Gretchen N. Neigh - US grants

[unreadable] DESCRIPTION (provided by applicant): Plasticity of the central nervous system encompasses changes in neurons and glia as well as the vasculature. Vascular disturbances may manifest as cerebral hypoperfusion and have been implicated in a variety of neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, depression, alcoholism, and substance abuse. Hypoperfusion impairs nutrient and oxygen delivery to neural tissue and can result in cellular edema, gliosis and perivascular inflammatory infiltrate. In addition, changes in angiogenesis can alter perfusion of neural tissue which may alter synaptic plasticity. Furthermore, a causal interaction may exist between hormone regulated angiogenesis and neurogenesis in the brain. Given the crucial role of neuronal vasculature in the maintenance of neural tissue, an understanding of the effects of chronic stress on brain vasculature may provide insights into the mechanisms that underlie stress-evoked changes in neural plasticity. The aims of the present research are to determine: (1) the effects of prenatal stress on vasculature in adulthood, (2) the role of the hypothalamic-pituitary-adrenal axis (HPA) axis in changes in brain vasculature, and (3) the behavioral implications of vascular changes in the brain. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Onset of Major Depressive Disorder (MDD) during adolescence can be particularly detrimental because it predisposes one to subsequent depressive episodes. Both patients with MDD and rats exposed to stress demonstrate altered cerebral metabolic activity in positron emission tomography studies. The reduction in metabolic activity is generally attributed to reduced glutamate release from neurons which thereby decreases regional glucose transport. Counter to this traditional dogma, it is possible that a primary reduction in facilitated glucose transport subsequently suppresses neuronal activity. Facilitated glucose transport is mediated by a family of transporters (GLUT). GLUTs are responsible for glucose transport across the endothelial cells of the blood brain barrier, and for uptake of glucose into astrocytes and neurons. The crucial role of GLUT is illustrated by the profound neurological deficits manifested in De Vivo disease, a rare genetic condition in which GLUT1 is not expressed. Furthermore, deficits in the expression and translocation of members of the GLUT family have been linked to neuropathological conditions including Alzheimer pathology, post-ischemic brain function, and post-traumatic brain injury deficits. Alterations in the expression or translocation of members of the GLUT family in either the endothelial cells of the blood brain barrier, astrocytes, or neurons could alter neuronal energy supply and thereby neuronal function, subsequently altering behavior. During periods of rapid development and increased plasticity, such as adolescence, the energetic demands of the system are heightened. At the onset of adolescence in the rat, glucose replaces ketones as the main fuel source of the brain and GLUT 3 expression increases, followed by an increase in GLUT 1 expression, in both astrocytes and endothelial cells. Therefore, changes in GLUT expression during the adolescent developmental period, could lead to longstanding changes in neuronal function. It is unknown whether chronic stress which induces depressive-like behavior in adolescent rats also alters cerebral GLUT protein expression or function, or whether alterations in cerebral GLUT during development are sufficient to change affective behavior. Given the crucial role of GLUT proteins in the transport of energy substrates into cerebral tissue, substantial evidence from PET studies of altered metabolism in limbic brain regions of depressed humans (a technique which depends on glucose transport), and evidence that glucose transporters are altered after stress exposure in adult rats, I propose to study the role of cerebral GLUT in adolescent depression using a rat model. The goals of the experiments described in this proposal are two-fold: (1) to determine if early life stress, specifically adolescent stress, which is known to be depressogenic, alters expression of glucose transporters in limbic brain regions in a pattern distinct from chronic stress exposure in adult rats, and (2) to assess the sufficiency of alterations in GLUT1 expression in the hippocampus to induce depressive-like behavior in adolescent versus adult rats. PUBLIC HEALTH RELEVANCE: Early life stress increases the risk of affective disorders and the prevalence of depressive disorders is increasing among adolescents. The neuropathological mechanisms of early onset depressive disorders are not fully understood, but given the energy demands of this life phase, metabolic changes in the brain may contribute to adolescent depression. The proposed work examines the hypothesis that glucose transporters in the adolescent brain are altered by stress and that these changes are capable of inducing depressive-like behaviors.

