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NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Cognition depends on context. The way we perceive stimuli, the predictions we make, and the actions we take all depend on the current situation. Considerable research has provided insight into how context affects neural processing, but relatively little is understood about how context itself is represented and learned. Here, we propose to combine computational models and electrophysiology in non-human primates to investigate the neural mechanisms that support context-dependent behavior. Our research builds on three recent theoretical models that use three different mechanisms for learning context representations and then using them to guide situationally-appropriate behaviors. These mechanisms include learning within prefrontal cortex, through the interactions between prefrontal cortex and basal ganglia, and through interactions between prefrontal cortex and hippocampus. To test the predictions of these models, we will simultaneously record neuronal activity from prefrontal cortex, hippocampus, and striatum of monkeys as they perform a context-dependent sequence prediction task. The proposed research has two primary aims: First, we aim to understand the structure of context representations in the brain. Monkeys will perform a sequential prediction task in which they must infer the context based on a cue and use it to predict subsequent stimuli. Each context will be associated with a unique sequence structure and designed in a way that allows us to understand the structure of the neural representation of context (as either compositional or conjunctive) and how this structure supports the generalization of knowledge between contexts. Recordings in prefrontal cortex, hippocampus, and striatum will test neural predictions from all three computational models about the nature of context representations in the brain. Second, we aim to understand how new contexts are learned. We will examine how different training regimes (e.g., blocked vs. interleaved contexts and transient vs. persistent cues) impact the formation and structure of context representations. Previous empirical and modeling work suggests that blocked training, while more difficult for standard neural networks, may benefit human learning by promoting compositional representations. Using neural recordings, we will test whether these findings extend to non-human primates and examine the role of prefrontal cortex, hippocampus, and striatum in learning under different training conditions. Overall, our research will provide insight into how the brain represents context and how these representations are shaped by learning experiences. This will refine our understanding of cognitive flexibility and lay the foundation for understanding, and addressing, disruptions in context-dependent processing associated with mental disorders including schizophrenia, obsessive-compulsive disorder, and anxiety.

NIDA - National Institute on Drug Abuse

SUMMARY: Dopamine, serotonin, and norepinephrine neurotransmitters are known to be critically involved in process underlying substance use disorder and psychiatric illness, as well as healthy motivated behavior, decision-making, and learning. However, little is known about how these signals coordinate and modulate subjective feeling and motivate behavior as mammals (including humans) navigate the world. Progress has been hindered by a lack of technology that permits fast, real-time, measurements that can discriminate and track dopamine, serotonin, and norepinephrine release simultaneously in areas of the brain where two or more of these neurotransmitters are co-released. A major challenge to current methods (e.g., fast scan cyclic voltammetry) is that the calibration models use to interpret in vivo data are trained in vitro and it is unclear how the background signal changes between these environments and how this affects the measured responses. This proposal capitalizes on (and seeks to radically improve) a technological innovation developed by the principal investigator, which resulted in the first successful colocalized measurements of dopamine and serotonin release with sub-second temporal resolution from the brains of consciously behaving humans. Here, we pursue two specific aims, which seek to develop a computational approach to extend these kinds of measurements to include simultaneous detection of norepinephrine and make these methods available for a larger area of preclinical animal model research and human clinical neuroscience research. In both aims we will be testing the overarching hypotheses that 1) the ‘background’ signal present in fast scan cyclic voltammetry measurements can be quantitatively characterized, mathematically modeled, and therefore subtracted using a model-based approach in in vivo research paradigms; and 2) that the “in vitro bias” in the mathematical models used in model-based electrochemistry can be corrected for if we can obtain a better characterization of the background signals in each of the in vivo, ex vivo, and in vitro conditions. The experiments and analyses proposed will begin to provide much needed clarity on the impact biological ‘interferents’ have on interpreting in vivo fast scan cyclic voltammetry data – currently the only approach amenable to sub-second multi-neurotransmitter detection in humans. We expect to develop mathematical models and calibration methods that can be used to predict and control for unwanted interfering signals while significantly improving detection methods for multi-neurotransmitter detection. Notably, these advances – to be shared via open-source online repositories – would accelerate ongoing efforts in the field aimed at understanding how dopaminergic, serotonergic, and noradrenergic systems coordinate to motivate behavior in humans and pre-clinical model organisms, and thereby provide insight into mechanisms underlying human mental health.

National Institutes of Health

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement supports confirmatory efficacy testing of non pharmacological therapeutic and preventive interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach. In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the mechanisms of action through which any intervention produces therapeutic change.

National Institutes of Health

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required). As part of NIMH's clinical trials pipeline NOFOs, this announcement supports confirmatory efficacy testing of non pharmacological therapeutic and preventive interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach. In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the mechanisms of action through which any intervention produces therapeutic change.

