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NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) and hypertension (HTN) are substantial public health concerns in the US and are important risk factors for other adverse outcomes including acute kidney injury and premature mortality. CKD and HTN are typically diagnosed later in life, yet our understanding of the prenatal and early life environ- mental determinants of reduced kidney function and HTN across childhood and early adulthood remains incipi- ent. This research, however, faces several barriers including lack of assessment of both neighborhood- and individual-level environmental stressors at specific early life stages coupled with long-term follow-up from birth to early adulthood. This project will address these research gaps by leveraging high-quality data from Project Viva, an ongoing longitudinal prospective pre-birth cohort of mother-child pairs followed since pregnancy. The overall goals of the proposed project are to examine the extent to which early-life exposure to disadvantaged neighborhood contexts and nephrotoxicants (i.e., air pollutants and metals) leads to later life kidney dysfunc- tion and higher blood pressure (BP). The investigators will: (Aim 1) examine associations of early-life neighbor- hood environment with kidney function and BP across childhood and early adulthood; (Aim 2) assess associa- tions of individual-level early-life exposure to candidate nephrotoxicants with kidney function and BP from mid- childhood to early adulthood; and (Aim 3) characterize urinary proteomic signatures underlying altered kidney function and BP trajectory from childhood to early adulthood, and examine these signatures as potential mark- ers of toxicant exposure. This innovative proposal will be the first to examine both neighborhood- and individ- ual-level environmental determinants of kidney function and BP trajectories. We will identify actionable risk fac- tors and molecular signatures to identify high-risk individuals and pinpoint when primordial prevention efforts have the greatest potential to prevent future CKD and HTN.

NIA - National Institute on Aging

PROJECT SUMMARY Cancer, mental health disorders, and substance use are leading causes of disease burden, disability, and premature death in the United States, with particularly large impacts among low-income populations. Identifying effective strategies to increase cancer screening and preventive care visits among low-income populations is critical to reducing this burden. Identifying effective strategies to increase cancer screening and preventive care visits among low-income populations is critical to reducing this burden. Because poverty is spatially concentrated in the U.S., income gains accruing to some residents of low-income neighborhoods could shift broader neighborhood economic conditions and generate health “spillover effects” among nonrecipients — through peer diffusion of healthy behaviors and other neighborhood improvements such as parks, transportation, and health clinics resulting from increased local economic activity. Evidence of neighborhood spillover effects on health could deepen understanding of how neighborhood economic conditions drive population health, equipping health systems and public health practitioners with evidence to better anticipate disease burden, prioritize community health investments, and improve health outcomes in low-income communities. We propose the first study to rigorously investigate neighborhood spillover effects of increased neighborhood income on health outcomes. We will study changes in neighborhood income resulting from neighborhood-level earned income tax credit (EITC) distributions, leveraging exogenous changes in distributions over time to rigorously estimate spillover effects. We will analyze individual level electronic health record data from 8.2 million patients in 1,222 primary care practices in all 50 states in the U.S. that is linked to U.S. Census Bureau data and tax returns. This unique dataset includes a large sample of individuals who live with or in proximity to each other, providing sufficient statistical power to estimate neighborhood spillover effects. We will investigate spillover effects stratifying by age to understand effects across the life course. Our Specific Aims are to: 1) estimate spillover effects of neighborhood economic conditions on health; and 2) test the robustness and heterogeneity of neighborhood spillover effects. Health outcomes from 2010-present will be characterized using electronic health records data and include cancer screening, preventive visits, mental health, and substance use disorders. We will estimate effects of state EITC distribution changes using staggered difference-in-differences with an event study framework. We will evaluate the reliability of our spillover effect estimates through multiple robustness checks and assess spillover effect heterogeneity by individual, neighborhood, and EITC characteristics. Our novel approach will serve as a template for future studies that investigate how health interventions targeting neighborhood economic conditions influence health.

NIMH - National Institute of Mental Health

Summary This proposal seeks to develop a networked trial emulation framework to enhance real-world evidence (RWE) generation on the causal effects of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) on mental health outcomes. While GLP-1 RAs have shown benefits for type 2 diabetes and obesity, their potential impact on neuropsychiatric health remains underexplored due to methodological challenges, including measurement errors, immortal time bias, incomplete drug adherence data, and decentralized multi-institutional data sources. This project addresses three critical gaps: (1) the need for systematic-error-corrected target trial emulation framework to improve causal effect estimation for mental health outcomes; (2) the lack of scalable methods for multi-institutional causal inference in neuropsychiatric research; (3) the challenge of accurately phenotyping drug adherence and mental health conditions using structured and unstructured clinical data. The proposed framework integrates systematic-error correction techniques, federated learning, natural language processing (NLP)-enhanced phenotyping, and tensor train decomposition to overcome these limitations. The success of this project will establish a robust, scalable approach for high-quality RWE generation, advancing the understanding of GLP-1 RAs' potential neuropsychiatric effects and informing clinical and regulatory decisions.