DESCRIPTION (provided by applicant): Although stress is part of life, the incidence of toxic stress is increasing among America's youth. This increased exposure to toxic levels of stress has substantial consequences and can precipitate and augment chronic mental and somatic health conditions throughout adulthood. While both men and women suffer the consequences of early life stress, the precise manifestation of chronic developmental stress varies in a sex-dependent manner. Chronic stress during adolescence is particularly harmful because of interactions of stressor exposure with the maturation the hypothalamic-pituitary-adrenal (HPA) axis and the reproductive axis. Alterations in these endocrine axes exert pervasive effects because many of the receptors for the hormones of these axes are transcription factors. The overarching hypothesis of this line of research is that altered regulation and function of transcription factors underlies the prolonged adverse effects of adolescent stress. The current application focuses on two transcription factors that our preliminary data suggest are altered by chronic adolescent stress: the glucocorticoid receptor (GR), a transcription factor that is the main effector of the HPA axis, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B), a transcription factor which mediates activation of inflammatory pathways. It is of interest to consider these transcription factors together because significant bidirectional crosstalk occurs between GR and NF?B. Based on our preliminary data, the central hypothesis of this proposal is that chronic adolescent stress leads to GR-centric modifications in adult females and NF?B-centric modifications in adult males. Completion of Specific Aim 1 will determine the extent to which adolescent stress alters regulation of the GR in adult male and female rats. These data will provide an essential understanding of the prolonged effects of adolescent stress on GR regulation which is necessary to determine whether adult GR dysregulation is a candidate mechanism for adolescent stress-induced chronic conditions. Specific Aim 2 will examine the influence of adolescent stress on regulation of NF?B in adult male and female rats. These experiments will provide information about the effects of adolescent stress on regulation and translocation of NF?B in adulthood and establish the degree to which NF?B is a candidate regulator of exaggerated inflammation following chronic adolescent stress. Specific Aim 3 will establish the extent to which adolescent stress alters adult gene expression specifically mediated by GR and NF?B. These data are complementary to the first two aims because in addition to regulation of transcription factors at the level of translocation, transcription factor effects can diverge at the point of gene transcription. Collectively, the data generated by this application will establish the extent to which chronic adolescent stress-induces changes in adult GR and NF?B. The proposed work will establish an understanding of sex differences created by chronic stress at the mechanistic level and provide the basis to develop a scientific foundation for clinical practice allowing for better management and elimination of stress-related disorders.

DESCRIPTION (provided by applicant): The Short-term Mentored Career Enhancement Award in Basic Behavioral and Social Sciences: Cross-Training at the Intersection of Animal Models and Human Investigation (K18) is a unique opportunity to fund significant and innovative research while simultaneously building the skill set, and thereby future scientific discovery potential, of a scientist. The current application proposes to secure training in human investigation for Gretchen Neigh, Ph.D., a behavioral neuroendocrinologist currently adept at the use of animal models to address questions of the neurobiological basis of behavior. Dr. Neigh's research portfolio focuses on potential metabolic underpinnings of behavioral disorders such as Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). The work proposed serves the dual purpose of extending Dr. Neigh's innovative hypotheses regarding glucose transport and origin of neuropsychiatric disorders from her current work in rodent models to assessments using human investigation. This training experience will provide a foundation for translational reciprocity in Dr. Neigh's research program and address a question of fundamental importance: assessment of the potential role of metabolism in manifestation of MDD and/or PTSD. Over 23 million people in the United States suffer from MDD or PTSD and these disorders compromise quality of life and generate significant economic burden. Both human and animal studies have provided evidence of changes in cerebral metabolism in these conditions and related animal models. The alterations in metabolic activity are generally attributed to reduced glutamate release from neurons which thereby decreases regional glucose transport. Counter to this traditional dogma, it is possible that a primary change in facilitated glucose transport subsequently suppresses neuronal activity. Facilitated glucose transport is mediated by a family of transporters (GLUT) that are responsible for glucose transport across the endothelial cells of the blood brain barrier, and for uptake of glucose into astrocytes and neurons. Deficits in the expression and translocation of members of the GLUT family have been linked to neuropathological conditions including Alzheimer pathology, post-ischemic brain function, and post- traumatic brain injury deficits. Alterations in the expression o translocation of members of the GLUT family in either the endothelial cells of the blood brain barrier, astrocytes, or neurons, could alter neuronal energy supply and thereby neuronal function, subsequently altering behavior. A