NIMH - National Institute of Mental Health

Schizophrenia is a heterogeneous, debilitating mental disorder with an extraordinarily large personal and socioeconomic impact. Although the disorder may first be recognized due to positive symptoms such as hallucinations and delusions, it is the negative symptoms and cognitive deficits, especially working memory, that account for functional disability. Antipsychotic medications, at best, have a small effect on cognition and functioning. Thus, in a disorder where cognitive deficits are a core feature driving disability, the need for non- pharmacologic cognition enhancing treatments to improve real world outcomes is more relevant than ever. Recent insights into the central role of neural oscillations in the frontal cortex, a key component in a neural circuit that supports working memory, provides a pathway for novel treatment development. Frontal activation during memory tasks is characterized by increased synchronous high frequency oscillations (30-45 Hz gamma waves) on EEG at frontal sites. This phenomenon of frontal gamma synchrony is directly correlated with performance on working memory tasks in healthy adults and is impaired in individuals with schizophrenia. Thus, we developed a neuromodulation intervention using gamma EEG neurofeedback (EEG-NFB) to increase synchronous activation of frontal gamma waves in an effort to improve neural processing in the frontal cortex and working memory. NFB provides real-time brain information feedback in the form of a visual or auditory metaphor so that the individual can modify their own brain activity. We conducted two preliminary clinical trials, an open trial, proof-of-concept study (R61), followed by a double-blind, placebo/sham-controlled, preliminary randomized clinical trial (RCT) to estimate the effect size of neurofeedback treatment on gamma response, working memory, and functioning in individuals with schizophrenia (R33). In the open trial R61 (n=31), individuals with schizophrenia showed significant improvements in both frontal gamma oscillations and working memory, as well as improvements in other cognitive domains, and improvement in working memory was correlated with greater training-related gamma responses. In the RCT (N=64), these significant improvements in working memory and gamma responses were replicated relative to a sham control, and improvements in working memory were again correlated with training-related gamma responses. Importantly, we also found significant improvement in functioning. An additional key finding was that EEG-NFB effects were heterogenous, just like the clinical disorder, in that, some participants responded very well, whereas others did not, thereby highlighting the need to identify which patients are more likely to benefit. Thus, we propose to conduct a larger confirmatory double-blind, placebo-controlled RCT of gamma EEG-NFB in individuals living with schizophrenia (N=104) with working memory and functioning as co-primary endpoints to confirm treatment efficacy and determine mediators and moderators of treatment response.

NIMH - National Institute of Mental Health

PROJECT SUMMARY The human serotonin transporter (hSERT) plays a critical role in regulating serotonin (5-HT) signaling across nearly all major systems in the body. Dysregulation of hSERT is linked to numerous psychiatric and gastrointestinal disorders, making hSERT a primary target for clinical therapeutics including selective serotonin reuptake inhibitors (SSRIs). While the core ion-coupled transport cycle of hSERT is well characterized, the allosteric mechanisms that fine-tune its activity to meet diverse physiological demands remain poorly understood. This proposal aims to define the structural mechanisms by which 5-HT and the microbial metabolite butyrate allosterically shape hSERT’s conformational landscape to modulate its function. Aim 1 will leverage innovative cryo-EM approaches capable of resolving the full range of conformational states that define hSERT’s transport cycle, enabling the distinct structural effects of ligand binding at the central (S1) and allosteric (S2) substrate- binding sites to be isolated and characterized. These conformational changes will be directly linked to transport activity using complementary 5-HT uptake and electrophysiological assays. Aim 2 will expand our understanding of hSERT allosteric regulation by identifying the binding site of butyrate, characterizing its effects on hSERT’s conformational equilibrium, and determining its impact on transport activity. The training plan outlined in this fellowship is designed to strengthen technical and conceptual expertise in membrane protein biochemistry, single-particle cryo-EM, and electrophysiology. Mentorship and training from Dr. Eric Gouaux, an internationally recognized leader in membrane protein structural biology, and Dr. Michael Kavanaugh, an expert in transporter electrophysiology, will ensure the successful completion of the proposed aims. Together, these studies will advance the fundamental understanding of hSERT regulation and contribute to a broader framework for understanding allosteric modulation in neurotransmitter transporters, informing the development of innovative therapeutic strategies for disorders involving transporter dysfunction.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT___________________________________________________________ Neurodevelopmental disorders (NDDs) like autism, intellectual disability, and ADHD are a global health concern. Progress in understanding the causes of NDDs has been slow and treatment options for core symptoms are limited, partially because these brain disorders currently do not have well-defined biological signatures of pathology that can be utilized in experimental neuroscience paradigms or targeted for intervention. There has been considerable recent progress in identifying statistically significant, high-confidence NDD genetic risk variants, including the heterozygous loss of the 16p11.2 chromosomal region (16pdel). Emerging evidence suggests that 16pdel impacts key prenatal neurodevelopmental processes, though the exact disease mechanisms remain elusive. Patients exhibit neuroanatomical features that could potentially be linked to dysregulated response to signal transduction pathway stimulation. Here, we will investigate how 16pdel fetal brain cells respond to key developmental signaling pathway stimulations at the molecular and cellular levels to identify potential dynamic context-dependent disease mechanisms. To address this question, we will leverage a novel in vitro human stem cell-based platform we developed called the "cell village," which enables large-scale, high-throughput analysis of molecular and cellular responses to cell-extrinsic stimuli across diverse neurotypical control and 16pdel patient donor cell lines. This approach minimizes technical variation and allows for systematic exploration of genetic and cellular variability in a controlled uniform environment. By integrating multi-omic datasets, our study aims to uncover the mechanistic links between gene expression, cellular phenotypes, and pathway activation in 16pdel brain cells in a dish. The proposal is structured around three specific aims: First, we will define the nature and dynamics of signaling dysfunction in 16pdels as hypersensitive, hyperresponsive, and/or hyperactivated in response to stimulation. Second, we will decipher the epigenetic mechanisms underlying pathway dysregulation by investigating chromatin accessibility, methylation patterns, and 3D genome organization in first-of-their-kind multi-omic villages. This aim seeks to determine if 16pdel cells are epigenetically primed for aberrant response to signaling pathway stimulation. Third, we will determine the cellular consequences of dysregulated signaling in 16pdels with a particular focus on neurogenesis and morphogenesis mechanisms. By elucidating the molecular mechanisms driving signal transduction pathway dysregulation in 16pdel fetal brain cells, as well as the impact on cellular functions critical for proper neurodevelopment, this research could illuminate the fundamental neurobiology of a high-confidence genetic risk factor associated with complex NDDs and nominate future targets for intervention, thus improving outcomes for patients and their families.

NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT Anxiety-related psychopathology is a serious detriment to mental health in the United States, with 19.1% of adults in the U.S. experiencing it annually. While current treatments yield symptom recovery in about 50% of patients, relapses remain a significant challenge. While context plays a crucial role in modulating perceived threat in animals, studying its effects in humans is limited by a lack of ecologically valid methods. The Aims of this application leverage immersive virtual reality (VR) to investigate how emotional and environmental contexts shape threat acquisition and extinction, with the aim of informing strategies to enhance treatment efficacy and reduce relapse. To this end, I draw on two experimental literatures, emotion induction and multi-context extinction, to model and examine the interplay between emotion, context, and fear learning. Aim 1 of this proposal will investigate the effects of mood induction on threat learning and extinction to test whether state-dependent factors contribute to responses to threat traditionally attributed to trait-level psychopathology. Findings on how mood or emotional states influence threat expectancy are mixed, potentially due to limited ecological validity, subjective interpretation, or variability in sensory engagement, problems that can be addressed by using immersive VR. Using VR experiences, participants will undergo emotion induction (positive, negative, or neutral) prior to Pavlovian threat conditioning or extinction. Fear induction may serve as a model for anxiety-related disorders, better simulating emotional states experienced by affected individuals and providing a more ecologically valid translational model for research in healthy subjects. This aim will also address fundamental theoretical questions about whether “fear conditioning” is directly modulated by an individual’s emotional state of fear. In Aim 2, I will examine neural correlates of multi-context extinction in ecologically valid VR environments. While threat learning is easily generalized across contexts, extinction is context specific. Thus, threat that is suppressed in the extinction context often reappears in a different context. This phenomenon, known as contextual renewal, often leads to the resurgence of fear in new settings, presenting a major challenge for psychotherapy. In animals, multi-context extinction is shown to reduce context specificity and strengthen extinction generalization. This aim builds and improves upon limited human research by employing immersive 3D environments inside an MRI environment and utilizing functional connectivity and advanced multivariate pattern analysis of fMRI data. The Aims laid out in this proposal will significantly enhance our understanding of the neurobehavioral mechanisms underlying emotion and contextual influences on threat learning and extinction. Through this training grant, I will gain expertise in virtual reality task design, fMRI multivariate pattern analysis, and the neuroscience of emotions, fear, and learning. Completion of these Aims will expand knowledge of the neuroscience of emotional learning and threat generalization and contribute to future treatments of anxiety- related psychopathology.

NIMH - National Institute of Mental Health

Converging innervation of somatostatin neurons in the lateral septum by the prefrontal cortex and hippocampus Abstract The lateral septum (LS) is a central hub in regulating various affective behaviors, including feeding, anxiety, fear, reward, sociability, and memory. The LS predominantly comprises heterogeneous GABAergic spiny neurons that receive inputs from various cortical and subcortical regions. However, how the LS integrates the information from different inputs remains unknown. Recent studies suggest that the LS's diverse functions may be attributable to both heterogeneous subpopulations and topographically organized structures that exhibit different input and output connections. Notably, the dorsal and ventral poles of the LS (dLS and vLS) have distinct and often opposing roles. This functional heterogeneity may be partially explained by distinct dorsal and ventral inputs from the hippocampus (e.g., dCA1 and vCA1), as well as competitive inputs from the infralimbic (IL) region of the prefrontal cortex (PFC). However, evidence is lacking for how these diverse inputs differentially innervate diverse cell types in the LS subregions. Recent studies indicated that somatostatin (SST) is highly expressed in the LS, and SST neurons are activated by diverse stressors, gating distinct fear responses. Given the topographic projections from the hippocampus and IL to LS subregions, a fundamental question raised is whether SST neurons in the dLS and vLS are convergently innervated by both the hippocampus and IL. In this proposal, we hypothesize that SST neurons within sub-circuits of the LS (i.e., dLS and vLS) exhibit distinct physiological properties and synaptic connections from their upstream IL and CA1 inputs. Specifically, while SST neurons in the dLS and vLS are selectively driven by dCA1 or vCA1 inputs, respectively, the vLS activity can be overridden by IL inputs through an IL-dLS-vLS disynaptic pathway. To test this hypothesis, we will utilize in vitro and in vivo physiological recording combined with intersectional viral approach and optostimulation. In Aim 1, we will determine how SST neurons within the LS subcircuits are innervated by IL and CA1 inputs in vitro. In Aim 2, we will determine the synaptic and functional responses of SST neurons within LS subcircuits to IL and CA1 inputs in vivo. We expect this study will provide novel information about the neural circuity that comprises the basis of affective functions, which may elucidate the pathophysiology of various disorders in which these processes are dysregulated.

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT During childhood and adolescence, tightly orchestrated processes profoundly restructure synaptic connectivity and neuronal physiology in the human neocortex. Defects in this maturation underlie childhood neurodevelopmental disorders including autism, but a key gap exists in our knowledge of these cellular, synaptic, and circuit changes in the juvenile human neocortex. We hypothesize that the postnatal maturation of distinct synapse subclasses and active neuronal properties is central to human neocortical circuit function, and that these processes are impaired in autism. To test this, we have developed a robust pipeline to retrieve and analyze specimens that must be resected during pediatric neurosurgical procedures to access deep epileptic foci, vascular malformations, or brain tumors. Due to comorbidity between autism and epilepsy, about 30% of these patients also have an autism diagnosis. In our preliminary results, we find that human neocortical glutamatergic synapses cluster into at least five distinct subclasses based on receptor content, and that this subclass composition diverges across postnatal ages and across species. We further find that active neuronal properties including spike rate adaptation increase through human adolescence, driven by elevation in BK-type calcium-activated potassium channels, and that these active physiology properties are reduced in children with autism. The proposed study will define the maturation of juvenile human neocortical neurons and synapses in individuals with and without autism in three specific aims. First, we will use conjugate array tomography to delineate human synapse subclasses based on molecular composition and ultrastructure and determine if a distinctive subclass that we have identified, which is enriched in AMPA- and NMDA-type glutamate receptors, emerges in adolescence. Second, we will use whole-cell physiology recording and single-cell transcriptomics (Patch-Seq) in human brain slices to determine if active physiology properties and synaptic plasticity of human neocortical neurons change through childhood and adolescence and if these changes are impaired in autism. Third, we will knock out synaptic proteins linked to autism and neurodevelopment using CRISPR in human brain slice cultures to determine if adolescent maturation of specific, human-enriched synapse subclasses is impaired. These aims are propelled by three key innovations: a novel definition of functionally interpretable synapse subclasses based on single-synapse analysis, an extraordinary pipeline between Stanford University and Lucile Packard Children’s hospital to rapidly access pediatric neurosurgical specimens, and a system for causal manipulation of synaptic proteins in human brain slice cultures. When completed, this study will yield key insight into the fundamental principles governing postnatal human neocortical maturation, and how this maturation is impaired in autism.

