Teresa M. Reyes, PhD - US grants

A central question in neuroimmunology concerns the mechanisms whereby information about peripheral immune activation is communicated to the brain. The cytokine cascade at the level of the blood-brain barrier (BBB) provides on likely pathway. Interleukin-6(IL-6) is reliably released in large quantities into the cerebrospinal fluid (CSF) following peripheral administration of IL-1. The 3 studies proposed for this fellowship are designed to further characterize this IL-6 response:1)to identify one possible cellular source of CSF IL-6,2)to analyze IL-6 bioactivity in blood and intrathecal compartments, and 3)to define a potential function for IL-6 in the CSF. Monkey endothelial cell cultures will be established to examine whether cells of the BBB can produce IL-6 upon stimulation with IL-1. To further localize the source of IL-6, an in vivo study will determine if an IL-6 concentration gradient exists within the intrathecal compartment. Soluble IL-6 receptor (sIL-6R), an endogenous agonist found in the blood can potentiate IL-6 effects, but it is absent from the CSF. Therefore, bioactivity of blood and CSF samples will be assessed during the IL-6 dependent cell lines, B9 and 7TD1. Lastly, IL-6 has effects on many neural and lymphoid cells, possibly including leukocytes in CSF. The influence of CSF (both with and without IL-6) on lymphocyte proliferation will be investigated. Characterization of IL-6 within CSF has important implications for understanding cytokine communication between the periphery and the CNS. Furthermore, these findings are relevant to diseases with neuroimmune sequelae, involving high cytokine levels or leukocyte infiltration into the CNS.

Loss of appetite is a significant obstacle in the treatment of chronic illnesses, including certain cancers and HIV infection. Pro-inflammatory cytokines released from activated immune cells are prime candidates for mediating this anorexia, yet a complete understanding of the neural pathways and mechanisms involved in this response remains elusive. The overall goal of this proposal is to explore the functional organization of neural circuits that underlie IL-1-induced anorexia. Interleukin-1 (IL-1), a cytokine which can potently inhibit feeding, will be used to model an acute infectious/inflammatory event. The arcuate nucleus (ARC) of the hypothalamus can be accessed directly by circulating macromolecules, expresses IL-1- receptors, and houses peptidergic neurons strongly implicated in the control of feeding. Correlated behavioral (feeding) and functional neuroanatomical (induced patterns of immediate-early gene expression) assays will be used to test a role of IL-1-sensitive ARC neurons in IL-1-induced anorexia. First, a discrete lesioning method will be used to test if the ARC plays a prominent and specific role in IL-1 mediated inhibition of food intake. Next, IL-1 sensitive ARC neurons will be characterized with respect to their expression of IL-1 receptors, and/or neuropeptides implicated in the stimulation and inhibition of appetite. Finally, axonal transport and selective fiber transection methods will be used to identify and characterize behaviorally relevant downstream targets of IL-1-sensitive ARC neurons. Collectively, the proposed studies will serve as a initial step in delineating the circuitry underlying the cytokine-induced feeding inhibitory response.