NIDA - National Institute on Drug Abuse

Chronic cannabis use is linked to poor physical and mental health. Young adults (age 18-21) with anhedonia, defined as deficient processing and experiencing of pleasure and rewards, are especially at risk for escalating their cannabis use. Anhedonia is a key transdiagnostic feature of many disabling conditions that have high rates of cannabis use and cannabis use disorder. Examining mechanisms of cannabis use escalation in young adults with elevated anhedonia is therefore highly significant as it would inform targeted prevention efforts for individuals who are at elevated risk. One reason young adults with anhedonia may be at risk for chronic cannabis use is because they abnormally process delta-9-tetrahydrocannabinol (D9-THC), the psychoactive ingredient in cannabis linked to the rewarding and reinforcing properties of cannabis. The few studies on the acute effects of D9-THC on reward processing have yielded mixed results, potentially due to not taking individual differences in anhedonia into account. Indeed, our preliminary study suggests that an individual’s level of anhedonia impacts how acute administration of D9-THC (relative to placebo) affects one’s neural response to rewards. Given that sensitivity to acute effects of other drugs (e.g., stimulants, alcohol) is a known risk factor for chronic use of those drugs, D9- THC’s effect on reward processing may be a mechanism for escalation to chronic cannabis use among young adults with anhedonia. The first goal of this project is therefore to examine how an acute laboratory administration of D9-THC (vs. placebo) impacts two aspects of reward processing: how individuals (a) anticipate receiving rewards (reward anticipation) and (b) learn associations between their actions and rewarding outcomes (reward-based reinforcement learning [RBRL]). Deficits in reward anticipation and RBRL have been robustly linked with anhedonia, but only examined in a handful of small D9-THC administration studies. The second goal of this study is to test if sensitivity to D9-THC’s effects on reward processes serves as a biomarker for escalation to chronic cannabis use in young adults with anhedonia. We will recruit 144 young adult (aged 18-21) occasional to regular cannabis users (who use less than daily) with a clinically significant range of anhedonia. At baseline, participants will undergo two double-blind, within-subject, drug-challenge visits (placebo vs. D9-THC), during which they will complete the reward anticipation and RBRL tasks in a fMRI scanner. All participants will then be followed for 2 years to assess future cannabis use and cannabis use disorder symptoms. A unique feature of this novel study is the assessment of two types of reward responses to acute D9-THC, as well as a longitudinal follow-up among a clinically-relevant sample. In sum, the present proposal has the potential to identify novel biomarkers for escalation to chronic cannabis use in an understudied, clinically relevant population – work that will ultimately inform targeted intervention and prevention efforts among young adult cannabis users at risk for chronic use.

NIA - National Institute on Aging

ABSTRACT Menopause is a major neuroendocrine transition experienced by nearly two million individuals in the United States each year. It is associated with increased rates of depression, social withdrawal, and loss of sexual motivation, posing significant challenges to mental health, interpersonal relationships, and public health. While hormonal decline has been implicated, the neural circuit mechanisms underlying these behavioral symptoms remain poorly understood. This proposal seeks to define how hormonal decline during reproductive aging disrupts a specific hormone-sensitive neural circuit and impairs female sexual behavior. Our work focuses on a projection from Cckar-expressing neurons in the ventromedial hypothalamus (VMHvlCckar) to the anteroventral periventricular nucleus (AVPV), a pathway that is essential for female sexual behavior and highly sensitive to ovarian hormones. Using a physiologically relevant menopause model induced by 4-vinylcyclohexene diepoxide (VCD), which gradually depletes ovarian follicles without surgery, we will determine how hormonal decline alters both the structural connectivity and functional activity of this projection. Specific Aim 1 will test whether structural atrophy of the VMHvlCckar to AVPV projection occurs with hormonal decline and whether it is reversible by hormone supplementation. Specific Aim 2 will examine how hormonal decline affects activity along this circuit, revealing where circuit dysfunction arises. Specific Aim 3 will use optogenetics to test whether activating this pathway restores sexual behavior and whether AVPV activity is necessary for hormone-induced behavioral rescue. By linking hormone-sensitive circuit remodeling to behavioral impairments, this study will identify new neurobiological targets for intervention. The findings may guide the development of circuit-based therapies to support mental health and social functioning during aging.

