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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.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Social memory is a critical process for learning to navigate the world, and deficits in social processing are common in neuropsychiatric disorders like autism, and Fragile X syndrome (FX). Current treatments for these disorders often fail to effectively address these social deficits, highlighting the need for a deeper understanding of the underlying mechanisms. A shared characteristic among these disorders is dysfunction of the hippocampus, a brain region recently linked to social memory. Hippocampal area CA2 and signaling of the social neuropeptide oxytocin within CA2 play a known role in social memory. However, research on the specific role of the dentate gyrus, a hippocampal region that sends direct excitatory input to CA2, during social memory processing, including oxytocin signaling, is lacking. The goal of this project is to identify how oxytocin signaling within the dentate gyrus contributes to social memory processing. My preliminary data shows that oxytocin increases the excitability and enhances synaptic transmission of dentate granule cells in wild type mice, while granule cell excitability may be impaired in a mouse model of Fragile X syndrome (FX mice). This project will use in vitro electrophysiology to record from dentate granule cells in response to oxytocin in wildtype mice and FX mice. Specific Aim 1 will identify potassium channels modulated by oxytocin in dentate granule cells. This aim will test the hypothesis that oxytocin modulates KV1 voltage-gated and KIR potassium channels. Preliminary data suggest that oxytocin enhances synaptic transmission from the entorhinal cortex to dentate granule cells, however, the locus and mechanism of this effect is not known. Specific Aim 2 will investigate how oxytocin modulates synaptic transmission in the dentate gyrus. Preliminary recordings from FX dentate granule cells found reduced excitability compared to wild type. Specific Aim 3 will determine the cellular mechanisms underlying this lower excitability and investigate if granule cell responses to oxytocin are impaired in FX mice. The results from this project will provide insight into the mechanisms behind oxytocin’s modulation of the dentate gyrus and may inform future treatments for prevalent social deficits. The findings anticipated from these proposed experiments will be the initial evidence of oxytocin’s modulation of KV1 in dentate granule cells, and the first indication that oxytocin modulates synaptic transmission to the granule cell layer, which may play a crucial role in social cognition. This fellowship will allow me to learn a wide array of in vitro electrophysiological and microscopy techniques, practice disseminating my research at national conferences, and acquire skills in mentoring and teaching undergraduate students. Through this fellowship I aim to develop not only essential technical skills, but also conceptual and professional competencies necessary for establishing a career as an independent researcher at an R1 institution.

NIMH - National Institute of Mental Health

Project Summary Across the 30 years (1992-2022) of our previous TG, Brandeis built a multi-disciplinary program encompassing faculty in Biology, Biochemistry, Chemistry, Mathematics and Psychology. We educate students (who themselves come from the same breadth of scientific backgrounds as our faculty) in the full range of Neuroscience topics from the molecular biology of neuronal non-coding RNAs to the cognitive effects of aging. Our tight-knit faculty collaborates across this range: each lab PI collaborates with multiple others, and most projects involve several levels of analysis. Our students are integral agents of this intellectually and spatially tight-knit neuroscience community, in that they typically work across more than one lab. The cohesion that results from this collaborativity is reflected in every aspect of the program—in coursework, rotations, thesis supervision, the shared availability of advanced instrumentation and the collegiality of interactions. The breadth of opportunity and interaction that characterizes Brandeis, and the close attention we pay to student progress, means that each student develops according to their individual needs, which in turn results in a very low attrition rate. Our students graduate with excellent credentials and go on to obtain positions in academia, health care, government and industry, and to directly contribute to the NIH mandate to benefit human health. A strong, abiding aspect of our program has always been our emphasis on quantitative thinking. Every area of Neuroscience is increasingly driven by large data sets; to be prepared for the myriad available careers in Neuroscience, students must become generally expert in the analysis of complex multivariate data. For this proposal, we evolve our approach to quantitative literacy, proposing extensive curricular changes that will ensure that our students graduate grasping the fundamentals of quantitation (rather than just knowing specific methods). Armed with an understanding of computational tools and programming, all of our students will have a solid foundation upon which to do rigorous research at any level of analysis. Program changes instituted for this proposal will ensure that the program of course work, rotations, multiple small-group colloquia, proposition exams, and participation in teaching does not keep our trainees from digging into their dissertation work before the end of Year 1. Laboratory research is not the sole focus of the first (or even 2nd) year at Brandeis, and our students are not supported on research grants in these critical first years. This training grant provides crucial funding to support students while they develop a broad set of intellectual skills. There are 20 mentors in our program and we are requesting funds for 8 trainees.

New Jersey Department of Human Services

NJDHS funds nonprofits and community organizations providing social services including mental health, substance use treatment, disability services, food assistance, and support for vulnerable populations across New Jersey.

