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NIH

305,509 veterans received a new diagnosis of strabismus (misalignment of the two eyes) between 2010 and 2021, and many of them have double vision (diplopia). Diplopia decreases the quality of vision and leads to the inability to perform tasks of daily living (like working, reading, and driving) with significant disability. Strabismus is a visible physical deformity that impairs the ability to make eye contact and affects self-esteem, mental health, employability, and overall quality of life. Eye- movement abnormalities and strabismus are sometimes associated with systemic or neurologic diseases. Diagnosis and treatment of eye movement abnormalities and strabismus rely on accurately determining the pattern and degrees of misalignment in different gaze positions and analyzing the accuracy of monocular and binocular eye movements. A team of professionals, including adult strabismus surgeons, orthoptists, and neuro-ophthalmologists, is involved in the labor and time-intensive process of obtaining this information. Treatment recommendations are broad, including placement of prisms in glasses, patching, surgery, imaging, labs, medication, or a combination. Immediate rehabilitation of quality of vision can be obtained by placing prisms in patient's glasses. A significant barrier to the care of veterans affected by strabismus is the lack of trained personnel (in and outside the VA system) to determine the magnitude, direction, and patterns of eye misalignment and eye movement abnormalities, leading to long wait times for an appointment. Thus, care and visual rehabilitation is frequently delayed for months. Eye-tracking technology that can be used to record eye movement abnormalities is commercially available. Still, a critical need exists for algorithms that can analyze this information to assist in patients' diagnosis, treatment, and workup. In this project, we aim to optimize current eye-tracking protocols and software to determine ocular misalignment, patterns of strabismus, and the dynamics of eye movements from the recordings. We will also employ machine learning computational techniques to uncover diagnostic characteristics from the eye movement recordings. The innovation of this proposal is to automate the eye movement and misalignment evaluation as well as the clinical interpretation and thereby reduce or eliminate the involvement of strabismus experts and neuro-opthalmologists. To validate the algorithms, we will compare them with the current standard of care - evaluation of sensorimotor manual measurements by experts. The availability of fast, reliable, and affordable assessments of eye motility and strabismus in every ophthalmology clinic in the VA Health Care system will make evaluation readily available and overcome current limitations. Treatment and workup recommendations will be immediately available, allowing veterans to be treated using existing technology and current personnel. The proposed study is the first and largest to use eye-tracking recordings to develop algorithms and software to classify eye misalignment and motility patterns, which will then be used to generate accurate treatment plans. At the Iowa City VA ophthalmology clinic and Center for the Prevention and Treatment of Visual Loss, we are uniquely positioned for success in this project by having an expert team of an adult strabismus specialist/surgeon, an orthoptist, and a neuro-ophthalmologist to perform manual measurements, accurate diagnosis, and treatment for these conditions. If successful, this system will assist healthcare professionals in detecting, diagnosing, and planning personalized treatment for strabismus patients, ultimately leading to improved outcomes and quality of care. Further, it will result in increased access to health care and faster treatment for Veterans, higher productivity for eye care providers, and reduced fee-based costs to the VA Health Care system for non-surgical cases. The veterans' ability to function independently and overall quality of life, self-esteem, and employability will improve.

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required)

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required)

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to two years of support for evaluation of target engagement and establishment of intervention parameters, and up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

National Institutes of Health

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 Clinical Trial Required). As part of NIMH's clinical trials pipeline, this NOFO encourages pilot research developing and testing novel psychosocial interventions and/or targets. Consistent with NIMH's emphasis on the experimental therapeutics approach to intervention development, it intends to speed the translation of emergent research in basic, behavioral, cognitive, affect, and neuropsychological science into preventative or therapeutic interventions. This RFA will provide up to two years of support for evaluation of target engagement and establishment of intervention parameters, and up to three years of support to replicate target engagement from prior studies and to test the association between target engagement and change in clinical outcome(s).