DESCRIPTION (provided by applicant): The basic goal of the following proposal is to provide the candidate with new formal exposure to aspects of mouse genetics and molecular biology, and additional training in functional neuroanatomy/systems neurobiology, all in the context of a research program designed to penetrate a problem of substantial basic and clinical interest/significance. Loss of appetite is an obstacle in the treatment of chronic illness, including certain cancers and viral infections. Proinflammatory cytokines released from activated immune cells are prime candidates for mediating this anorexia, yet a complete understanding of the neural pathways and mechanisms involved in this response remains elusive. Previous work has implicated certain neurochemical systems (melanocortins and corticotropin-releasing factor (CRF)) and sites of action (paraventricular and arcuate nuclei of the hypothalamus (PVH, ARH)) as involved in the mediation, but a clear overview of the organization and chemical coding of the underlying circuitry has remained elusive. Experiments in this proposal will track changes in gene expression in parallel with behavioral responses (decreased food intake) in an attempt to describe the functional neuroanatomical framework of sickness-induced anorexia. The specific goals of this proposal are to (1) identify central structures involved in illness-associated anorexia, their peptidergic phenotype and the functional relevance of pathways between involved structures (2) interrogate the specific involvement of proopiomelanocortin (POMC) and melanocortin-4 receptor (MC4R) and (3) investigate whether CRF ligands may be involved in mediating sickness-induced anorexia, either downstream or independently of MC4R activation. The proposed studies will provide the candidate an exceptional opportunity to master a variety of new techniques under the guidance of experts in functional neuroanatomy (Dr. Paul Sawchenko), genetic targeting (Dr. Kuo-Fen Lee), and viral delivery systems (Dr. Inder Verma), all at the Salk Institute. These studies build on the candidate's prior research, and provide a bridge to expand the breadth and depth of research questions addressed. At the conclusion of these studies, the candidate will be well positioned to obtain an independent academic research position.

DESCRIPTION (provided by applicant): Intrauterine growth retardation (IUGR) affects approximately 10% of all US infants. These small-for- gestational age (SGA) babies face increased risk for immediate morbidity and mortality, as well as long-term neurobehavioral disabilities (e.g., attention deficit hyperactivity disorder (ADHD), addiction, schizophrenia). While adverse metabolic and cardiovascular outcomes have been well characterized in these infants, the coincident neurobehavioral disabilities and specific central nervous system (CNS) abnormalities have received significantly less attention. The mechanisms linking IUGR and neurobehavioral disabilities are poorly understood and warrant further investigation, as this knowledge is critical for early diagnosis and intervention. To shed light on these issues, we propose the integration of behavioral, neuroanatomical, and epigenetic approaches to understand the long-term CNS impact of IUGR. Using a well-characterized rodent IUGR model (low protein diet fed to pregnant mice), we have found evidence for behavioral components of ADHD, including altered reward processing and hyperactivity. These behaviors involve dopamine (DA), and in both animal models of and human patients with ADHD, alterations in DA signaling have been documented. Our IUGR offspring have altered expression of genes that control dopamine synthesis and activity, suggesting that dopaminergic function is also altered as a result of the low protein diet and may underlie the observed neurobehavioral changes. We have also identified hypomethylation and increased expression of CDKN1c in IUGR animals, a gene critical for dopaminergic cell differentiation, which may alter the developmental trajectory of dopaminergic neurons. Additionally, we observe altered methylation, both globally and in a gene-specific manner, as well as significant increases in the expression of genes that play an important role in DNA methylation, including DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2). This proposal will test the central hypothesis that maternal low protein diet directly affects DNA methylation in the developing CNS, leading to behavioral changes and dopamine dysfunction, in a manner similar to what is observed in ADHD. In four aims, experiments will (1) test the hypothesis that IUGR animals demonstrate a behavioral profile consistent with ADHD (2) examine dopamine expression and function within the mesolimbic/ mesocortical circuitry (3) determine whether Cdkn1c overexpressing mice replicate the behavioral or gene expression phenotype of the IUGR mice and (4) complete a genome-wide screen of differentially methylated genes in the CNS of IUGR mice. PUBLIC HEALTH RELEVANCE: Intrauterine growth retardation affects up to 10% of all babies born in the US. These babies can have neurobehavioral disabilities, including an increased risk for attention deficit hyperactivity disorder (ADHD). Experiments proposed in this application will use an animal model to explore the underlying mechanisms for these brain and behavior changes and potentially identify possible avenues of intervention.