NIMH - National Institute of Mental Health

OVERALL - Summary: The Developmental AIDS Research Center New York-New Jersey – Center for Actionable NeuroHIV Biomarkers and Integrated Omics, (NYJ-CAN-BIO) proposes to develop the infrastructure and collaborative resources at Weill Cornell Medicine (WCM) and Rutgers Health (RH) to enable actionable neuroHIV biomarker driven discovery research. This Center is committed to provide expertise, cutting-edge technologies and training for identifying multidimensional biomarkers that are mechanistically meaningful, diagnostically useful, and translatable towards the development of transformative therapies for HIV-associated CNS dysfunction and strategies focused on the eradication of latent HIV within the CNS. While advances in understanding the pathophysiology of HIV effects on the CNS in the era ART have yielded much progress, current biomarkers are not specific to the CNS, and their utility for biotyping neuroHIV clinical manifestations remains unclear and a significant gap in our efforts to resolve the underlying mechanisms and efforts towards HIV eradication in the CNS. A major barrier to progress in the field is a lack of integrated centralized center to coordinate these efforts. NYJ-CAN-BIO is committed to filing this gap and advance a framework for neuroHIV biomarker discovery, fostering innovation, and promoting collaborative efforts to improve the delineation of CNS disease heterogeneity and clinical outcomes in people with HIV or at risk across the Bi-State (New York and New Jersey) area, a region with one of the highest burdens of HIV across the country. NYJ-CAN-BIO will pioneer biomarker-driven approaches that harness our researchers across two institutions and their basic, clinical and translational infrastructures, integrating cutting-edge technologies, such as 3D organoid and physiological systems, advanced multi-omic platforms and emerging innovations in computational analytics and AI that would ultimately provide a resource and biomarker expertise across the exciting nationwide of DARC and ARC networks beyond the bistate area. The Directors of the Center, Dr. Lishomwa Ndhlovu (WCM) and Dr. Tricia Burdo (RH) and Cores have demonstrated excellence and leadership in neuroHIV and will capitalize on the current expertise of affiliated investigators at WCM and RH through the establishment of an integrated Administrative (AC), Developmental and Mentorship (DMC), and Biosignature (BC) Core structure. To achieve these goals, NYJ-CAN-BIO proposes three aims. Aim 1 will catalyze actionable biomarker-driven neuroHIV research through formation of an AC that integrates translational clinical data with omics driven technologies, computational analytics and 3D brain organoid and physiological system-based modeling across collaborating institutions. Aim 2 will train and support all-encompassing cohorts of early-career, new and established investigators in the emerging fields of neuroHIV, biological indicators of disease, immunology, computational neuroscience, 3D brain organoid and physiological system-based modeling. Aim 3 will guide the discovery, validation, and dissemination of multimodal biomarker discovery omics platforms, computational analytics and human-biology-based new approach methodologies.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract The “Opioid Crisis Response Act of 2018” is a key legislative effort to address the opioid epidemic in United States, recognizing opioid overdoses as one of the nation’s most pressing public health threats. Opioid related deaths have surged since 1999, with over 82,000 deaths in 2022 alone, driven primarily by synthetic opioids like fentanyl. To combat this crisis, there is an urgent need for new translational tools and strategies to better understand the neurobiology of opioid addiction. The mu opioid receptor (MOR) plays a critical role in regulating the respiratory system and neuropsychiatric functions, directly impacting the key concerns of the opioid epidemic – respiratory failure and addiction. Despite its importance in various diseases, the full scope of its role of MOR and its ligands in complex addiction mechanism in human brains remains unclear. To address this, we are developing a new translational tool to study the molecular and cellular mechanisms of receptor dysregulation that contribute to substance abuse and mental health disorders. Non-invasive, quantitative positron emission tomography (PET) imaging of MOR in the human brain will provide crucial perspective into how MOR density and occupancy are linked to its dysregulation. While a handful of conventional MOR-PET probes exist and offer valuable insights through preclinical and clinical imaging studies, they are either too potent or not sensitive enough for studying neurobiology of MOR in the living brain. This proposal focuses on the final preclinical evaluation of a safe, widely accessible PET neuroimaging probe18F-fluorocarfentanil (18F-FCFN). Our team recently developed four derivatives of 18F-FCFN and validated their in vivo suitability as PET neuroimaging probes in rats through proof-of-concept studies. Based on our prior findings, published in 2025, two 18F-FCFN candidates emerged with promising features – high brain uptake, favorable selectivity and specific binding to MOR. We now propose completing final evaluations in higher species to select the best 18F-FCFN candidates for clinical translation. In AIM 1, we will assess the in vivo pharmacokinetics, selectivity, and binding potential (BPND) of these two 18F-FCFN candidates in non-human primates (NHPs) and select the top candidate for further evaluations. In AIM 2, we will determine the whole-body biodistribution and radiation dosimetry of the selected 18F-FCFN candidate in NHPs, along with conducting acute toxicology studies to assess its safety for human use. This work is critical for selecting and advancing the top 18F-FCFN candidate to first-in-human trials.