NIMH - National Institute of Mental Health

Synaptic connections between neurons are fundamental computational units in the brain that contribute to virtually all neurological functions. For this reason, synapses have been extensively characterized across structural, functional, and molecular levels, revealing insights into the mechanisms through which synapses are established during brain development and deepening our understanding of how impairments in synaptic maturation contribute to autism and related disorders. Nevertheless, our ever-growing understanding of synapses has yet to give rise to effective pharmacological strategies for treating neurodevelopmental conditions. One reason for this lack of progress is that the specific population(s) of synapses that are affected in autism, and the precise ways in which their development goes awry, remain to be defined. Though synapses are widely considered to be the sole domain of neurons, seminal work in the early 2000s demonstrated that neurons also form functional synaptic connections with oligodendrocyte precursor cells (OPCs), a highly proliferative population of glia that makes up about 5% of the brain. OPCs express the requisite neurotransmitter receptors and signaling modules necessary to receive, interpret, and respond to synaptic innervation, and neuron-OPC synapses have been suggested to influence a range of functions including but extending beyond myelination. Yet, despite our relatively deep understanding of synaptic communication between neurons, synapses between neurons and OPCs remain poorly understood across all levels of analysis. Intriguingly, among all brain cells, OPCs are the highest expressers of synaptic adhesion molecules in the Neuroligin family, key mediators of synapse development that are among the strongest genetic drivers of autism risk. This observation raises the possibility that, despite the predominant view that impairments in the development of neuron-neuron synapses underlie autism, deficits in the development of neuron-OPC synapses could contribute as well. However, almost nothing is known about the mechanisms through which neuron-OPC synapses are assembled and refined in the contexts of either health or disease. In this application, we propose to examine the development of neuron-OPC synapses by harnessing the retinogeniculate pathway of the mouse visual system as a model for interrogating postnatal circuit refinement. In Aim 1, we will employ anatomical and electrophysiological approaches to map the maturation of synapses between neurons in the retina and OPCs (or neighboring relay neurons) in the visual thalamus in the presence or absence of OPC-expressed Neuroligins 1-3. In Aim 2, we will employ a proteomic screen to define the molecular composition of neuron-OPC synapses during development in an unbiased manner. Given that neuron- OPC synapses are the only synapse class through which neurons communicate directly with glia, virtually any insights into the development of neuron-OPC synapses will represent a significant advance for the field, and may inform new therapeutic strategies for treating disorders of brain development.

National Institutes of Health

-Purpose. The purpose of this Funding Opportunity Announcement (FOA) is to request research applications to examine the neurobiological impact of psychotherapeutic medications upon the immature brain, with particular emphasis upon mapping the precise developmental profile of physiological response to psychotropic agents used in the treatment of mental disorders in children. Responsive research includes -studies in model systems, including animals, and in human populations. -Mechanism of Support. This funding opportunity will use the NIH Research Project Grant (R01) award mechanism. Applications of related or identical scientific scope are solicited also under the Small Research Grant (R03) and the Exploratory/Developmental Grant (R21) award mechanisms, responding to FOAs PA-06-180 and PA-06-181, respectively. -Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received.

NIDA - National Institute on Drug Abuse

PROJECT SUMMARY/ABSTRACT Many evidence-based preventative interventions have been developed to prevent substance use, physical and mental illness, and promote positive educational and social outcomes among adolescents. Among these, caregiver-mediated interventions boast strong effects that are mediated by effective parenting skills. However, the impact of these interventions is severely limited by low rates of home practice of intervention skills among caregivers. To address this research-to-practice gap, researchers have been investigating barriers and facilitators of caregiver engagement, focusing in large part on intervention attendance. Strategies for increasing caregivers' home practice of skills remain underexamined. Yet, caregiver home practice is a key component of theorized intervention effectiveness and has been found to impact parenting behaviors and subsequent child outcomes over and above that of attendance. Therefore, the next important step in supporting parenting behavior change is to develop implementation support strategies for evidence-based interventions that target caregiver home practice specifically. This K01 Mentored Research Scientist Development Award will develop and pilot a digital behavior change intervention for use as an adjunct to an evidence-based preventative intervention. The digital behavior change intervention aims to increase caregivers' home practice of intervention skills. Informed by the theory of planned behavior, habit formation principles, and relapse prevention theory, the intervention will leverage mobile health technologies (mHealth) to circumvent and problem solve common barriers to home practice including home practice intention, frequency of practice, home practice competence, and maintenance of intervention skills. The intervention will be developed as a smartphone application (i.e., “app”) with components informed by a qualitative assessment of barriers to caregiver home practice and refined through direct stakeholder input on design requirements to optimize acceptability and feasibility. The intervention will be piloted with 48 caregiver participants as an adjunct to Bridges, an evidence-based intervention for adolescent substance use prevention and mental health promotion. Findings from this project have the potential to improve caregiver home practice, intervention engagement broadly, and ultimately boost effectiveness and public health impact of numerous caregiver- mediated interventions. In response to NOSI NOT-OD-23-031, this administrative supplement seeks the support of personnel to support the continuation of proposed project activities (e.g., participant recruitment, qualitative and quantitative data collection, pilot trial of the digital behavior change intervention) within the original timeline. No changes have been made to the aims, goals, or scope of the work proposed in the funded K01 application.

