from our preliminary data and prior studies, and it is motivated by many aspects of the ASD phenotype: These include increased perceived salience of sensory stimuli and evidence of reduced top-down control in ASD, which manifest across a range of atypical behaviors characteristic of the disorder. Thus far, mapping feedforward and feedback inputs non-invasively in the human brain has been methodologically challenging. Here we propose a multimodal neuroimaging approach, which combines (a) effective connectivity measures using millisecond temporal resolution magnetoencephalography (MEG) with (b) highly novel submillimeter-resolution layer- specific 7T functional MRI. We will use these advanced techniques to characterize feedforward and feedback flow of information along the auditory cortical hierarchy, in 90 ASD and 60 neurotypical (NT) adults, ages 21- 35, with average or above average IQ. Using our multimodal research design, which is firmly rooted in laminar neurophysiological recordings in non- human primates, we will pursue the following Specific Aims: (1) Test the hypothesis that feedforward inputs are abnormally increased in ASD relative to NT individuals; (2) Test the hypothesis that feedback inputs are abnormally decreased in ASD relative to NT individuals; (3) Test the hypothesis that the extent to which feedforward and feedback inputs in the ASD group are indeed different, is predictive of ASD severity and the extent of auditory processing deficits, assessed behaviorally. We expect that the results of this study will lead to a substantially more detailed, comprehensive, and mechanistically motivated framework for the wide range of functional connectivity abnormalities observed in ASD.

NIMH - National Institute of Mental Health

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

NIMH - National Institute of Mental Health

HIV is a major public health concern with 39.9 million people living with HIV as of 2023. Depression is the most common neuropsychiatric comorbidity seen in this population, affecting 30-50% of people with HIV (PWH), a prevalence almost two times greater than the general population. Depression in PWH is associated with increased morbidity and mortality. Thus, understanding the neurobiological mechanisms underlying depression in PWH is highly important. We propose that HIV-associated depression is mediated by activation of the kynurenine pathway (KP). Recent data from our group show that increased quinolinic acid (QUIN) and decreased kynurenic acid (KynA), both KP metabolites, are associated with depression and anhedonia severity in women with HIV, suggesting a role for the KP in depression pathogenesis in PWH. However, the mechanisms by which the KP drive depression pathogenesis are not characterized. We will examine mechanisms by which the KP contributes to depression in PWH. We hypothesize that the KP is mediating HIV-associated depression pathogenesis through its effects on the blood-brain barrier (BBB) and CD14+CD16+ monocyte function, which have both been implicated in depression and HIV neuropathogenesis. We will investigate this hypothesis with the following aims: Specific Aim 1: Assess the effect of KP metabolites on BBB permeability and function of CD14+CD16+ monocytes matured and infected with HIV in vitro. We will characterize mechanisms through which KP metabolites increase in vitro BBB permeability and transmigration and inflammatory function of CD14+CD16+ monocytes matured and infected with HIV in vitro. We will test effects of KYN, QUIN, and KynA on BBB permeability and TJP as a mechanism for BBB disruption. We will examine transmigration and inflammatory mediator production of KYN-treated in vitro matured and HIV-infected human CD14+CD16+ monocytes. Hypotheses: 1) QUIN, but not KynA, increases BBB permeability by altering BBB TJP; 2) KYN increases migration across the BBB and inflammatory mediators of CD14+CD16+ monocytes. Specific Aim 2. Examine the associations between peripheral KP activity, in vitro BBB permeability, CD14+CD16+ monocyte transmigration, and depressive symptom severity in PWH and PWoH. We will enroll 70 virally suppressed PWH and 70 PWoH and evaluate them for depression/anhedonia severity. Using plasma and PBMC from participants, we will assess peripheral KP activity, BBB permeability, and CD14+CD16+ monocyte transmigration. Multivariate analyses will determine associations of KP metabolites, BBB permeability, and PBMC transmigration with depression/ anhedonia severity in both groups. Hypothesis: Increased peripheral QUIN, decreased KynA, increased BBB permeability, and increased CD14+CD16+ monocyte transmigration will correlate with greater depression/ anhedonia severity in PWH. Impact: Understanding the effects of KP dysregulation on BBB integrity and monocyte function in the context of HIV and depression may identify targets to mitigate depression in PWH, enhancing quality of life and survival.