NIMH - National Institute of Mental Health

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NIMH - National Institute of Mental Health

PROJECT SUMMARY/ABSTRACT: Bipolar spectrum disorders (BSDs) are associated with major personal and public health burdens. Despite this heavy burden, the etiology of BSD is not fully understood. Further research on risk factors for BSD during adolescence, when likelihood of first onset of a BSD is highest, is needed to understand how BSD onset and symptoms can be better predicted and interventions delivered earlier. Determining the degree of risk for BSD conferred by various predictors is a vital step toward creating intervention and prevention programs that can identify individuals most at risk in order to reduce the likelihood of BSD onset, delay onset, or lessen course severity. Extant research has established several person-level factors that confer risk and influence dysregulation throughout the course of BSDs. The social and circadian rhythm model of BSDs posits that social and circadian rhythm dysregulation can result in mood symptoms and episodes. In another separate line of research, evidence suggests that hypersensitivity to rewards confers risk for BSDs. Researchers have suggested that the reward and circadian models of BSD risk and course can be combined into a joint, bidirectional model, such that disturbance in one of these systems, through a feedback loop, may promote dysregulation in both systems, contributing to mood symptoms and episodes. Additional theoretically and empirically supported predictors can be combined statistically with reward and circadian factors to better predict risk of bipolar symptoms. These factors include family history of BSDs, hypomanic personality, higher trait impulsivity, exposure to childhood adversity, affective lability, and substance use. However, the means by which predictive factors may be combined to better inform risk for bipolar symptoms is poorly understood. Although myriad risk factors for BSDs have been identified, little work has been done to statistically integrate information obtained through a multimodal approach to determine which individuals are most at risk. Thus, the proposed project seeks to evaluate empirically derived risk groups based on multimodal assessment of multiple risk factors for BSD during adolescence, a critical developmental period in which onset of BSDs is most likely. I will use participants from my sponsor's R01 study, which aims to examine the interplay of reward and circadian factors longitudinally to predict first onset of BSDs, add measures of additional risk factors, and statistically integrate these multimodal risk indicators with latent class analysis to evaluate the predictive utility of empirically-derived risk groups. My sponsors and I have designed a training plan involving coursework, workshops, experiential learning, and mentorship that will allow me to develop greater expertise in the development of mood pathology, learn advanced statistical methods required for this project, and gain the skills necessary for my future career as an independent clinical scientist. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists.

Tigrean Community Association in Seattle

The Tigreans in Seattle have been disconnected from their families in Ethiopia for over two years due to the unrest and blockage of the region. There is no telephone, electricity, or Internet. Tigreans here are distressed and getting chronic disease like hypertension and mental health disturbances. This project will provide outreach, support, and health resources for Tigreans in Seattle who have lost contact with friends and relatives in Ethiopia. This project will be completed by December 29, 2023.