NIMH - National Institute of Mental Health

Project Summary/Abstract The goal of the proposed project is to develop to develop an innovative digital health platform to support families who have a teenager diagnosed with attention deficit hyperactivity disorder (ADHD) who is driving (during permit period or post licensure). Parents of teens with ADHD routinely cite that one of the greatest sources of stress and frustration centers on the issue of driving. Teens with ADHD are at significantly increased risk of crash, more likely to have multiple crashes, and more likely to have their driving license suspended. In addition, teens with ADHD are more likely to have challenges in securing a license during the permitting process. We propose the development of an app that will enable joint parent and teen goal setting, monitoring and personalized feedback. Telematics data enables that development of the proposed app. Development will also be guided by evidence-based strategies for engaging with parents and teens with ADHD and iterative feedback that will be collected from the intended user population. The needs of the intended population will be considered throughout the development process and in phase I, a prototype of the platform will be tested with the intended population for usability and acceptability. We have assembled a team with complimentary expertise to develop the methods of engagement, content, user interface and app, and to conduct the needed testing.

Administration for Community Living

Disability and Rehabilitation Research Projects (DRRP) Program: Research on Resilience and Positive Mental Health Outcomes Among People with Spinal Cord Injury

Administration for Community Living

Under this particular DRRP priority, the grantee must conduct research toward resilience and positive mental health outcomes among people with spinal cord injury. This grant will have a 36-month project period, with three 12-month budget periods.

Administration for Community Living

Under this particular DRRP priority, the grantee must conduct research toward resilience and positive mental health outcomes among people with spinal cord injury. This grant will have a 36-month project period, with three 12-month budget periods.

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to support investigators who have the interest and capability to join efforts for the discovery of in vivo chemical probes for novel brain targets. It is expected that applicants will have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds.Through this NOFO, NIH wishes to stimulate research in:Discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Eye Institute (NEI), and/or National Institute on Aging (NIA) andDiscovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms.Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes.

National Institutes of Health

The purpose of this Notice of Funding Opportunity (NOFO) is to support investigators who have the interest and capability to join efforts for the discovery of in vivo chemical probes for novel brain targets. It is expected that applicants will have, in hand, the starting compounds (validated hits) for chemical optimization and bioassays for testing new analog compounds.Through this NOFO, NIH wishes to stimulate research in:Discovery and development of novel, small molecules for their potential use in understanding biological processes relevant to the missions of National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Eye Institute (NEI), and/or National Institute on Aging (NIA) andDiscovery and/or validation of novel, biological targets that will inform studies of brain disease mechanisms.Emphasis will be placed on projects that provide new insight into important disease-related biological targets and biological processes.