DESCRIPTION (provided by applicant): Environmental factors contribute to the risk for autism spectrum disorders (ASD), and a greater understanding of these factors is needed. An adverse in utero environment significantly impacts the developing central nervous system (CNS) and can result in serious neurobehavioral outcomes, such as ASD and anxiety. Abnormal birthweight is a biomarker of adverse in utero environment, and can be affected by maternal diet or hypertension, uterine or placental dysfunction, and maternal smoking and/or drug use. In total, small-for-gestational age (SGA) or large-for-gestational age (LGA) may affect over half a million American infants every year. Importantly, epidemiological evidence indicates that both SGA and LGA infants are at an increased risk for ASD. Thus, common intrauterine environmental conditions may predispose infants to ASD and anxiety. We have developed two mouse models based on an adverse in utero environment that result in SGA or LGA offspring by feeding pregnant dams a low protein diet or high fat diet, respectively. These SGA and LGA offspring have significant behavioral and CNS gene expression differences pointing to dysfunction in the dopaminergic, serotonergic and opioid systems, which are known to be altered in ASD and anxiety. Importantly, expression levels of MeCP2 are significantly different in both SGA and LGA offspring, identifying MeCP2 expression as a potential important epigenetic mechanism responsive to adverse in utero conditions. Accumulating evidence suggests that MeCP2 is critical for synaptic plasticity, and deficits in synaptic function may underlie some components of ASD. Further, MeCP2 deletion results in Rett Syndrome in humans and a hypothalamic specific MeCP2 deletion resulted in altered social behavior in mice. In two aims, this proposal will (1) examine the development of social and anxiety-related behaviors in SGA and LGA offspring and compare the critical periods of pregnancy or lactation and (2) analyze genome-wide gene expression changes in SGA and LGA mice and MeCP2 promoter residency using genome wide chromatin immunoprecipitation-sequencing (ChIP-Seq) and profiling technology in medial prefrontal cortex and amygdala. We hypothesize that both SGA and LGA animals are at increased risk for altered social and anxiety-related behaviors, and that alterations in expression of MeCP2 contribute to differential gene expression and adverse neurobehavioral outcomes. The development of these models will allow for future studies of neurobiological mechanisms that link adverse in utero environment and altered social and emotional behaviors with an eventual goal of the development of targeted therapeutics and interventions. PUBLIC HEALTH RELEVANCE: Adverse prenatal conditions can affect the development of the infant brain, increasing the risk for neurobehavioral disabilities, such as autism spectrum disorders (ASD) or anxiety. Experiments proposed in this application will use animal models to examine brain and behavior changes in response to adverse in utero conditions and potentially identify possible avenues of intervention.

DESCRIPTION (provided by applicant): Intrauterine growth retardation (IUGR) affects approximately 10% of all US infants. These small-for- gestational age (SGA) babies face increased risk for immediate morbidity and mortality, as well as long-term neurobehavioral disabilities (e.g., attention deficit hyperactivity disorder (ADHD), addiction, schizophrenia). While adverse metabolic and cardiovascular outcomes have been well characterized in these infants, the coincident neurobehavioral disabilities and specific central nervous system (CNS) abnormalities have received significantly less attention. The mechanisms linking IUGR and neurobehavioral disabilities are poorly understood and warrant further investigation, as this knowledge is critical for early diagnosis and intervention. To shed light on these issues, we propose the integration of behavioral, neuroanatomical, and epigenetic approaches to understand the long-term CNS impact of IUGR. Using a well-characterized rodent IUGR model (low protein diet fed to pregnant mice), we have found evidence for behavioral components of ADHD, including altered reward processing and hyperactivity. These behaviors involve dopamine (DA), and in both animal models of and human patients with ADHD, alterations in DA signaling have been documented. Our IUGR offspring have altered expression of genes that control dopamine synthesis and activity, suggesting that dopaminergic function is also altered as a result of the low protein diet and may underlie the observed neurobehavioral changes. We have also identified hypomethylation and increased expression of CDKN1c in IUGR animals, a gene critical for dopaminergic cell differentiation, which may alter the developmental trajectory of dopaminergic neurons. Additionally, we observe altered methylation, both globally and in a gene-specific manner, as well as significant increases in the expression of genes that play an important role in DNA methylation, including DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2). This proposal will test the central hypothesis that maternal low protein diet directly affects DNA methylation in the developing CNS, leading to behavioral changes and dopamine dysfunction, in a manner similar to what is observed in ADHD. In four aims, experiments will (1) test the hypothesis that IUGR animals demonstrate a behavioral profile consistent with ADHD (2) examine dopamine expression and function within the mesolimbic/ mesocortical circuitry (3) determine whether Cdkn1c overexpressing mice replicate the behavioral or gene expression phenotype of the IUGR mice and (4) complete a genome-wide screen of differentially methylated genes in the CNS of IUGR mice.