NIMH - National Institute of Mental Health

Project Summary Biological accounts of reinforcement learning posit that dopamine encodes reward prediction errors (RPEs), which are multiplied by a learning rate to update state or action values. The learning rate is often assumed to be constant, but studies in humans, monkeys, rats, and mice, have found behavioral evidence for dynamic learning rates. In volatile environments, dynamic learning rates allow animals to learn faster when the world is changing, and more slowly when the world is stable. While dopamine is thought to instantiate RPEs, we recently found that dopamine release in the ventral striatum did not reflect learning rates, suggesting that dopamine-independent mechanisms determine the rate of error-driven learning. Moreover, we present strong preliminary data showing that inactivation of the orbitofrontal cortex (OFC) eliminates dynamic learning rates behaviorally, and that OFC neurons that project to the ventral striatum seem to encode the learning rate in their firing rates. In this proposal, we will determine how OFC projections to the ventral striatum dictate the rate of error-driven learning at behavioral and neural levels. This proposal will use a novel behavioral paradigm in rats, in which reward statistics vary over latent blocks of trials. We previously found strong behavioral signatures of dynamic learning rates in rats performing this task. High-throughput behavioral training will generate dozens of trained subjects for experiments in parallel, accelerating the rate of research progress. We will use optogenetics and electrophysiology to record from and manipulate OFC neurons that project to the ventral striatum, to determine if this projection pathway dictates behavioral learning rates (Aim 1). We will use electrophysiology and optogenetics to relate behavioral learning rates and activation of OFC neurons that project to the ventral striatum to trial-by-trial changes in evoked spiking in the striatum (Aim 2). We will use optical methods to measure dopamine release in the striatum and activation of OFC axon terminals, while simultaneously recording action potentials from the ventral striatum, to relate endogenous fluctuations in coincident dopamine and OFC inputs to trial-by-trial plasticity of evoked spiking (Aim 3). These experiments will test key predictions of “three-factor” plasticity rules in behaving animals. These experiments will address a major open question, which is how specific output pathways from OFC interact with downstream circuits to coordinate value-based decisions and learning. Neuromodulatory systems including dopamine are implicated in myriad neuropsychiatric disorders including schizophrenia and depression. A greater understanding of the circuit mechanisms by which they coordinate different aspects of behavior and interact holds promise for revealing novel therapeutic targets for these disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Early life stress (ELS) significantly increases the risk of postpartum psychiatric conditions, especially cognitive impairment. Given the time gap between ELS events and the postpartum period, identifying high-risk individuals with ELS and intervening early appears feasible. However, understanding this longitudinal relationship through human studies alone is challenging, necessitating animal models. Most animal studies on postpartum psychiatric disorders focus on behavioral changes after hormone injections, neglecting the pathological trajectory from ELS to postpartum cognitive impairment. To address this, we developed a new mouse model to explore how ELS affects postpartum behaviors. In our model, female mice exposed to mild social isolation during late adolescence (SILA) do not show increased levels of plasma corticosterone (CORT) or significant behavioral changes. Pregnancy/delivery alone do not lead to notable abnormalities. Notably, by postpartum day (PD) 7, mice exposed to SILA exhibit behavioral changes related to mood, social cognition, and parenting only when combined with pregnancy and delivery. SILA dams also exhibit elevated and sustained plasma corticosterone (CORT) levels, mirroring those in postpartum depression patients. While CORT levels in SILA and non-SILA dams are similar in late pregnancy, SILA dams show higher levels from PD 0, persisting for at least three weeks postpartum, aligning with long-lasting behavioral changes. Blocking glucocorticoid receptors (GR) during the first postpartum week improves SILA dams’ behavior, highlighting CORT’s role in ELS-associated postpartum changes. Our proposal will use this new mouse model to functionally and transcriptionally investigate how enhanced and sustained levels of plasma CORT alter neuronal function and lead to behavioral deficits in the first postpartum week, focusing on social novelty recognition. Our preliminary data suggest that removing GR expression or optogenetically activating the glutamatergic neuronal projections from the anterior insula to the prelimbic cortex (AIPrL glutamatergic pathway) can ameliorate deficits in social novelty recognition observed in SILA dams. CORT influences gene transcription via GR, a nuclear receptor acting as a transcriptional activator and suppressor. Thus, we hypothesize that continuous GR activation by CORT during the initial postpartum week disrupts the transcriptional regulation in the AIPrL glutamatergic pathway, reduces their synaptic activities in PrL, and consequently impairs social novelty recognition in stressed dams. This study will determine how CORT affects the AI-PrL glutamatergic pathway via GR in stressed dams, elucidate the molecular mechanisms involved, and evaluate the impact on social novelty recognition and other behaviors. The findings aim to explain how adolescent psychosocial stress leads to social cognition deficits in mothers, guide interventions to mitigate these effects, and provide crucial insights into postpartum social behavior impairments affecting mothers, their children, and families.