polymorphism in GLUT1 has been demonstrated in humans and linked to altered progression and prognosis in cancer and diabetic nephropathy. Alterations in the availability of GLUT1, due to genetic differences in expression, may alter the relative risk 0f development of aberrant behaviors following trauma, leading to the manifestation of MDD and/or PTSD. Given the crucial role of GLUT proteins in the transport of energy substrates into cerebral tissue, evidence of altered cerebral metabolism in neuropsychiatric disorders, and evidence that glucose transporters are altered after stress exposure in animal models, the proposed work tests the hypothesis that a polymorphism in GLUT 1 will decrease the incidence of MDD and/or PTSD following trauma exposure. This work challenges the standard paradigm because cerebral GLUT is a novel point of origin for consideration in the pathophysiology of MDD and PTSD as it is generally accepted that the changes in glucose transport that are documented in imaging of patients are the result of altered neuronal activity as opposed to the cause of altered neuronal activity. Specific Aim 1 will determine the extent to which a polymorphism in GLUT 1 decreases the manifestation of MDD following trauma exposure. DNA samples will be assessed for the rs710218 polymorphism in GLUT 1. Multivariate analyses will be conducted to determine if individuals that have been exposed to trauma and have the polymorphism are resistant to the manifestation of MDD. Specific Aim 2 will ascertain the degree to which a polymorphism in GLUT 1 decreases the incidence of PTSD following trauma exposure. Similar to work described in Aim 1, Aim 2 will again assess the influence of the GLUT 1 polymorphism on outcome from trauma, but in this case the focus will be on PTSD. Completion of the proposed work will provide novel and innovative insight into a potential metabolic susceptibility of genetic origin to trauma-induced mental health impairments. Appreciation for the role of metabolic factors in the manifestation of behavioral disorders will provide a new direction of consideration for novel therapeutic options. In addition, the proposed work will facilitate the cross- training of an established behavioral neuroscientist, Dr. Gretchen Neigh, currently specialized in investigation of the neural substrates of behavior using animal models, in human investigation. Enhancement of Dr. Neigh's training will lead to increased translational reciprocity in her research program and through her interactions with trainees and collaborators will improve interactions between clinical and basic researchers in the behavioral sciences.

? DESCRIPTION (provided by applicant): Trauma exposure is high in HIV-infected individuals both prior and subsequent to infection. The incidence of post-traumatic stress disorder (PTSD) has been reported to be between approximately 5% - 15% among the 30 million people living with HIV (PLWH). PTSD is a severely debilitating, stress-related psychiatric illness associated with intrusive and fearful memories as well as flashbacks, and nightmares of the traumatic event(s) for much of the victims' lives, and significant impairment in routine daily activities. Th challenges presented by PTSD are magnified in PLWH because PTSD leads to poor adherence to antiretroviral (ART) medications, increasing the odds of virologic failure. PTSD also increases sexual risk behaviors, increasing the risk of transmission. The neurobiology of PTSD has been a topic of intense study over the past two decades; however, there is minimal understanding of the neurobiology of PTSD within the context of HIV. Two systems that have been repeatedly documented to drive PTSD symptoms are the neural circuitry that underlies the startle response and the endocrine axis that controls the body's response to stress. Therefore, the current application will test the central hypothesis that HIV exacerbates PTSD symptoms and augments underlying neurobiological correlates of PTSD in women. One limitation to studying the interaction of trauma and PTSD with HIV is the high likelihood of trauma exposure within PLWH, making it difficult to identify a control group for rigorous experimental analysis. In order to address this previous limitation, the current work will compare the impact of similar levels of trauma exposure between PLWH and individuals at high risk for HIV. The population selected for this study will be recruited from the Atlanta site of the NIH-funded Women's Interagency HIV Study (WIHS) which recruits from a population with overlapping recruitment for the NIH-funded Grady Trauma Project (GTP). The GTP has studied the impact of trauma exposure in a predominantly African American population for nearly 10 years focusing the proposed work on one of the most at-risk populations of PLWH, southern African-American women. The current project leverages the expertise in these two established studies and synergistically combines their individual areas of expertise positioning the generated body of work for maximum impact in the shortest amount of time possible. In the proposed project, we will examine the clinical, physiological, and neuroendocrine correlates of fear extinction as an intermediate phenotype of trauma-related symptoms. We will use dimensional approaches to symptom analyses (Aim 1), innovative biobehavioral assessments (Aim 2), and cutting-edge biomolecular techniques (Aim 3) in order to better understand the pathophysiology of PTSD co-morbid with HIV. The identification of the biological correlates of interactions among trauma processes and HIV infection has the potential to lead to better treatment approaches in terms of both pharmacological and behavioral interventions ultimately leading to improved ART adherence, reduced risk behaviors, and an enriched quality of life.