NIMH - National Institute of Mental Health

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that disproportionately affects women, particularly those from underserved populations who face higher rates of trauma exposure. PTSD is associated with trauma-related hyperarousal (TRH), which is characterized by increased psychophysiological hyperarousal, including exacerbated fear-potentiated startle, deficits in fear extinction, and increased skin conductance response to trauma reminders. Despite evidence perimenopausal women exhibit peak PTSD prevalence rates and greater symptom severity compared to younger, reproductive-aged women, the biological mechanisms underlying this increased vulnerability to the psychological consequences of hormonal variation remain unclear. The current study aims to investigate the role of the endocannabinoid system, specifically anandamide (AEA), in modulating the severity of TRH during the menopause transition in Black women. The proposed research will test the hypothesis that lower AEA concentrations over the menopause transition will be associated with decreased estradiol concentrations and increased TRH. We will employ a combination of psychological assessments, fear conditioning paradigms, and biological measures to provide a comprehensive understanding of the mechanisms driving TRH exacerbation during perimenopause. The findings from this research have the potential to inform the development of targeted interventions for trauma-exposed women during this critical period of vulnerability. In addition, the F32 fellowship under the guidance of a distinguished mentoring team will provide the applicant with essential training in clinical and translational women's health research, neuroendocrinology, psychophysiology, advanced statistical methods, and scientific communication. This training will be crucial for the applicant's career development as an independent researcher focused on investigating the impact of trauma on women's health across the lifespan, particularly in underserved populations who suffer disproportionately from the adverse health impacts of trauma exposure.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Memory consolidation is an important process in memory retention, whereby short-term memories are transformed into long-term ones. Memory retention is facilitated when novel or salient experiences occur within 1-2 hours before or after memory encoding. Novelty-induced memory consolidation relies on the locus coeruleus-hippocampus pathway and involves the de novo synthesis of an–as–yet–unidentified group of proteins known as plasticity-related proteins (PRPs) in the hippocampus. These PRPs are thought to play a critical role in memory consolidation by stabilizing synaptic plasticity. However, the precise mechanism through which these newly synthesized PRPs facilitate the consolidation of synaptic plasticity and memory in the hippocampus remains unclear. This uncertainty primarily arises from the limited availability of loss-of-function techniques capable of perturbing the function of the target PRP with a minute temporal resolution and selectively within this memory process. This project aims to develop innovative molecular tool, using chemical-based manipulation, that enable the rapid and precise inactivation of endogenous target proteins in specific cell types during memory consolidation without genetic modification. Specifically, upon a chemical trigger, our new tool is designed to relocate a target PRP from its active site to other subcellular locations within a timeframe of minutes. This relocation can be achieved in specific neuron types in the hippocampus of freely moving rats undergoing memory tasks. To demonstrate the utility of this tool, we have selected activity-regulated cytoskeleton associated protein (ARC), one of the major PRPs, as a model target. Success in this endeavor will not only shed light on the elusive molecular mechanisms of memory consolidation by identifying key PRPs but also potentially reveal new pharmacological targets to improve memory retention. Moreover, the flexible and modular nature of this genetically encoded tool opens the door to its use in a broad range of biological applications beyond memory research.

NIMH - National Institute of Mental Health

Cognitive flexibility is required to adjust behavior to changes in the environment. Decades of work have highlighted the role of the prefrontal cortex (PFC), which integrates subcortical and cortical inputs, including from the mediodorsal nucleus of the thalamus (MD) in enabling cognitive flexibility. The proper wiring of these inputs during development is required for optimal prefrontal cortex maturation and miswiring is thought to lead to psychopathology. For instance, studies tracking adolescents with high clinical risk for schizophrenia show hypoconnectivity between MD-PFC, predicting disease onset later in life. Despite advances in antipsychotic medications, the vast majority of schizophrenia patients develop deficits in cognition and working memory that remain largely intractable with limited therapeutic options. Neuromodulation by so-called cognitive enhancers is an emerging field in neuroscience. Over the last decade one promising neuromodulator class is acetylcholine, whose phasic release in PFC has been linked to cognitive performance and attentional selectivity. In fact, cholinergics have become a mainstay treatment for alleviating the cognitive symptoms of mild-to-moderate Alzheimer’s dementia, and in late 2024 the first cholinergic drug was approved for treating various schizophrenia symptoms. More recently, cholinergics have been used to reverse aberrant thalamocortical connections in the visual system even when administered in adulthood, raising the possibility of “reopening” plasticity windows and potentially remediating psychiatric deficits at the neural circuit level. Here, I will determine whether acute adult cholinergic modulation in the PFC modulates attentional set shifting performance and whether enhancing acetylcholine in the adult PFC rescues cognitive deficits in an established developmental model with decreased thalamo-prefrontal projections. I will then attempt to reopen cortical plasticity via sub-chronic cholinergic augmentation in our developmental model. To this end I will use a combination of a transgenic mouse model, viral circuit-restricted expression of DREADD inhibition, fiber photometry, a fluorescent acetylcholine biosensor, optogenetics, and behavioral tests. Aim 1 will measure real-time acetylcholine dynamics during attentional set-shifting behavior and determine through optogenetic modulation whether acetylcholine supports working memory and attentional set shifting behavior. Aim 2 will use parallel optogenetic and pharmacological means to determine whether acute or sub chronic enhancement of acetylcholine reopens cortical plasticity in our published MD-PFC impaired mouse model. These studies will determine how acetylcholine interacts with thalamocortical projections in PFC during cognitively-demanding behavior, and may also be instructive in addressing whether cholinergic modulation in adulthood can restore a developmental imbalance in activity that increases risk for developing a psychiatric disorder.