NIEHS - National Institute of Environmental Health Sciences

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a leading and rising cause of disability in adolescents, a group undergoing rapid brain development and therefore uniquely vulnerable to environmental stressors that increase psychiatric risk. Chlorpyrifos, a widely used organophosphate pesticide, has been linked to neuropsychiatric symptoms in adolescents, but whether it directly induces symptoms or instead produces latent neurobiological changes that increase vulnerability to future stressors remains unclear. Most animal studies have focused on prenatal or adult exposures, leaving a critical gap in understanding how chlorpyrifos affects the adolescent brain and shapes long-term psychiatric risk. Preliminary data demonstrate subtle but consistent anhedonia-relevant behaviors following adolescent chlorpyrifos exposure; while these changes do not constitute full pathology, they suggest chlorpyrifos alters brain function in ways consistent with a latent vulnerability state—sensitizing the brain in ways that predispose the brain to exhibit MDD-relevant outcomes following subsequent stressors. Social stressors such as bullying and isolation, which are well-established contributors to adolescent-onset MDD, are also on the rise. Real-world exposures often involve multiple, co-occuring risks, underscoring the need to investigate their combined impact on the developing brain. The objective of this research is to use a translational mouse exposure model to identify MDD-relevant behavioral, immunological, and brain circuit changes following adolescent chlorpyrifos alone and in combination with social stress. I hypothesize that chlorpyrifos induces a vulnerability state, producing brain circuit and immune changes with minimal MDD- relevant behaviors, and that co-exposure with social stress leads to susceptibility, marked by the active emergence of MDD-relevant behaviors and pathology. In Aim 1, I will test whether chlorpyrifos alone induces neurophysiological and immunological changes without many behavioral effects. In Aim 2, I will assess how combined chlorpyrifos and social stress exposures influence MDD-relevant behavioral, brain circuit, and immune outcomes. This project will uncover, for the first time, how adolescent chlorpyrifos exposure changes brain-wide mechanisms relevant to MDD, both independently and in interaction with social stress. More broadly, this fellowship will provide integrated training in psychiatry, neuroscience, and environmental toxicology through individualized mentorship and guided research. The highly collaborative and interdisciplinary environment at the University of Iowa through the Iowa Neuroscience Institute and Environmental Health Science Research Center offers an ideal setting for this work. This training plan will support my development as a physician-scientist focused on how environmental exposures during sensitive developmental windows shape long-term brain health. My long-term goal is to help advance environmental health approaches within psychiatry and neuroscience to better protect child and adolescent mental health.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Suicide rates in the US have risen approximately 34% since the Surgeon General’s call to make suicide prevention a national priority in the U.S over 20 years ago. Without a science-driven paradigm shift in our understanding of suicide, there is little prospect of a breakthrough in suicide prevention. A better explanatory model of suicidal behavior could offer new methods to recognize those at heightened risk for suicide; identify novel, modifiable treatment targets for suicide prevention; and assess the impact of such intervention in at-risk patients. We have proposed a stress-diathesis model of suicidal behavior wherein suicidal behavior is the result of interactions between an immediate stressor (generally, an external life event), clinical stressors (such as untreated depression), and a diathesis—a collection of traits underlying the predisposition to suicidal behavior that includes response styles to stress. However, little is known about how naturalistic stress interacts with risk factors to facilitate transition from suicidal ideation to behavior in high-risk depressed patients. This Conte Center grant will address this knowledge gap by examining neurotransmitter and circuitry elements underlying responses to naturalistic stressors, focusing on the glutamatergic system and cognitive factors, as well as the impact of ketamine (randomized to low vs. standard dose) on responses to daily life stress. Studying a large group of higher-risk depressed suicide attempters relative to depressed non-attempters and healthy volunteers, we will use novel and converging approaches across projects to increase our understanding of suicide pathogenesis, thereby identifying potential biomarkers and treatable targets for suicide risk. Project 1 will use ecological momentary assessment to measure suicidal ideation and mood symptoms in the context of daily stress and quantify change in these variables following ketamine administration. In the same sample, Project 2 will use multimodal MRI to characterize the downstream effects of altered glutamate and functional neurocircuitry on mood- and cognition-related risk factors for suicide, specifically, memory alterations, deficits in emotion regulation, and glutamatergic pain processing. This sample will also undergo PET imaging in Project 3 to examine synaptic density and mGluR5 binding, and assess their role in stress responses. Project 4 will use spatial and single nuclei cell type specific transcriptomics in postmortem brain tissue to examine suicide and impact of recent life stressors, homologous to Projects 1-3. Project 5, a mouse study, will examine helplessness, stress responses, and memory at the circuit and molecular components and the impact of ketamine. Project 6 will harness the rich, multimodal dataset of Projects 1-5 to model high dimensional and complex data in profiling suicidal behavior. We aim to delineate a model of suicide risk linking molecular and neurobiological mechanisms to clinical factors and real-world responses to stress, with the long-term goal of enhancing stress resilience as a suicide prevention approach.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Animals exhibit a remarkable array of flexible behaviors. Birds alternate between caching and retrieving food based on availability; rats reroute when familiar paths are blocked; humans revise strategies mid-game in chess. This ability to flexibly switch strategies or generate new solutions is central to intelligent behavior and is often impaired in neuropsychiatric disorders such as autism spectrum disorder and schizophrenia. Prior research has yielded key insights into what supports such cognitive flexibility: internal models of the world, including spatial and episodic knowledge encoded in the hippocampus (HPC) and abstract rules encoded in the prefrontal cortex (PFC). However, we still lack a mechanistic understanding of how the brain engages these models in real time to guide strategy switching and problem-solving. This proposal addresses this gap by identifying internal strategy states—latent variables computed by the brain that track the currently active policy for selecting goal-directed actions—and by dissecting the neural computations that encode, update, and drive transitions between these states. I will combine large-scale electrophysiology with closed-loop optogenetics in freely behaving rats performing strategy-switching and problem-solving tasks. I will assess behavioral and neural data by integrating two complementary theoretical frameworks: (i) reinforcement learning and Bayesian inference to formalize latent behavioral strategies and valuation processes; and (ii) dynamical systems modeling to uncover how neural population activity implements these cognitive operations. I will test the central hypothesis that the flexible control and generation of strategies arise from structured population dynamics in medial PFC (mPFC) implementing computations that: (i) direct HPC to simulate future scenarios that inform strategy switching (Aim 1); (ii) track and update strategy values to determine when to switch (Aim 2); and (iii) integrate input from the orbitofrontal cortex to select among multiple strategies and generate new solutions (Aim 3). By causally linking neural dynamics to strategy switching, selection, and generation, this work will reveal algorithmic and implementational principles of cognitive flexibility, laying the groundwork for my long-term goal: to elucidate the division of computational labor across PFC subregions and their interactions with subcortical regions (e.g., thalamus) during multi-strategy problem-solving. The K99 phase will support my transition to independence through training in multi-region, high-density electrophysiology coupled with real-time optogenetics, as well as advanced behavioral and dynamical systems modeling. I have assembled a mentorship team (Drs. Loren Frank, Joshua Berke, and Nathaniel Daw) and collaborators (Drs. Vikaas Sohal and Scott Linderman) with complementary expertise spanning experimental, technological, and theoretical domains of systems neuroscience. This award will also provide professional development in lab management, leadership, scientific communication, and grant writing, which will position me to launch an independent research program focused on the neural basis of intelligence and creative behavior.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Memory is an essential cognitive process dependent on the consolidation of experience into stored memories and generalized knowledge. We know not all memories are stored, and we know memories undergo a transformation from episodic events into abstract understanding. However, the neural underpinnings of this process of memory consolidation remain unclear. The hippocampus is a brain region critical for memory formation, and the medial prefrontal cortex (mPFC) is a brain region involved in memory storage and abstracted knowledge; these regions are bidirectionally connected and are candidate brain networks for the selection of memories for consolidation and the transformation of memory traces into generalized knowledge. Further, the sleep sharp-wave ripple (SWR) is a brain oscillation known to be involved in memory consolidation during which privileged hippocampal-mPFC communication occurs. While systems consolidation theory offers predictions of how the hippocampus and mPFC interact during SWRs to consolidate memories, these predictions have so far been difficult to causally test in the absence of multi-site neural recordings with optogenetic manipulations. To test the hypothesis that cortical-hippocampal information flow preceding SWRs is critical for the selection of memories for consolidation, this project aims to silence mPFC activity in conjunction with simultaneous large- scale electrophysiology recording of the hippocampus. This will determine the role of the mPFC in influencing hippocampal activity during SWRs, providing a mechanism by which memory traces are selected for consolidation (Aim 1). In addition, to test the hypothesis that hippocampal-cortical information flow during SWRs is critical for the emergence of consolidated, generalized cortical representations, I will specifically inhibit mPFC activity during SWRs. This will evaluate whether mPFC activity during this brain oscillation is necessary for the transformation of memory traces and the development of neural representations of generalized knowledge (Aim 2). Completion of these aims has the potential to yield fundamental insights into the neural mechanisms of memory consolidation. This study will be carried out in the lab of research sponsor, Dr. Loren Frank, at the University of California, San Francisco (UCSF). The Frank Lab is located in the Sandler Neurosciences Center, which is home to a highly innovative and collaborative community of faculty and students pursuing neuroscience investigation. Pursuing this project will accomplish the training goals of gaining expertise in in vivo electrophysiology data acquisition, developing quantitative data analysis skills, and improving my scientific communication. The training plan under this fellowship will provide preparation for an independent career as an academic neuroscientist-neurologist with the long-term goal of revealing neural circuits underlying cognitive processes and flexible behavior. In addition to the proposed research, this preparation will be achieved via composition of scientific manuscripts, engagement with vibrant intellectual communities, and neurology-geared clinical activities.