Centers for Disease Control and Prevention - ERA

<p>The Agriculture, Forestry, and Fishing (AgFF) sector is essential to the safety, security, and economic stability of the U.S. because it produces the nation's food, fuel, and fiber.&nbsp;&nbsp;At the same time, AgFF workers experience some of the highest occupational fatality and non-fatal injury rates of any sector. AgFF workers also face increased risk of poor mental health, death by suicide, and substance use disorder.&nbsp;</p><p>The National Institute for Occupational Safety and Health (NIOSH) is committed to addressing a wide range of occupational health and safety hazards affecting people who work in the production, processing, and transportation of AgFF products.</p><p>This notice of funding opportunity (NOFO) will support up to twelve regional NIOSH Centers for Agriculture, Forestry, and Fishing Safety and Health (AgFF Centers). Each AgFF Center will advance the NIOSH mission and priorities through high-quality research, education, training, and outreach. Key Center activities include:</p><ul style="list-style-type:disc;"><li data-list-item-id="ecbc15055073bfd4ee1bee7fafd580922">Conducting high-quality, multidisciplinary science, with an emphasis on intervention and implementation research;&nbsp;</li><li data-list-item-id="ea8c3dd54dc1292a89bb61a1cdf2eb69a">Advancing AgFF research-to-practice (r2p) by translating scientific discoveries into practical, real-world solutions;</li><li data-list-item-id="e560e02d11c0e68e6bd98948fa1c0f846">Developing and evaluating technology, including AI and automation, to reduce workplace hazards and improve health outcomes for AgFF workers;</li><li data-list-item-id="ef6f1fb998df5b92ffd4d4c31230ac51a">Engaging with a variety of regional and national partners to effectively communicate new knowledge and best practices;</li><li data-list-item-id="ed88da01ebac507ea824283572a8d57fd">Integrating food systems and One Health approaches into occupational safety, health, and well-being; and</li><li data-list-item-id="e7a784ea833b49df8fac02fa4b226b921">Improving the coordination and collection of data on injury, illness, disability, and death for AgFF workers.</li></ul><p style="margin-left:.25in;">AgFF Centers work closely with NIOSH AgFF program leadership and collaborate with other AgFF Centers, NIOSH scientists (when applicable), academic and research partners, industry and community groups, and other organizations. Funded Centers are expected to have significant, widespread, and sustained local and regional impact. Together, these efforts should collectively contribute to the national advancement of AgFF workers' safety, health, and well-being.&nbsp;</p>

Centers for Disease Control and Prevention - ERA

The Agriculture, Forestry, and Fishing (AgFF) sector is essential to the safety, security, and economic stability of the U.S. because it produces the nation's food, fuel, and fiber. At the same time, AgFF workers experience some of the highest occupational fatality and non-fatal injury rates of any sector. AgFF workers also face increased risk of poor mental health, death by suicide, and substance use disorder. The National Institute for Occupational Safety and Health (NIOSH) is committed to addressing a wide range of occupational health and safety hazards affecting people who work in the production, processing, and transportation of AgFF products.This notice of funding opportunity (NOFO) will support up to twelve regional NIOSH Centers for Agriculture, Forestry, and Fishing Safety and Health (AgFF Centers). Each AgFF Center will advance the NIOSH mission and priorities through high-quality research, education, training, and outreach. Key Center activities include:Conducting high-quality, multidisciplinary science, with an emphasis on intervention and implementation research; Advancing AgFF research-to-practice (r2p) by translating scientific discoveries into practical, real-world solutions;Developing and evaluating technology, including AI and automation, to reduce workplace hazards and improve health outcomes for AgFF workers;Engaging with a variety of regional and national partners to effectively communicate new knowledge and best practices;Integrating food systems and One Health approaches into occupational safety, health, and well-being; andImproving the coordination and collection of data on injury, illness, disability, and death for AgFF workers.AgFF Centers work closely with NIOSH AgFF program leadership and collaborate with other AgFF Centers, NIOSH scientists (when applicable), academic and research partners, industry and community groups, and other organizations. Funded Centers are expected to have significant, widespread, and sustained local and regional impact. Together, these efforts should collectively contribute to the national advancement of AgFF workers' safety, health, and well-being.