DESCRIPTION (provided by applicant): While many factors may contribute to initial and continued drug use, exposure to stress at any point in the addiction cycle appears to worsen this disease. Therefore, it is critical to advance our knowledge about the neurobiological underpinnings of stress. The role of stress in drug addiction/relapse has not been addressed in previous Stress Neurobiology Workshops, and is therefore the focus of the current workshop. A Neurobiology of Stress Workshop will be organized for June 12-15th, 2012 at the University of Pennsylvania, Philadelphia, PA. This rigorous scientific meeting will bring together preclinical and clinical researchers who study stress-brain interactions. This Workshop addresses an important need to strengthen the community of stress researchers in a manner that will maximize the productivity and clinical benefit of future stress research. Thus, the Workshop will provide a unique opportunity for researchers to participate in face-to-face examination of recent research advances, to share perspectives, identify relevant issues, debate controversies and exchange diverse expertise. Five sessions are planned in which invited speakers will present new research work, novel ideas, and examination of clinically relevant issues. These sessions are: (1) The role of stress in drug addiction and relapse, (2) Epigenetics and Stress, (3) Neurobiological mechanisms underlying stress-related disorders, (4) Molecular Mechanisms and Neural Circuits in Stress Regulation, and (5) Stress effects in vulnerable development time periods. A keynote presentation will be given by Dr. George Koob. In addition to the discussion time within each session, the Workshop features extensive time for interaction among all attendees at the opening data blitz reception, shared daily lunch period, Poster Session, and a social hour. A priority of the Workshop is to foster the professional development of new investigators and women by including them at all levels of meeting organization and Program participation. Further the Workshop will nurture career development of graduate students and postdoctoral researchers by giving them ample opportunity to participate in the Workshop via the data blitz session, Poster Session, discussion sessions, and issue-related luncheon roundtables. Travel Grants will be made available to select trainees through a merit based application process, with a detailed plan in place to recruit applications from interested minority candidates. This revised application of a highly scored initial application has incorporated all of the reviewers suggestions. PUBLIC HEALTH RELEVANCE: The adverse effects of stress on mental and physical health have come to the fore as one of the most pressing biomedical problems in our society. The proposed Neurobiology of Stress Workshop to be held June 12-15th at the University of Pennsylvania will bring together basic, preclinical and clinical researchers and affiliated trainee in order to significantly enhance the productivity and clinical benefit of future stress research.

DESCRIPTION (provided by applicant): Maternal infection during pregnancy is common and can cause adverse neurodevelopmental outcomes in the fetus, such as intellectual disability and deficits in executive function. Importantly, maternal infection during pregnancy is virtually impossible to prevent as detection occurs only after infection, when damage to the fetus may have occurred. Therefore, strategies and therapeutics must be developed to promote and support healthy brain development in the offspring subsequent to exposure to maternal infection. These types of interventions must first be developed in an animal model. The primary barriers to progress in this area are two-fold; (1) the animal model must be translationally relevant and (2) evaluation of higher cognitive function in a mouse is challenging. The most widely used model of prenatal maternal infection involves the use of systemic administration of bacterial (lipopolysaccharide, LPS) or viral (poly I:C) mimetics. However, the validity of these animal models to the most common clinical scenarios during human pregnancy has not been demonstrated. In contrast to the systemic models, an in utero or local model more aptly mirrors intrauterine infection and/or chorioamnionitis (inflammation of the fetal membranes). Intrauterine inflammation is common, present in 6% of term births, and results in over 240,000 affected births per year. To that end, we have developed a mouse model of intrauterine inflammation (intrauterine LPS administration) that leads to offspring born at term with postnatal brain injury, characterized by aberrant dendritic arboritization of fetal neurons. Importantly, this mouse model serves to most aptly mimic the most common human clinical scenario by which a fetus would be exposed to prenatal inflammation. In adulthood, exposed offspring demonstrate significant gene expression changes in neuronal and glial pathways, most notably in the prefrontal cortex. In two aims, we will examine executive function and anxiety and depression-related behaviors in exposed offspring, as well as evaluate dopaminergic dysfunction as a potential mechanism. This collaborative team includes Dr. Elovitz, a physician-scientist whose experience at the bedside led directly to the development of a translationally relevant mouse model of intrauterine infection and Dr. Reyes, a neuroscientist with experience in developmental programming, neuroimmunology and assessment of higher cognitive function in the mouse. !