NIMH - National Institute of Mental Health

ABSTRACT This project aims to investigate the roles of a newly identified population of neurons in the supramammillary nucleus (SuM) that are essential for threat learning and avoidance behaviors. These neurons are activated by diverse stressors and may play critical roles in threat conditioning and persistent avoidance. The specific aims of this research are to: (1) elucidate the temporal dynamics and causal roles of these neurons during threat learning, avoidance, and extinction using fiber photometry, optogenetics, and behavioral assays; (2) determine whether these neurons selectively excite neuron populations in the nucleus accumbens (NAc) to promote threat avoidance; and (3) reveal the neural types in SuM and which are recruited during threat learning and sustained avoidance using advanced molecular techniques such as Projection-TAGs, barcoded retrograde viruses, and Act-seq with single nucleus RNA sequencing. By characterizing this novel neural circuitry, the project aims to advance our understanding of active coping mechanisms and contribute to the development of new treatments for stress and anxiety-related disorders by identifying potential therapeutic targets.

NIMH - National Institute of Mental Health

Neuropsychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) remain a major clinical and translational challenge. These conditions affect over 6% of the U.S. population and account for substantial long-term disability and healthcare burden. Despite extensive genetic and imaging studies, most cases remain idiopathic with no identifiable molecular etiology, limiting our ability to stratify patients or design mechanism-based treatments. A critical barrier is the lack of tools to quantify circuit-level dysfunction in human brain tissue at sufficient resolution to resolve disease- specific features. Traditional approaches—animal models, neuroimaging, and postmortem tissue— either lack species relevance or cannot capture dynamic circuit activity with cellular precision. This project introduces Neural Navigator, a standardized platform for quantifying circuit pathophysiology in patient-derived cerebral organoids using multi-electrode array (MEA) recordings and machine learning–based modeling. Preliminary data show that core electrophysiological features—spike rate, inter-spike interval, burst duration—differ reproducibly across SCZ, BPD, and control lines. Using dynamic modeling, Neural Navigator achieves >90% classification accuracy following electrical stimulation. Aim 1 will generate a longitudinal dataset of spontaneous and evoked MEA activity across 75 cerebral organoids (25 per condition) from days 90 to 270, establishing reproducible profiles of circuit development and disease-associated phenotypes. Aim 2 will validate Neural Navigator as a quantitative pipeline that integrates stimulus-response network modeling (SRDNM), a sink–source index of information flow, MRMR-based feature selection, and interpretable classification models. This approach will produce the first reproducible framework for stratifying idiopathic psychiatric disease using human brain tissue. All models, code, and datasets will be released in FAIR-compliant formats. The resulting platform will support mechanistic disease quantification and provide quantitative endpoints for future therapeutic discovery and drug screening applications.