NIMH - National Institute of Mental Health

Abstract Despite the high prevalence of major depressive disorder (MDD) and its projected rise as the leading cause of global disease burden by 2030, treatment efficacy remains suboptimal. First-line antidepressants have modest efficacy (~50%), and high placebo response rates (~40%) contribute to the failure of antidepressant trials and hinder new drug development. While research underscores the role of antidepressant expectancies in modulating mood across various brain regions, there is a critical need to elucidate how expectancy-driven neural dynamics interact with downstream mood regulation processes to induce sustained mood improvement. Our recent work provides the first computational account of antidepressant placebo effects, where reinforcement learning (RL) model-predicted expectancies—encoded in the salience network (SN)—trigger mood changes perceived as reward signals, which reinforce antidepressant expectancies through an expectancy-mood loop. Furthermore, we and others have demonstrated that enhanced functional connectivity (FC) between the SN and default mode network (DMN) during expectancy processing and at rest predicts long-term antidepressant placebo effects. This evidence suggests that antidepressant expectancies, originating from contextual treatment cues, are represented in the SN and influence mood regulation through top-down connections with the DMN. To test this hypothesis, this study will investigate the causal roles of the SN, DMN, and SN-DMN FC in antidepressant placebo effects using Theta Burst Stimulation (TBS). In a 2x3 factorial design, 200 patients with MDD will be randomized to three counter-balanced TBS conditions (intermittent, continuous, and sham, within-subject) targeting either the SN or DMN (between-subject). These acute experimental manipulations will modulate trial-by-trial expectancy and mood ratings and the neural encoding of model-based expectancies and mood reward signals during the “antidepressant placebo fMRI task”, which manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and sham visual neurofeedback. Led by experts in placebo effects, reinforcement learning, depression, and neuromodulation, this study combines a robust theoretical framework, state-of-the-art neuroimaging, precision functional mapping for personalized TBS targeting, and accelerated TBS, ensuring scientific rigor. The insights gained from this study will deepen our understanding of the neural mechanisms behind placebo effects, enhancing clinical trial design, advancing neuroimaging predictors of treatment response, and accelerating the development of expectancy-based interventions for MDD.

NIMH - National Institute of Mental Health

Prenatal infections cause maternal immune activation (MIA), a major risk factor for several neurodevelopmental disorders, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). Consequently, elucidating the mechanisms by which MIA alters brain function is critical for understanding the pathophysiology of these disorders and developing effective treatments. While the effects of MIA on neurons and microglia have been extensively studied, the impact of MIA on astrocytes, key regulators of brain physiology and homeostasis, remain unknown that significantly impedes our understanding the mechanisms of MIA-induced neurobehavioral abnormalities. To address this major knowledge gap, we conducted pilot studies that suggest that MIA increases impulsivity-like behaviors and amphetamine-induced hyperactivity and enhances extracellular levels of glutamate (GLU) and dopamine (DA) in the dorsal striatum (DS). MIA also increased pro-inflammatory signatures of astrocytes, including up- regulation of the Nuclear Factor kappa B (NF-κB) pathway and increased GFAP immunoreactivity in DS astrocytes. Collectively, these novel findings support our overarching hypothesis that MIA increases astrocyte reactivity, leading to increased gliotransmission (e.g., GLU), which in turn enhances DS DA release and DA- dependent behaviors. To test this hypothesis, we will leverage the expertise of the research team in molecular, physiological and neurobehavioral approaches and conduct the following Specific Aims: In Aim 1, we will identify the MIA-induced cellular and physiological changes characteristic of astrocyte reactivity. In Aim 2, we will determine the circuit mechanisms by which MIA increases DA signaling. In Aim 3, we will identify the molecular mechanisms whereby reactive astrocytes contribute to MIA-induced cellular and behavioral abnormalities. These studies will enhance the current understanding of the effects of MIA on brain functions and generate new insight into potential treatment strategies for MIA-associated neurodevelopmental disorders.