DESCRIPTION (provided by applicant):Impulsivity, acting without appropriate forethought and/or choosing small, immediate rewards over a larger, delayed reward, is a component of numerous mental health disorders, including attention-deficit hyperactivity disorder, substance abuse, and bipolar and antisocial personality disorders. Additionally, impulsivity increases the likelihood of making poor health choices, and has been linked to both smoking [1] and obesity [2], which are leading causes of mortality in the US [3]. These are preventable deaths, which could be reduced by changing behavior. Given the broad negative impact of impulsive behavior, a better understanding of the underlying molecular mechanisms is critical. There is currently a need for better animal models in which to study the neural circuitry that drives impulsive behavior. Current animal models to study impulsivity primarily involve the study of natural genetic variation (e.g. high versus low impulsivity in behavioral tasks), as well as a handful of (mono)genic mutations. Neurobiological information has been gained through the use of lesion studies, bearing in mind the associated limitations of this approach, as well as through the study of drugs which induce impulsive behavior. Because the etiologies of impulsivity are likely diverse, work in animal models that test the importance of specific environmental antecedents is needed. We propose that offspring born to dams fed a high fat diet during pregnancy represent a novel animal model in which to study the neurobiology of impulsivity in a model that has construct and face validity. Excessive gestational weight gain and maternal obesity, which affect over half of US pregnancies, significantly increase the risk for a baby to be large for gestational age (LGA). In our model, dams are fed a high fat (HF) diet during pregnancy and lactation, and the offspring are born LGA. These LGA offspring display an increase in impulsivity. Gene expression profiling of the prefrontal cortex reveals a relationship between impulsivity and changes in the µ and ?- opioid receptors (MOR and DOR). LGA animals have an increase in microglial activation within the PFC, which may contribute to executive function deficits like impulsivity. The goal of the present proposal is to test specific molecular mediators driving impulsivity in LGA mice. The overarching strategy is to use sophisticated operant behavioral testing to examine the role of opioids and microglial activation in a novel model of impulsivity (LGA mice). These two mediators are interconnected and experiments will test not only direct effects on impulsivity, but interactions between the mediators as well. In both aims, two behavioral tasks, the 5 choice serial reaction time task (5CSRTT) and delay discounting (DD), will be used to determine impulsive action and impulsive choice, respectively.