NIMH - National Institute of Mental Health

Childhood anxiety and depression (collectively, internalizing disorders) are a critical public health need. Early adolescence and the emergence of puberty is a pivotal moment wherein internalizing symptoms begin to rise, especially in girls. It is also a period when subcortical brain systems subserving motivated behaviors, including amygdala (negative emotions) and dorsal/ventral striatum (reward processing) increase in reactivity, and regu- latory capacity in the frontoparietal network (FPN) decreases. These cognitive-affective networks are linked to development of internalizing disorders, but the specific mechanisms remain poorly understood. The proposed project will investigate two such constructs that are impacted by these developing cognitive-affective brain net- works, perseverative thought disengagement and reward learning, in order to characterize their relationship to internalizing symptoms and the role of puberty in early-adolescent girls. Perseverative thought (PT) disengage- ment refers to the capacity to disengage from intrusive, repetitive and uncontrollable thoughts such as worries and rumination (i.e., PT), which are known contributors to internalizing symptoms in girls. Reward learning refers to the skills and strategies used to learn from rewards in the environment, which requires solving the explore/ex- ploit dilemma (whether to explore for new rewards or exploit known rewards). Using computational modeling of explore/exploit paradigms, deficits in uncertainty-directed exploration, or exploration aimed specifically at un- known parts of the environment, is linked to internalizing symptoms. Using a parallel structure, the Aims of this project will be to characterize the neural correlates of 1) PT disengagement and 2) uncertainty-directed explora- tion and their relationship to internalizing symptoms in 100 adolescent girls aged 9-14. As an Exploratory Aim, we will investigate relationships between the two constructs in these same participants. This project will take a transdiagnostic approach, recruiting girls on the basis of self-reported PT, as a risk factor for future internalizing symptoms. Girls will complete two study visits: an interview (conducted virtually) to determine topics of frequent PT, and an MRI visit to complete both PT disengagement and reward learning tasks. Functional MRI data will be analyzed using a general linear model (GLM)-based approach and internalizing symptoms will be measured transdiagnostically via questionnaire. Behavior from the explore/exploit (reward learning) task will be modeled using the previously-validated SCEPTIC model, fit to the data using Bayesian approaches, and related to fMRI data using frequentist multilevel models. The proposed training plan leverages a world-class research environ- ment with a team of highly skilled mentors and consultants to provide the candidate with area knowledge in adolescent neurodevelopment and puberty and training in computational modeling and Bayesian statistics. In line with NIMH’s Strategic Objectives, the proposed work will characterize neurodevelopmental processes po- tentially amenable to behavioral and neural intervention with life-long benefits in internalizing disorders.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Major Depressive Disorder (MDD) is associated with emotional memory deficits that have substantial downstream consequences, but treatment is limited by poor understanding of the upstream mechanisms driving such behavior. Our recent work applying the Drift Diffusion Model (DDM) suggests that depression disrupts emotional memory by increasing “old” evidence accumulation for both old and new negative material, indicating a negative bias specific to retrieval. The DDM can account for the negative retrieval bias in depression via two mechanisms: increased familiarity, in which depression strengthens evidence for all negative memories—even false ones; or motivated retrieval, in which depression increases the propensity for judging all negative evidence as “old”—even if it is weak. Thus, it is unclear whether depression affects the quality of negative memories or the way they are acted upon, limiting both basic and applied depression research. The proposed work distinguishes the familiarity vs. motivated retrieval accounts via the Parceling Recognition Into Strength and Motivation (PRISM) task, which isolates memory strength from decision processes by generalizing single-item recognition behavior to forced choices between targets and lures. The logic is elegant: Though a motivation to respond “old” can bias single-item judgments, it cannot play a role when judging which of two items is old; thus, familiarity is implicated when differences in accumulation rates extend across tasks, and motivation is implicated when they do not. By extending the PRISM task to emotional memory in depression, the PI seeks to more precisely characterize the negative retrieval bias, with the primary goal of identifying false familiarity vs. motivated retrieval as potential targets for basic and applied research (Aim 1). Moreover, the PI will build expertise in model-based neuroimaging (Goal 1) and curate a practical skill set in clinical research (Goal 2) by running a functional magnetic resonance imaging (fMRI) version of the PRISM task to identify brain areas supporting retrieval that are affected by depression (Aim 2). With substantial research and training opportunities available at McLean Hospital/Harvard Medical School, the mentorship of Dr. Dan Dillon (a well-established clinical neuroscientist), Dr. Courtney Beard (an outstanding translational researcher and licensed clinical psychologist), and Dr. Michael J. Frank (a renowned computational neuroscientist), with consultation from Drs. Jeffrey Starns (developer of the PRISM task), Dr. David Badre (a leading cognitive neuroscientist with expertise in fMRI), and Dr. Avram Holmes (an expert in large-scale brain networks focusing on emotion and cognition), the applicant will receive advanced training in career development, model-based fMRI, and translational research. Together, the proposed research and training plans will launch the PI into an independent research career focused on identifying neurocognitive treatment targets for depression.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The onset of youth psychopathology is often preceded by exposure to stressful life events (SLEs). Despite substantial research on the neurodevelopmental consequences of severe forms of adversity, like maltreatment, the mechanisms that explain the powerful link between less severe but common SLEs and adolescent psychopathology remain understudied. This project is focused on uncovering these mechanisms using an innovative research design that leverages intensive longitudinal within-subject assessments to characterize how SLEs are related to dynamic changes in in emotion, cognition, behavior, and neural function over time in ways that may contribute to the emergence of psychopathology. The study capitalizes on a unique dataset acquired during the first project period designed to study these processes at a sufficiently fine-grained level of temporal specificity to identify mechanisms underlying the link between SLEs and adolescent psychopathology as they unfold in real time. The dataset acquired in the initial project-the Studying Adolescence in Rea/­ Time (STAR) study-is truly unique, including more than 1,500 monthly neuroimaging sessions, 1,800 monthly assessments of clinical and behavioral data, 1,400 months of usable continuous passive data from smartphones and wearable devices, 1,300 months of neuroendocrine samples, and 45,000 completed ecological momentary assessment (EMA) surveys. The intensive longitudinal design of the STAR study allows mechanisms linking SLEs to psychopathology to be identified in real time and in the real world along multiple data streams that cut across numerous RDoC domains and levels of analysis (neuroimaging, clinical, and behavioral measures; digital phenotyping; neurobiology; and EMA), generating true translational targets for intervention. The renewal focuses first on how monthly fluctuations in exposure to SLEs within individuals are associated with the pace of biological aging across multiple bodily systems-including pubertal development, cellular aging, and BrainAGE-and the role these metrics of aging play as mechanisms linking SLEs with psychopathology. Second, we evaluate metrics of brain function that serve as mechanisms in the relationship between SLEs and psychopathology by leveraging cutting edge methods from precision neuroscience to identify cortical networks separately within each individual in our study. This approach to characterizing brain mechanisms underlying risk for psychopathology has been proposed as a crucial path forward that addresses recently discovered problems in the stability of brain-behavior associations. Integrative analyses will isolate those mechanisms-across numerous levels of analysis-that explain the most unique variance in individual­ level prediction of psychopathology risk in this dataset. Study findings will provide critical information regarding the specific domains of emotion, cognition, social behavior, biology, and neural function that are influenced by exposure to SLEs and increase vulnerability to psychopathology. These mechanisms represent modifiable targets for interventions to prevent the onset of stress-related psychopathology in children and adolescents.