NIMH - National Institute of Mental Health

Project Summary/Abstract The overall goal of this proposed program is to expand the workforce of HIV Social and Behavioral Science Researchers who will use their advanced research training and experiences with dissemination and implementation research to improve the uptake of, and access to, current biomedical and behavioral interventions to reduce HIV in the U.S. The Advancing Research Careers in HIV Program (hereafter referred to as the program) is a two-year, multi-component, evidence-based research education mentoring program that is uniquely focused on educating and guiding master’s level students in public health, nursing, and social work toward advanced doctoral degree programs in Social and Behavioral Science Research, and eventual careers in HIV science. Our program's focus on terminal master's students in health sciences directs qualified applicants to HIV research early in their graduate education. It also provides a structure to integrate HIV- focused Social Behavioral Science Research skills and experiences with their existing applied disciplinary training, producing scholars who will be better prepared to conduct implementation and dissemination HIV research. The program is grounded in the expanded Social Cognitive Career Theory, with learning experiences that promote progression through stages of the theory. Our pedagogical approach will use the following High- Impact Educational Practices to promote transformational learning: a) Interprofessional Education Strategies, b) Cohort-Based Learning Strategies, and c) a Mentoring Ecosystem. Students will participate in HIV-focused Social Behavioral Science and Dissemination and Implementation Science academic coursework using experiential learning approaches, a Mentored Research Experience using a hybrid apprenticeship model, development and monitoring of an Individual Development Plan, community research dissemination engagement activities, local and national academic conferences, and an Interprofessional Education Community of Practice. Students will also interface with researchers from the program’s External Research Mentor Network and NIH-funded HIV Research Networks, as well as HIV practitioners and health departments through our Community Oversight Board and Community Partners. Our evaluation will be guided by the Updated Consolidated Framework for Implementation Research to assess the program outcomes, and to conduct a systematic assessment of multilevel implementation contexts to guide future expansion of the program to other Universities. Selection into the program will be merit-based and focused on an interest in a doctoral-level research career in HIV, and a desire to be part of a multidisciplinary HIV workforce. Program operations will comply with federal requirements to ensure a professional and respectful training environment. This program supports the priorities of the NIH Strategic Plan for HIV and HIV-Related Research, the NIMH Division of AIDS Research, and the Ending the HIV Epidemic in the U.S. initiative. All activities are structured to promote measurable achievement, academic progression, and readiness for advanced research training.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Neuropsychiatric disorders, prevalent in nearly half of the U.S. population over a lifetime, are increasingly linked to immune dysregulation. Among these, allergic inflammation has emerged as a key contributor, highlighting an understudied connection between the immune system and mental health. Animal models reveal a causal relationship between allergic inflammation and heightened avoidance behaviors, a core symptom of mood and anxiety disorders. Unlike predominantly studied bacterial or viral immune challenges, allergic inflammation represents a distinct T helper cell type 2 (TH2)-mediated response triggered by nonpathogenic environmental stimuli, which activates emotion-related brain centers, including the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). These regions are critical for regulating social and anxiety-like behaviors. Converging evidence positions interleukin-4 (IL-4), a key TH2 cytokine elevated during allergic inflammation, as a potential modulator of mPFC circuits and their projections to the BLA, driving avoidance behaviors. This project seeks to determine how IL-4 impacts mPFC dynamics and contributes to heightened avoidance during allergic inflammation. In Aim 1, we will investigate the quantitative relationship between mPFC IL-4 and avoidance behavior during allergic inflammation, identify local IL-4-producing cell types, and determine the impact of heightened mPFC IL-4 on mPFC-BLA responses during avoidance. In Aim 2, we will examine how IL-4 modulates mPFC microcircuit activity and alters mPFC-BLA output and its contributions to allergic inflammation-induced neuroadaptations, defining its role as a non-classical neuromodulator. In Aim 3, we will test the necessity of mPFC IL-4Rα in allergic inflammation-associated mPFC-BLA responses and avoidance behaviors. By integrating advanced molecular, cellular, and circuit-level approaches, this research will uncover novel cytokine-driven mechanisms underlying behaviors associated with neuropsychiatric disorders and identify new immune-based therapeutic targets to address these complex disorders.

NIMH - National Institute of Mental Health

Project Summary: This K01 proposal aims to advance Dr. Dana Díaz's career through a mentored research project and training plan focused on data-driven, brain-based subtyping of children with obsessive-compulsive disorder (OCD) and subclinical obsessive-compulsive symptoms (sOCS) and its application to a novel cognitive control training (CT) intervention. OCD is a chronic, impairing condition affecting 1-2% of youth. Additionally, one in five children experience sOCS, which diminish quality of life and increase the risk of developing OCD and other psychiatric disorders. Impairments in cognitive control, the ability to flexibly adapt thoughts and behaviors, likely contribute to intrusive obsessions and compulsive urges. Middle childhood is a critical developmental period when cognitive control circuits develop, obsessive-compulsive symptoms fluctuate, and many children initiate treatment for OCD. Thus, interventions that enhance cognitive control during middle childhood may be key in improving or preventing symptoms before they become entrenched. CT has shown promise in improving cognitive control and symptom severity in pediatric ADHD, but it has yet to be tested in children with OCD or sOCS. Furthermore, little is known about the neural underpinnings of cognitive control deficits in pediatric OCD and sOCS, and nothing is known about neural predictors of CT response in these populations. Heterogeneity in OCD symptom presentation and still-developing neural networks for cognitive control in child patients may contribute to the mixed findings in pediatric OCD, which have largely relied on group-averaging approaches that do not account for individual differences. To address these limitations, this innovative project will employ data-driven machine learning (ML) clustering to identify unique subtypes of baseline brain activity patterns in cognitive control networks. Children aged 8-12 with OCD and sOCS will complete an fMRI cognitive control task prior to participating in an at-home, 4-week CT intervention. The following aims will be pursued: (Aim 1) Identify ML-defined subtypes of cognitive control network function in pediatric OCD; (Aim 2) Identify subtypes of cognitive control that distinguish between or cut across OCD and sOCS; (Aim 3) Determine which subtypes predict pre-to-post-CT improvements in cognitive control. This K01 project will help define treatment targets and provide pilot data for a future R01 grant. To ensure successful completion of these aims, Dr. Díaz will focus on the following training goals: (Goal 1) Gain expertise in neural substrates of cognitive control in children with OCD and sOCS; (Goal 2) Gain experience conducting clinical trials research for experimental medicine; and (Goal 3) Learn to leverage data-driven machine learning of fMRI data for personalized medicine. These training objectives will lay the foundation for Dr. Díaz's long-term career goals of becoming an independent clinical-translational researcher, using advanced statistical methods to elucidate developmentally sensitive mechanisms of childhood psychopathology, informing novel targets for treatment and prevention.