NIMH - National Institute of Mental Health

7. Project Summary/Abstract We make hundreds of decisions a day. Value-based decision-making requires the orchestration of multiple processes that enable us to learn from prior experience and then use this information to guide our behavior. Deficits in decision-making are common in psychiatric disorders that result from disruptions in how value is estimated or assigned, how value estimates influence action selection, or the ability to make inferences about the environment to guide decisions. These disruptions are unresponsive to current treatments and contribute to the functional disability evident in mental illness. Hence, a deeper understanding of the mechanisms underlying adaptive and maladaptive reward learning is required to address this unmet therapeutic need. Here, we will use fiber photometry, optogenetics, and computational modeling in rats performing two translational behavioral tasks to identify the neurophysiological mechanisms underlying value-based decision-making. The orbitofrontal cortex (OFC) and the striatum are essential mediators of reward processing and decision-making, and both the ventromedial and lateral subregions of the OFC (vmOFC and lOFC, respectively) project glutamatergic neurons to the striatum in a topographic manner; the vmOFC mostly innervates the medial striatum (mS) whereas lOFC preferentially targets central striatal regions (cS). Identifying how these distinct orbito-striatal pathways contribute to specific aspects of value-based decision-making is essential. We aim to (1) identify how dynamic changes in vmOFC→mS and lOFC→cS circuit activity mediate flexible reward learning and (2) determine how alterations in circuit activity disrupt this process. Specific Aim 1 will use dual-color fiber photometry to measure the activity of the vmOFC→mS or lOFC→cS circuits with simultaneous measurement of local OFC parvalbumin-positive (PV+) GABA interneuron activity. Specific Aim 2 will use complementary gain- or loss-of-function optogenetic interventions to confirm the functional relevance of neural activity during behavior. These optogenetic manipulations – targeting orbito-striatal glutamate circuits or OFC PV+ interneurons – will be delivered to (1) enhance the dynamic changes in neural activity associated with optimal task performance or (2) perturb normal neural activity and induce behaviorally distinct disruptions value-based decision-making. Each Specific Aim will evaluate value-based decision-making in rats tested in a probabilistic reversal learning (PRL) or 2-step reinforcement learning task. Computational models of reinforcement learning will provide an in-depth analysis of behavioral performance, and regression analysis will determine how changes in neural activity contribute to task performance. With a multidisciplinary approach and high cell-type- and circuit-specificity, our findings will elucidate the neurobiological mechanisms underlying decision-making and provide critical insight for the development of new and effective therapeutic strategies for mental illness.

NIMH - National Institute of Mental Health

Project Summary: Although the resting memory CD4+ T cells are the best-recognized long-lived reservoirs of latent HIV provirus, it is now well accepted that the myeloid cells, especially of the central nervous system (CNS), including perivascular macrophages and microglial cells are the major target of HIV. The molecular mechanisms relevant to HIV latency are primarily defined by analyzing HIV latency in latently infected CD4+ lymphoid cells. However, very little is known about HIV latency/persistence in myeloid cells. Notably, the presence of HIV-harboring myeloid cells in the CNS is documented to be the key factor contributing to CNS inflammation and promoting HIV-associated neurocognitive disorder (HAND) in HIV patients. Microglial cells are the main HIV reservoir in the CNS, yet there is a gap in the knowledge regarding our understanding of the molecular mechanisms that maintain HIV reservoirs in those cells. Our long-term goal is to identify and characterize the underlying molecular mechanisms that regulate HIV latency in the CNS. We have shown the vital role of DNA-PK in supporting HIV transcription and latency-reactivation in both lymphoid and myeloid cells. Recently, we published one more article, bringing a total of 3 articles on this subject. The objective of this grant is to characterize the role of DNA-PK during HIV latency and define the molecular mechanisms by which DNA-PK supports HIV transcription in the main CNS reservoir, microglial cells. Based on our published and preliminary findings, we have hypothesized that DNA-PK modulates HIV transcription in microglial cells by reducing RNAPII pausing during HIV transcription. For testing our hypothesis, in Aim 1, we will establish the role of DNA-PK in relieving RNAPII pausing during HIV transcription and latency- reactivation in microglial cells, by Stimulating RNAPII processivity (elongation capability) and Relieving restrictions exerted by negative elongation factors to HIV transcription. In Aim 2, we will characterize the role of DNA-PK-induced chromatin modifications in regulating HIV gene expression and latent reservoir in microglial cells. Our rationale is that since HIV latency is primarily regulated at the transcriptional level, defining the precise and all mechanism(s) that regulate HIV transcription in microglial cells will offer novel therapeutic opportunities to target HIV reservoirs in the CNS. These studies will also provide a well-defined therapeutic target in the form of DNA-PK, and this new knowledge will be valuable for both basic and translational research. The proposed research is innovative because, besides iPSCs-derived human microglial cells (IDMs), it uses a novel ex vivo model system for HIV latency in microglia, that for the first time, allows the studies of the molecular correlates for HIV entry and exit into latency in microglial cells, which is otherwise an impossible task due to insufficient availability of brain autopsy specimens. This contribution is significant since the identified mechanisms, which regulate HIV transcription and latency in microglial cells, will facilitate the designing of optimized therapies targeting CNS reservoirs of HIV, and contributing towards cure approaches.