NIMH - National Institute of Mental Health

Project Summary This investigation will conduct a ancillary neuroimaging study of a subgroup of participants (N=48) of a larger clinical trial (N=186) comparing a dopamine agonist (Pramipexole) vs. an SSRI (Escitalopram) for antidepressant efficacy in Major Depressive Disorder in persons with HIV. The neuroimaging study will investigate dopaminergic mechanisms underlying Major Depressive Disorder in persons with HIV infection (Aim 1) and in antidepressant treatment response (Aims 2). Participants of the imaging substudy will undergo FDA approved SPECT/CT imaging for analysis of striatal (caudate, putamen) dopamine transporter (DaT) levels. Multiparametric MRI will be used to interrogate striatal, midbrain regions (caudate, putamen, substantia nigra, and ventral tegmentum) and specific networks (Salience, Somatomotor, Default Mode, and Central/Frontal Executive). Research Domain Criteria will be used to evaluate specific symptoms of depression. We will test the hypothesis that striatal dopaminergic levels are reduced in both groups prior to treatment and correlate with severity of RDoC measures and brain alterations quantified with MRI (Aim 1). We hypothesize that pramipexole, as a dopamine agonist, will reverse decrements in DA transmission to a greater extent than Escitalopram following 24 weeks of treatment. The pramipexole group will show greater remission in symptoms and this change will correlate with changes in DaT levels and in brain imaging measures (Aim 2). This study will yield critical insights concerning dopaminergic mechanisms underlying the markedly higher risk of depression in persons with HIV and have broad relevance to an understanding of MDD which impacts 264 million persons worldwide.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Depression is associated with more disability worldwide than any other medical illness. The current lack of widely effective treatments demonstrates our limited understanding of the etiology and biological mechanisms of this complex disorder. Gaps in knowledge regarding the fundamental pathophysiology of depression have served to limit novel diagnostic and treatment approaches, contributing in large measure to its enormous public health burden. Our proposed clinical and translational research project aims to provide a rigorous test of the hypothesis that heightened peripheral immune function and increased blood-brain barrier (BBB) permeability contribute to major depressive disorder (MDD) and anhedonia severity in humans. If successful, this work will establish essential, previously uncharacterized, neuroimmune aspects of the pathophysiology of MDD that will allow for refined treatment targeting and disorder subtyping in the future. The work will be conducted over three independent, yet synergistic study aims. In Aim 1, we will characterize peripheral myeloid cell biology in association with depression and anhedonia. In Aim 2, we will characterize BBB permeability and reward circuit functional connectivity in association with depression and anhedonia. In Aim 3, we will characterize the temporal dynamics of immune, BBB, and reward circuit features in association with depression and anhedonia over a 3- month follow up time. To support all Aims, we will enroll N=150 medically healthy adult individuals aged 18 to 55 years, including N=100 adults with MDD and N=50 unaffected adult volunteers with no history of psychiatric disorder. All individuals will undergo detailed clinical and behavioral assessment, blood collection for myeloid cell characterization including transcriptional and proteomic profiling, and neuroimaging with dynamic contrast enhancement (DCE) and diffusion-prepared arterial spin label (DP-ASL) MRI for estimation of BBB permeability and resting-state functional connectivity (RSFC) for assessment of the nucleus accumbens (NAc)-ventromedial prefrontal cortex (vmPFC) reward circuit. To characterize change in our measured neuroimmune metrics overtime, all participants will return to our laboratory for repeated characterization 3 months following the initial assessment. Based on an estimated 80% retention, N=120 total cases will be available to explore the temporal dynamics of our measured neuroimmune features and coherence with fluctuations in symptoms and other clinical and environmental factors overtime.

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to encourage applications seeking to develop the next generation of brain stimulation devices for treating mental health disorders. Applications are sought that will either 1) develop novel brain stimulation devices or 2) significantly enhance, by means of hardware/software improvements, the effectiveness of brain stimulation devices that are currently U.S. Food and Drug Administration (FDA)-approved or cleared. Novel devices should move beyond existing electrical/magnetic stimulation and develop new stimulation techniques capable of increased spatiotemporal precision as well as multi-focal, closed-loop approaches. Applications seeking to develop new capabilities should focus on significant enhancement of the spatial resolution, depth of delivery, and/or precision of the device. Incremental changes to existing devices (e.g., software updates) are not withinthe scope of this announcement.

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to encourage applications seeking to develop the next generation of brain stimulation devices for treating mental health disorders. Applications are sought that will either 1) develop novel brain stimulation devices or 2) significantly enhance, by means of hardware/software improvements, the effectiveness of brain stimulation devices that are currently U.S. Food and Drug Administration (FDA)-approved or cleared. Novel devices should move beyond existing electrical/magnetic stimulation and develop new stimulation techniques capable of increased spatiotemporal precision as well as multi-focal, closed-loop approaches. Applications seeking to develop new capabilities should focus on significant enhancement of the spatial resolution, depth of delivery, and/or precision of the device. Incremental changes to existing devices (e.g., software updates) are not withinthe scope of this announcement.