Abstract The goal of the present application is to obtain partial funding for trainee programming at the 2017 annual meeting of The PsychoNeuroImmunology Research Society (PNIRS). The PNIRS is an international organization for researchers in a number of scientific and medical disciplines, including psychology, neurosciences, immunology, physiology, pharmacology, psychiatry, behavioral medicine, infectious diseases, endocrinology and rheumatology, who are interested in interactions between the nervous and immune systems, and the relationship between behavior and health. The PNIRS meeting is unique among conferences in that it occurs annually and focuses on all aspects of brain ? immune interactions and the domains in which these interactions are studied. The scientific program format includes (1) named lectureships, which provide leaders in the field an hour in which to present their work in depth, (2) symposia, to highlight some of the newest research in the field, and (3) oral sessions chosen from the top scoring abstract submissions to allow for the full representation of the interdisciplinary topics of interest to the PNIRS members. Importantly, a select number of trainees are chosen to present within the oral sessions, providing an important opportunity for early-stage trainees. The majority of the scientific content of the meeting is within the poster session. Poster sessions occur during un-opposed time slots, which are scheduled to maximize participation by attendees. In addition to the Scientific Program, a half-day Educational Short Course and a Professional Development Workshop (trainees only) is presented on the day prior to the meeting. The title of the 2017 PNIRS Short Course is: Resilience and PNI: From Clinical to Basic Science. During the past three PNIRS annual meetings, cancer-related research has been well represented in the scientific program, with approximately 25% of the oral session talks and/or symposia directly relevant to cancer research. Because the local organizing committee members are all from the University of Texas MD Anderson Cancer Center, and because of the close physical proximity of the meeting location (Galveston, TX is approximately 50 miles from MD Anderson Cancer Center), we anticipate that attendees at the meeting will include a large number of cancer researchers and that cancer-related content will be strong.

Abstract Topic DAT18-09: Effects of Opioids and their Antagonists on Fetal and Neonatal Brain Development Today, there are unprecedented numbers of pregnant women using opioid drugs leading to a rise in the numbers of infants exposed to these drugs in utero. Healthcare resources are improving the survival rate of these neonates, but we know relatively little about their long-term prognosis. Of the few studies that track long-term outcomes, results in humans indicate consistent behavioral problems related to executive function, self-control, and cognition. In addition to drugs of abuse such as morphine or heroin, medication assisted treatment (MAT) with methadone or buprenorphine is the standard of care for stabilizing opioid dependent mothers. While MAT is effective in limiting the severity and incidence of neonatal abstinence syndrome to improve immediate neonatal outcomes, these treatments are still opioid drugs, cross the placenta to the developing fetus, and cause behavioral problems in the offspring. In humans, children born to mothers on methadone and/or buprenorphine have cognitive deficits and impairments in tasks that require inhibitory control, planning, adaptability, and short-term memory. While the human data on maternal opioid use indicate long-term executive function deficits, very few rodent studies have studied behavioral deficits and none specifically examine executive function. The present application is designed to fill that research gap. Microglia, the brain's resident immune cells, may mediate adverse effects of maternal opioid use on the brain because microglia respond to opioid drugs and play a critical role in neurodevelopment and behavior. Opioids can activate microglia through toll-like receptor 4 (TLR4) and stimulate the release of cytokines and chemokines. Inhibiting microglia or their inflammatory signals reduces the behavioral response to opioids, in humans and rodents. Furthermore, maternal opioid exposure decreases offspring cortical dendritic complexity, suggesting that microglial-mediated pruning may be involved in the behavioral phenotypes. Therefore, the proposed studies will test the hypothesis that maternal opioid exposure and medication-assisted treatment will adversely affect the offspring brain and behavior through activation of microglia via TLR4. In addition to testing this hypothesis, an additional goal of this proposal is to refine a mouse model of maternal opioid exposure and establish a foundation for future studies to evaluate additional cellular and molecular mechanisms and begin to address efficacy of potential therapeutic interventions. Across three aims, we will assess executive function with advanced operant testing, and evaluate synaptic proteins, spine density and neuron-microglia interactions using immunohistochemistry and confocal imaging.