NIMH - National Institute of Mental Health

Project Summary/Abstract Neuropsychiatric disorders often emerge during childhood and adolescence, and many involve maladaptive learning and memory. Persistent memories of salient positive or negative events can contribute to the onset and maintenance of disorders like addiction and anxiety; yet we lack a mechanistic account of how affective experiences drive selective memory prioritization throughout development. Dopaminergic and noradrenergic projections to the hippocampus have been implicated in long-term memory for emotion-related events and research in nonhuman animal models suggests that dopamine and norepinephrine systems may follow different developmental trajectories. Whether a developmental asymmetry is also present in humans and how it may impact emotion-related learning and memory processes that render youth vulnerable to neuropsychiatric disorders is unknown. The proposed research aims to establish a mechanistic account of how emotional experiences drive selective memory prioritization over human development. We will investigate neuromodulatory system function and its relations to emotional memory over development using behavioral, psychophysiological, neuroimaging, and computational approaches. Aim 1 examines how affect induced by outcomes in a classic probabilistic reinforcement learning task influences memory and neuromodulatory-linked function from childhood to adulthood. Aim 2 assesses how naturalistic affect during emotional video watching relates to memory and brain function. Aim 3 characterizes age-related change in catecholamine function longitudinally, using neuromelanin-sensitive MRI as proxy, and relations with everyday emotional memory. This research has the potential to: 1) establish affective contributions to memory selectivity and persistence in controlled experimental, naturalistic experiential, and everyday memory studies; 2) determine relations between multiple non-invasive proxy measures of noradrenergic and dopaminergic system function and emotion-related memory across development; 3) provide a multimodal, cross-sectional, and longitudinal characterization of neuromodulatory-linked function; 4) delineate neurocognitive phenotypes that may relate to risk for psychopathology and inform the development of early interventions.