National Institutes of Health

<p>The purpose of this Notice of Funding Opportunity (NOFO) is to encourage applications seeking to develop the next generation of brain stimulation devices for treating mental health disorders. Applications are sought that will either 1) develop novel brain stimulation devices or 2) significantly enhance, by means of hardware/software improvements, the effectiveness of brain stimulation devices that are currently U.S. Food and Drug Administration (FDA)-approved or cleared. Novel devices should move beyond existing electrical/magnetic stimulation and develop new stimulation techniques capable of increased spatiotemporal precision as well as multi-focal, closed-loop approaches. Applications seeking to develop new capabilities should focus on significant enhancement of the spatial resolution, depth of delivery, and/or precision of the device. Incremental changes to existing devices (e.g., software updates)are not within the scope of this announcement. Applications should be submitted by multi-disciplinary teams with a variety of expertise including systems neuroscience, engineering, clinical, and regulatory affairs.</p>

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to encourage applications seeking to develop the next generation of brain stimulation devices for treating mental health disorders. Applications are sought that will either 1) develop novel brain stimulation devices or 2) significantly enhance, by means of hardware/software improvements, the effectiveness of brain stimulation devices that are currently U.S. Food and Drug Administration (FDA)-approved or cleared. Novel devices should move beyond existing electrical/magnetic stimulation and develop new stimulation techniques capable of increased spatiotemporal precision as well as multi-focal, closed-loop approaches. Applications seeking to develop new capabilities should focus on significant enhancement of the spatial resolution, depth of delivery, and/or precision of the device. Incremental changes to existing devices (e.g., software updates)are not within the scope of this announcement. Applications should be submitted by multi-disciplinary teams with a variety of expertise including systems neuroscience, engineering, clinical, and regulatory affairs.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Social attachments play a central role in most, if not all, levels of human interaction, from parent-child attachment to enduring partnerships with mates. Many neuropsychiatric disorders manifest with severe disruptions to interpersonal interactions, significantly impacting health and relationships. Despite the importance of attachment, little is known about the neural pathways mediating these behaviors, or how they are impacted by environmental or genetic factors that disrupt relationships. Prairie voles (Microtus ochrogaster) form social attachments to their mates (pair bond) and demonstrate enduring social monogamy. Pair bonded prairie voles prefer huddling with their partners and aggressively reject other potential mates, providing a powerful system to understand the fundamental mechanisms that mediate the formation and expression of enduring attachments. Pioneering work identified the peptide hormones vasopressin (Avp) and oxytocin (Oxt) as critical mediators of pair bonding and complex social behaviors in diverse species, including humans. The deep similarity in genetic and neuroanatomic structures between humans and other eutherian mammals and the conserved roles of these hormones throughout vertebrates suggests that findings in the prairie vole model may inform our understanding of human attachment behaviors. To understand behavioral modules underlying social attachment and their genetic, molecular, and neural architecture, we developed 1) a rigorous battery of social behavior paradigms, 2) tools for genomic analysis, and 3) in vivo imaging approaches to monitor neural activity, coupled with 4) molecular genetics in prairie voles, to analyze distinct components of attachment behaviors. Our recent work has revealed previously unappreciated nuances in the neuromodulatory control of pair bonding. We find that signaling by the oxytocin (Oxtr) and vasopressin 1a receptors is strikingly not required for the formation of partner. Rather, Oxtr function controls the timing and promiscuity of pair bonding and influences reciprocal social interactions between mates. Using unbiased profiling of gene expression, characterization of expression changes in components of various neuromodulatory pathways, in vivo imaging of the activity of other neuromodulatory systems, and pharmacologic manipulations of these pathways in specific brain regions, we find that separate signaling pathways appear to regulate distinct components of social attachment behaviors. Here, we extend these studies to determine how these and other neuromodulatory pathways act, and interact, in specific brain regions across the formation of bonds and subsequent social interactions to influence enduring social relationships between mates.

NIMH - National Institute of Mental Health

Project Summary Many research groups concentrate on elucidating the substrates underlying reward approach or avoidance behaviors, resulting in a wealth of datasets detailing neuronal circuits governing motivation. However, the dynamics of opposing motivational circuits operating during approach/avoidance conflicts remain poorly understood. This knowledge gap is significant, as compromised approach/avoidance behaviors are hallmark features of anxiety, depression, and addiction. The nucleus accumbens (NAc) is a key mediator of approach/avoidance conflict. Here, we propose to characterize the role of NAc neurons and astrocytes and circuits in influencing approach/avoidance conflict behaviors in mice, using fiber photometry, virally-mediated cellular signal ablation, and optogenetics in mice trained in the platform-mediated avoidance task. In Aim 1, we will characterize how NAc neurons and astrocytes encode approach/avoidance conflict learning and expression with calcium fiber photometry in mice training in the platform-mediated avoidance task. In Aim 2, we will ablate signaling of NAc neurons and astrocytes to probe their role in approach/avoidance conflict learning in mice training in the platform-mediated avoidance task the activity of NAc cell types and circuits during behavioral conflict in platform-mediated avoidance. In Aim 3, we will optogenetically silence NAc neurons and astrocytes to probe their role in approach/avoidance conflict expression in mice training in the platform-mediated avoidance task. Findings from this work will shed light on how NAc mediates approach/avoidance conflict and potentially shed light into the role of NAc in psychiatric disorders involving poor approach/avoidance behaviors.