NIMH - National Institute of Mental Health

Project Summary Bipolar disorder (BD) is among the deadliest and most costly psychiatric disorders in young people due to its severe and recurrent mood episodes of depression and mania which disrupt functioning, substantially increase the risk for suicide and premature death, and frequently require emergency or inpatient care. As each subsequent mood episode worsens prognosis, prevention of severe mood events in young people with BD is central to mitigating its enormous personal and societal burden. However, prevention is hindered by the lack of widely deployable tools to identify which affected individuals are at risk of a severe mood crisis event within a specific interval and which can guide individualized care. Through this mentored K23 award, the candidate, a PhD-prepared psychiatric nurse practitioner, will build upon her background in early intervention for BD, data- driven analytic approaches, and qualitative methods. Her program of training and research are designed to leverage real-world data and advanced analytic machine learning methods to efficiently identify young individuals with BD at risk for severe mood events and develop a deployment-focused clinical decision support intervention in partnership with clinicians and patients that could be rapidly translated to clinical care (NIMH Strategic Objectives 4.1 and 4.2). Through planned training activities, the candidate will gain a strong skillset in advanced predictive analytics and machine learning using electronic health record (EHR) and administrative data, mixed methods for stakeholder engaged intervention development, embedded health systems research, and BD clinical epidemiology. She will leverage robust, longitudinal health system data from two learning healthcare systems in the Mental Health Research Network, HealthPartners and Kaiser Permanente Northern California, and engagement with clinicians and patients where care is delivered. In Aim 1, rigorous machine learning methods will be used to estimate risk of severe mood crisis events, as indicated by mood-related inpatient hospitalization or emergency visits, over six-month intervals based on rich longitudinal EHR and claims data in a large sample of over 13,200 young patients with BD aged 15-39 years. In Aim 2, to maximize the translational impact of the models, clinicians and patients will be engaged, using a modified Delphi approach and qualitative interviews, in development and evaluation of a clinical decision support tool to guide personalized prevention and early intervention for BD mood crises. This research is a critical step in the candidate's long-term goal of leveraging data-driven approaches to improve individualized, patient-centered delivery of mental health services for individuals in the early course of BD and other serious mental illnesses. Her clinical and research background, expert mentoring team, and embedded research environment ideally positions her to accomplish the research and training aims, building the foundation for a next-step R01 that will externally validate and rigorously evaluate the risk prediction models and decision support tool developed in this proposal.

NIMH - National Institute of Mental Health

SUMMARY Obsessive-compulsive disorder (OCD) is prevalent, frequently chronic, and linked to elevated mortality and substantial functional impairment. Available pharmacological treatments have only modest response rates. New treatment strategies are urgently needed. New biological insights are likely to facilitate progress. Analyses of brain structure in OCD have begun to shed some light on associated circuit abnormalities. However, studies to date have focused on single structural measures, such as cortical thickness and regional volume. There is no a priori reason to think that these convenient measures are the most informative; a wealth of other measures such as curvature metrics and morphological similarity indices remain unexplored in OCD. Furthermore, few studies have examined biological correlates of the patterns of spatial variation associated with OCD diagnosis. We address these substantial knowledge gaps in the current proposal. We have developed a pipeline to systematically assess all available metrics of brain structure in parallel: cortical surface area (and Jacobian determinant, an analogous measure for subcortical structures), cortical thickness (and radial distance, an analogous measure for subcortical structures), regional volume, five measures of curvature (sulcal depth, curvature index, Gaussian curvature, folding index, and mean curvature), and two brain network-derived measures (MIND and csMIND, a novel measure developed here). Pilot analyses validate the analytic pipeline and suggest that curvature indices and network measures, which have not previously been assessed in OCD, may provide particular insight. We will apply this pipeline to structural data from 2,274 OCD cases and 2,280 control, collected at 26 sites worldwide as part of the ENIGMA-OCD consortium, of which the PI is a longtime member. We will then apply a novel statistical approach based on canonical correlation to assess the relationship of the spatial maps derived from this structural analysis with maps of a range of biological functions: gene expression (i.e. imaging transcriptomics), neurotransmitter receptor and transporter density (derived from PET imaging), excitation/inhibition ratio, myelination, metabolism (derived from PET metabolic imaging), and correlates of various cognitive functions. This will provide new insight into candidate biological contributors to the observed structural differences in OCD. Finally, in an exploratory analysis, we will systematically compare structural findings in OCD, and their functional correlates, with those from commonly comorbid conditions, establishing which findings are specific to OCD and which are more general markers of transdiagnostic pathology. In aggregate, this work will provide by far the most comprehensive study of the structure of the OCD brain to date. Furthermore, the methods developed and validated here are of broad applicability; future applications of this approach to other diagnoses within the ENIGMA consortium will provide additional insight into the structural and functional underpinnings of illness.

NIMH - National Institute of Mental Health

Project Summary Fragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and the primary genetic cause of autism. FXS is caused by CGG repeat expansions or missense/frameshift mutations in the Fmr1 gene encoding Fragile X Messenger Ribonucleoprotein (FMRP), a protein with RNA-binding activity thought to act as a translational repressor. In addition to intellectual disability, FXS patients present seizures, macroorchidism, irregular physical features, and metabolic symptoms. The prevailing hypothesis of FXS pathogenesis posits FMRP as a promiscuous RNA-binding protein that targets hundreds of brain mRNAs, with excessive translation of these mRNAs being the underlying cause of the synaptic and neural network defects and physiological impairment of FXS. However, clinical efforts targeting the aberrant translational upregulation of FMRP target transcripts have not led to clinical benefit, and recent ribosome profiling studies surprisingly indicated a positive role of FMRP in regulating mRNA translation. Thus, the mode of translational regulation by FMRP remains uncertain, and investigations into new biological functions of FMPR or novel pathogenic mechanisms of FXS are warranted. Translational control exerts immediate influence on the composition and abundance of the proteome, making it particularly important when fast cellular response is desired. Defective translational control is profoundly linked to human diseases. Beyond translation initiation, elongation and termination are also key steps subjected to intricate regulation. During elongation, ribosome slowdown and stalling can occur. Some are functional and facilitate cellular dynamics, such as co-translational protein folding and subcellular targeting. Others are detrimental and can be triggered by mRNA damages or secondary structures, insufficient supply of aminoacyl-tRNAs, or stress. Ribosome slowdown and stalling can result in collision, which is sensed as a proxy for aberrant translation and can trigger ribosome-associated quality control (RQC). Key factors involved in RQC include the ubiquitin ligase ZNF598 that marks collided ribosomes and the ASC-1 complex (ASCC) that dispatches the leading collided ribosome. This then triggers downstream events, including ribosome subunit splitting and recycling, and release of stalled nascent peptide chains for clearance by the proteasome. In Preliminary Studies, we discover that FMRP performs a previously unrecognized role in handling collided ribosomes. We hypothesize that inadequate handling of collided ribosomes on synaptic and autism related FMRP target transcripts is a fundamental cause of FXS. To test this hypothesis, we propose the following Specific Aims: 1) Dissect the biochemical mechanisms of FMRP regulation of collided ribosomes; 2) Identify synaptic transcripts regulated by FMRP at the ribosome collision step. By establishing a novel mechanism of FMRP action in handling ribosome collisions, these studies will address current controversies surrounding the molecular function of FMRP and lay the foundation for future investigations into the role of FMRP in synaptic and neuronal processes underlying the pathogenesis of FXS and related mental disorders, ultimately offering treatments for patients suffering from these devastating diseases.