Abstract Survival rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer, are now close to 90%, but survivors of childhood cancer are at an increased risk for long term cognitive deficits, particularly affecting executive function (e.g., attention, planning, inhibitory control, cognitive flexibility). The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients, and is closely associated with executive function deficits. Thus a pressing need exists to define the mechanisms that link MTX exposure to cognitive dysfunction, to guide development of intervention strategies to protect the developing brain, reduce symptoms and optimize quality of life in ALL survivors, during childhood, adolescence, young and full adulthood. To that end, we have developed a translationally relevant mouse model of leukemia survival that combines cancer exposure (mouse leukemic cell line (L1210 cells) with contemporary chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) administered during early life. PFC development extends through adolescence, which renders this area of the brain particularly vulnerable to early life chemotherapy. Providing a solid premise for the proposed experiments, our mouse model recapitulates executive function deficits observed in ALL patients. Additionally, in response to early life cancer + chemotherapy, we have found an increase in the proinflammatory molecules IL-1 and CCL2, as well as a decrease in white matter associated genes within the PFC. In Aim 1, single cell RNA sequencing will be used to define the effects of cancer and/or chemotherapy on the transcriptional profile of the PFC. MTX disrupts folate metabolism to inhibit cell growth, but this disruption also leads to increased levels of the proinflammatory metabolite, homocysteine (HCY), in both plasma and cerebrospinal fluid. Increased HCY can drive inflammation, oxidative stress and is associated with both white and gray matter damage, as well as cognitive impairment. Further executive function deficits have also been linked to altered synaptic function, and microglia, a brain resident immune cell, can contribute to synapse elimination via the CD11b(CR3)-C3 phagocytic pathway. Therefore, we hypothesize that MTX-driven increased HCY levels will lead to neuroinflammation and oxidative stress, leading to gray and white matter damage, and altered synaptic pruning in the prefrontal cortex, which underlie deficits in executive function. To test this hypothesis, HCY-lowering strategies (folate and B vitamin supplementation, or the antioxidant, N-acetylcysteine amide) will be evaluated in Aim 2. Aim 3 will test the necessity of IL-1 activity while Aim 4 will test the necessity of microglia in mediating the chemotherapy-associated cognitive deficits, as well as neuroinflammation and oxidative stress, leading to gray and white matter damage, and altered synaptic pruning in the prefrontal cortex

Typical institutional efforts to increase the number of racial/ethnic minority and disadvantaged college students (URMs) in the biomedical pipeline primarily focus on building research and professional development skills. Indeed, enhancing these skills will increase preparedness for graduate school. However, many URMs face additional barriers in pursuit of a neuroscience doctoral degree that are not addressed by conventional summer undergraduate research programs. To address this critical need, the goal of the Research Innovation in NeuroScience Education for Underserved Populations (RISE UP) summer research program at the University of Cincinnati is to provide a unique learning experience that combines both traditional and innovative approaches to inspire undergraduate URMs to pursue a career in neuroscience. We will accomplish this goal using the following methods: (1) an aggressive and focused effort to recruit 50 outstanding RISE UP summer scholars from around the country with an interest in neuroscience over the proposed funding period; (2) provide training in the essentials of research at the University of Cincinnati (e.g., responsible conduct of research/ethics training) and the fundamentals of neuroscience research; (3) create individualized research experiences in top-notch neuroscience laboratories that closely match their career interests; (4) design innovative seminars and workshops that strengthen academic and professional development to facilitate entry into neuroscience doctoral programs; (5) lead inspiring socio-emotional seminars and workshops that tap into and provide solutions for contemporary issues that URMs disproportionately face in pursuit of a neuroscience doctoral degree; (6) provide cultural competency and implicit bias training for the entire RISE UP community; (7) provide a two-pronged mentoring strategy that includes a RISE UP faculty mentor and a diversity ambassador; (8) ensure long-term investment in each RISE UP scholar that extends beyond the proposed summer funding period. Importantly, NINDS funding for the RISE UP program will supplement the strong financial support from the College of Medicine for diversity recruitment and inclusion in neuroscience education. Considering the current funding climate, it is becoming increasingly difficult to attract, recruit, and retain students, especially URMs, in neuroscience, and innovative approaches are urgently needed to encourage and support historically underrepresented students to remain in the biomedical pipeline. Funding for the RISE UP program will allow us to do this by intervening early on in the educational pipeline to prepare our scholars for the academic and socio-emotional rigors of graduate school.