NIMH - National Institute of Mental Health

Project Summary/Abstract. Close to 20% of Americans suffer from internalizing disorders like depression, anxiety, and posttraumatic stress in their lifetime (National Center for Health Statistics, 2023). These conditions disproportionally affect young adults, and prevalence rates have risen 30% in the past five years (Santomauro et al., 2021). Moreover, there is considerable comorbidity across internalizing disorders and heterogeneity within disorders (Price et al., 2019; Spinhoven et al., 2014), highlighting the need to identify transdiagnostic biomarkers for effective screening and treatment. Deficits in emotion regulation (ER) is a hallmark risk factor for internalizing disorders (Aldao et al., 2010, 2016). Specifically, low flexibility in ER strategy use – the inability to use a large and varied repertoire of strategies flexibility according to contextual demands – has been linked to internalizing disorders transdiagnostically (Wen et al., 2021, 2024, 2025). However, the neurobiological mechanisms by which flexibility in ER influences internalizing disorders remain largely unclear. Elucidating such mechanisms is a critical step to advancing effective, targeted clinical interventions. In this K99/R00, three aims are proposed to examine the mechanism of ER flexibility in internalizing disorder etiology. In the K99 phase, a large-scale longitudinal dataset (PI: Craske) containing resting state fMRI data and self-reported ER from young adults with varying levels of internalizing disorder severity will be analyzed. Dynamic co-activation pattern analysis will be used to identify functional brain network dynamics (e.g., transitions between the salience, default mode, and central executive networks), and examine associations with ER flexibility as assessed by an innovative, validated index of ER flexibility developed by the Candidate (Wen et al., 2021, 2024; Aim 1). These functional brain network dynamics will then be evaluated in relation to broad symptom dimensions underlying internalizing disorders transdiagnostically (Aim 2). In the R00 phase, new data will be collected for individuals with clinical levels of internalizing symptom severity. Variables include internalizing symptoms, ER flexibility, functional network dynamics, stress, and cognitive control that is theorized to underlie ER (LeMoult & Gotlib, 2019). Path analyses will be conducted to compare two models with hypothesized neurobiological pathways by which ER flexibility influences broad internalizing symptom dimensions (Aim 3). This proposed K99 training will be conducted with Dr. Michelle Craske (primary mentor) and Dr. Lucina Uddin (co-mentor) at UCLA, with guidance from an advisory committee of experts in neuroimaging and psychopathology research. This environment will help the Candidate achieve the career development goal of acquiring of new skillsets in functional neuroimaging and knowledge in functional brain dynamics. The proposed training will provide the Candidate with intellectual and technical training needed to launch an independent research program at a top academic institution studying the neurobiological mechanisms by which emotional processes influence the etiology for internalizing disorders broadly.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT This proposal aims to elucidate a potential neurobiological mechanism of stress-induced social behavior deficits. Chronic stress is well-known to contribute to neuropsychiatric disorders such as major depressive disorder and post-traumatic stress disorder, and social dysfunction is often cited by patients as a major quality of life problem. Based on previous work from the lab, transposable element (TE) dysregulation has been identified as a driver of social behavior deficits in stress- naïve mice. TEs are known to be silenced in the genome by KRAB zinc finger protein (KZFP) transcription factors, which collectively bind the transcriptionally repressive cofactor TRIM28. Using novel synthetic TRIM28 variants delivered into the medial prefrontal cortex (mPFC) of male and female mice, this study will probe the connection between chronic stress, mPFC TE stability, and social behavior. The synthetic TRIM28 variants, TRIM28WT and TRIM28VPR, exert opposing forms of transcriptional control, with TRIM28WT acting as a gene repressor and TRIM28VPR as an activator. Aim 1 seeks to determine the behavioral outcomes of applying synthetic TRIM28 variants to mice who have undergone chronic social stress, thereby providing training in the application of translationally relevant chronic stress paradigms. Restabilizing TEs via TRIM28WT is predicted to reverse stress-induced social behavior deficits. Aim 2 seeks to characterize the mPFC transcriptional correlates of these behaviors, in terms of both canonical genes and TEs, using bulk RNA sequencing of microdissected mPFC tissue. Moreover, Aim 2 will relate these gene transcriptional changes to known changes induced by chronic social stress in the absence of TRIM28 manipulations. This will clarify the gene and TE transcriptional responses to chronic stress and will provide training in the analysis of complex bioinformatic data. Collectively, this project aims to understand the role of TE stability in the mPFC in stress-induced social behavior deficits, ideally culminating in a novel approach to address the gap in quality of life for people with chronic stress associated neuropsychiatric disorders.

National Institutes of Health

Purpose. This Funding Opportunity Announcement (FOA) issued by the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), invites investigator-initiated research grant applications for studies focused on the early identification and treatment of mental disorders in children and adolescents. Specific examples include studies focused on: the validation of early diagnosis of mental disorders in youth, especially in young children; the development of new interventions to treat mental disorders and prevent the exacerbation of associated functional impairment; the efficacy and safety of new and existing treatments; the identification and evaluation of predictors of treatment response and underlying mechanisms of action for new and existing treatments; the long-term effectiveness and impact of early intervention on later course; and the factors that promote or impede access to services and impact the effectiveness of services for these patients in community and practice settings. Assessment methods may include behavioral, neuropsychological, neuroimaging, and other physiological measures or markers. Intervention strategies to be studied may include pharmacological, psychosocial, and rehabilitative interventions, separately or in combination. Mechanism of Support. This FOA will use the NIH Research Project Grant (R01) award mechanism. Applications of related or identical scientific scope are also solicited under the NIH Small Research Grant (R03), the NIH Exploratory/Developmental Grant (R21), and the NIMH Clinical Exploratory Research Grant (R34), responding to FOAs PA-06-180, PA-06-181, and PAR-06-248, respectively. Funds Available and Anticipated Number of Awards. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications received. Eligible Institutions/Organizations. Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Small Business; For-Profit Organization (Other than Small Business); State Government; U.S. Territory or Possession; Indian/Native American Tribal Government (Federally Recognized); Indian/Native American Tribal Government (Other than Federally Recognized); Indian/Native American Tribally Designated Organization; Non-domestic (non-U.S.) Entity (Foreign Organization); Hispanic-serving Institution; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); Alaska Native and Native Hawaiian Serving Institutions; Regional Organization; Other(s): Eligible agencies of the Federal government; Faith-based or community based organizations.