NIMH - National Institute of Mental Health

Project Summary Local protein synthesis at dendritic synapses undergoing morphological plasticity is essential for late long-term potentiation (L-LTP) and subsequent memory consolidation. Anterograde transport of mRNAs to these synapses supports local protein translation. However, non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), are also transported to dendritic synapses alongside mRNAs. Despite their presence, the roles and mechanisms of lncRNAs in dendritic function and synaptic structural plasticity remain poorly understood. Our previous work identified SLAMR (Synaptically Localized Activity-Modulated lncRNA) as a lncRNA transported to dendritic spines following neuronal stimulation. SLAMR modulates local translation and is essential for activity- dependent changes in spine size. Loss of SLAMR function decreases translation and spine density, while its gain of function enhances both translation and spine density. Additionally, SLAMR expression increases in the hippocampal CA1 region following contextual fear conditioning, and its knockdown inhibits fear memory consolidation. However, the mechanisms by which SLAMR modulates neuronal translation and its role in synaptic signaling remain unclear. I hypothesize that SLAMR directly interacts with translation factors to modulate dendritic translation, and that this activity is crucial for its role in synaptic plasticity and memory consolidation. To test this hypothesis, Aim 1 will investigate whether SLAMR directly interacts with canonical translation machinery. Using in vitro translation and immunoprecipitation assays, I will assess SLAMR’s interactions with translation factors. Negative controls will include antisense SLAMR and the unrelated lncRNA Gas5. Additionally, targeted ribosome affinity purification will identify mRNAs whose translation is modulated by SLAMR. I will validate these targets using puromycin proximity ligation (Puro-PLA), fluorescence in situ hybridization (FISH), spine imaging, and whole-cell patch-clamp recordings. In Aim 2, I will explore the effects of functional manipulations of SLAMR on hippocampal neuron morphology and signaling ex vivo. Dendritic branching and spine morphology will be analyzed using lightsheet and stimulated emission depletion (STED) microscopy, respectively, while synaptic properties will be assessed through whole-cell and extracellular patch- clamp recordings. Behavioral tests will evaluate the impact of SLAMR gain of function on long-term memory storage. Together, these studies will provide new insights into SLAMR’s role in hippocampal synapse function and plasticity, potentially uncovering therapeutic strategies to enhance memory or dendritic branching through localized translation stimulation.

NIMH - National Institute of Mental Health

Auditory verbal hallucinations (AVH) are among the most distressing and common symptoms of psychotic disorders, including schizophrenia. Persistent AVH predicts poor outcomes including suicide. Antipsychotic drugs, the primary treatment for AVH, are ineffective in ~1/3 of patients and often abandoned due to severe side effects related to off-target drug effects. Thus, there is an urgent need to develop new treatments that are more selective and better tolerated—and ideally personalized. Decoded neurofeedback (DecNef) is a novel, well-tolerated fMRI neurofeedback technique that allows individuals to modify their brain activation patterns in real time, through implicit trial-and-error learning, based solely on feedback indicating how similar their current activation pattern is to a target pattern. DecNef could thus provide a novel therapeutic avenue for selectively reshaping local brain-activation patterns associated with AVH, thereby decreasing AVH symptoms. The intermittent nature of AVH enabled “symptom-capture” functional-neuroimaging studies by our group and others that consistently showed increased activation in speech-selective regions of auditory association cortex concurrent with AVH events. These studies motivated neuromodulation interventions—using tDCS, rTMS, and conventional real-time fMRI neurofeedback—aiming to reduce activation or excitability at a coarse regional level, which had limited success. Our recent data shows that more granular activation patterns within speech- selective auditory cortex distinguish AVH from non-AVH silent events, and from speech-evoked responses, and do so in a subject-specific manner—with activation patterns being more informative than overall activation. Among existing neuromodulation tools, DecNef is uniquely suited to selectively target these granular within- region activation patterns relevant to AVH, and to do so using personalized targets. Given this, the proposed two-phase project aims to test personalized DecNef training for AVH, first evaluating target engagement and tolerability (R61) and then clinical benefit for AVH amelioration (R33). Individuals with schizophrenia with treatment-resistant AVH will undergo fMRI DecNef training based on subject-specific active (non-AVH) or control (speech location) activation patterns. Go/No-Go criteria for the R61 will include significant within-subject engagement of the target pattern with active DecNef training (with greater expression than in the control group), preliminary evidence for AVH improvement, and a low discontinuation rate (<25%). In the R33, patients will undergo a double-blind, controlled (active DecNef vs. control DecNef) parallel randomized clinical trial evaluating efficacy for AVH amelioration. Optimal dosing (number of sessions) will be informed by R61 data. We will also evaluate the relationship between target engagement and AVH improvement (target validation). We expect this work to provide an initial validation of personalized DecNef as a novel, safe, and selective circuit intervention for AVH in schizophrenia, and to pave the way for a broader use of this technique for psychosis across neuropsychiatric disorders—and for severe mental illness more generally.

NIMH - National Institute of Mental Health

The medial prefrontal cortex (mPFC) is a midline cortical region critical for cognition and implicated in neurodevelopmental disorders such as autism spectrum disorders (ASD). Developmental plasticity has been demonstrated in cortical regions associated with sensory function, but much less is known about this in mPFC. Developmental plasticity occurs during critical periods in which plasticity is enhanced, and as such is a period of time in which ongoing experiences shape the ultimate formation of mature functional circuits. Recent evidence suggests an adolescent critical period for mPFC, but the exact timing and underlying synaptic and molecular mechanisms are unclear. To investigate this, we developed a high-throughput assay to test a key form of plasticity, Long Term Potentiation (LTP), in the brain slices of the mouse mPFC. Using multielectrode recording arrays, we record local field potentials and from these extract current-source density (CSD) signals to clearly differentiate pre- and post-synaptic components. Our preliminary data show that while mPFC brain slices from juveniles fail to exhibit LTP, slices from older adolescents have robust LTP, with adult slices showing reduced plasticity. This aligns with the maturation of perineuronal nets (PNNs), specialized extracellular matrices that stabilize circuits by ‘freezing’ plasticity and contributing to mature circuit function. In Aim 1, we will rigorously define mPFC developmental plasticity by mapping LTP and PNN expression across development, which will refine the key time points for complementary in vivo experiments while minimizing animal use. In Aim 2, we will manipulate PNNs and neural activity to test their role in critical period regulation. By degrading PNNs or using Designer Drugs Exclusively Activated by Designer Drugs (DREADDs) to reduce inhibitory activity in the mPFC, we will assess whether the critical period can be reopened in adults. This research integrates high-throughput electrophysiology methods with molecular analyses to uncover mPFC critical periods. Understanding these mechanisms will not only provide insights into prefrontal development but also inform therapeutic strategies for disorders with altered plasticity, such as autism or schizophrenia. 1

NIMH - National Institute of Mental Health

Delusions – unfounded and often bizarre beliefs – can be a highly distressing feature of psychotic illnesses. They frequently do not respond to pharmacological or psychosocial treatments, and advancing treatment development requires a clearer understanding of their specific underlying mechanisms. Prior research has implicated abnormalities in social cognition, particularly in paranoid, persecutory delusions. Other work suggests that more general mechanisms of belief formation may underlie delusions. Prediction errors may play a central role in both social and non-social accounts of delusions; however, the content, computations, and implementation of these aberrant error signals have yet to be established. The goal of the current proposal is to evaluate the roles of social and non-social prediction errors in delusions among individuals with schizophrenia, compared to control participants without delusions. This proposal includes three specific aims that span various levels of analysis: Specific Aim 1: Examine social and non-social Kamin blocking as behavioral metrics of prediction error processing in patients and controls and explore their relationship with delusion severity. Specific Aim 2: Apply state-of-the-art computational modeling to social and non-social Kamin blocking behaviors to quantify prediction errors, learning rates, and weighting parameters relevant to delusions. This aim will investigate whether these factors differ by task frame and if such differences are associated with symptoms. Specific Aim 3: Use functional neuroimaging and neuromelanin scanning to determine how social and non-social Kamin blocking is implemented in the brain and explore their relationships to dopamine and noradrenaline sytem integrity and delusions. Together, these aims will provide a rigorous account that spans the bio-psycho-social processes implicated in delusions. This integrated approach will provide the foundation for developing rational and targeted treatment strategies.

NIMH - National Institute of Mental Health

Abstract Adolescence is a period characterized by the refinement of higher cognitive functions and social behaviors, but also as a period during which many psychiatric disorders arise. Part of this susceptibility is due to changes in GABAergic inhibitory transmission occurring in limbic structures, particularly the prefrontal cortex (PFC) and the hippocampus (HC). Our published work has shown that brief systemic interventions during adolescence are sufficient to disrupt the maturation of the GABAergic system in the PFC causing an imbalance of excitation (E) and inhibition (I) which in turn affect the integration and output of the region. However, current systemic interventions and genetic animal models preclude us from examining the contribution of individual brain regions to the development of normal and maladaptive behaviors. Our long-term goal is to identify prefrontal and hippocampal circuits that are subject to plasticity during adolescence and define how those changes support normal behavioral transitions into adulthood. The gap in knowledge is whether the refinement of the E-I ratio in each structure enables the maturation of specific behavioral circuits, and most importantly when such window occurs. Interestingly, a consistent finding neurodevelopmental disorders such as schizophrenia and autism has been a regional reduction of the protein parvalbumin (PV), a calcium binding protein developmentally expressed in a subpopulation of GABAergic interneurons, namely PV-positive interneurons (PVIs). PV expression is intimately related to the inhibitory capacity of PVIs: preventing the normative increase of PV during adolescence is sufficient to decrease GABAergic, but not glutamatergic, synaptic transmission in adults. Such a manipulation causes disinhibition without lesioning the structure or passing fibers, more realistically mirroring a permanent E- I imbalance. Our central hypothesis posits that disinhibition of the vHC or the PFC during adolescence will differentially affect limbic circuits, giving rise to non-overlapping behavioral phenotypes. To evaluate this hypothesis, we will use a short hairpin RNA (shRNA) interference approach to partially deplete PV into the ventral HC (PVshRNA-vHC) or the PFC (PVshRNA-PFC) during early or late adolescence, followed by measurements in cognitive and social behavioral domains. By individually disrupting the E-I balance of the vHC and the PFC, this grant will provide much needed information on how the vHC and PFC contribute to the normal development of cognitive and social behaviors and at the same time have a positive impact by increasing our understanding of the source, heterogeneity, and time course of behavioral abnormalities in mental disorders.