Angela J. Grippo, Ph.D. - US grants

DESCRIPTION: (provided by applicant): This research proposal addresses physiological mechanisms and processes underlying the association between depression and cardiovascular disease. Human studies demonstrate a strong link between depression and coronary artery disease but have not progressed beyond correlational methods. The current proposal will examine the underlying mechanisms in depression and cardiovascular pathology by using a rodent model of depression (chronic mild stress) and a combination of behavioral, physiological, and pharmacological techniques. Rats will be exposed to chronic mild stress to induce the depression-associated sign of anhedonia (a reduced capacity to experience pleasure), and tested for cardiovascular impairments (Aim 1). Autonomic nervous system imbalance will be examined as a mechanism for the cardiovascular dysfunction (e.g., elevated heart rate and reduced heart rate variability) associated with the chronic mild stress model (Aim 2). In addition, central serotonin activity will be examined as a common pathophysiological factor underlying both depression and cardiovascular/autonomic dysfunction (Aim 3). This research will extend our knowledge of the interactions between psychological and physiological conditions, and possibly prompt the development of new treatments for patients with depression and/or cardiovascular disease.

[unreadable] DESCRIPTION (provided by applicant): This proposal addresses central oxytocinergic mechanisms underlying the interactions of affective behaviors, neuroendocrine function, and autonomic activity by investigating the effects of social isolation in female prairie voles. This research is directly relevant to health issues such as social behavior, depression, anxiety, and heart disease. Study 1 employs radioimmunoassay, enzyme immunoassay, and immunocytochemistry to investigate the time course of hormone changes in plasma and hypothalamic brain tissue following social isolation in voles (Aim 1). Study 2 examines depression- and anxiety-like behaviors and endocrine function, and uses radiotelemetry to measure autonomic parameters, in response to social isolation (Aim 2). Study 3 investigates specific oxytocinergic mechanisms that might underlie stressor-induced changes by examining central (intracerebroventricular) administration of oxytocin and/or an oxytocin antagonist to alter the behavioral, neuroendocrine, and autonomic responses to social isolation (Aim 3). The present research will enhance our understanding of how the social environment impacts behavior, physiology, and brain function, and can aid in developing new treatments for patients with affective disorders and cardiovascular disease. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This research will use behavioral, autonomic, and neuroendocrine approaches to investigate the hypothesis that neural mechanisms involving oxytocin underlie the documented association between depression and heart disease. Disorders relating to negative affect, such as depression and anxiety, are recognized risk factors for cardiovascular disease; this relationship is especially important for individuals with specific vulnerabilities (such as persons with a family history of heart disease or aging populations). Psychological and physiological responses to stressors, and in particular reactions in the social context, play an important role in the development of affective symptoms and behaviors, and have been linked directly to cardiovascular dysfunction. Furthermore, evidence indicates that oxytocin mediates behavioral and physiological processes associated with stress and social experiences, and therefore this neuropeptide may have a mechanistic role in the link between mood and cardiovascular disorders. The current research project will use a rodent model, the socially monogamous prairie vole, to study the behavioral, neuroendocrine, and autonomic responses to a social stressor (social isolation), and the potential oxytocinergic mechanisms that underlie these responses. Converging evidence suggests that the prairie vole provides a unique model system for studying responsiveness to social experiences, and that this species has utility for studying autonomic mechanisms related to mood and cardiac function. Experiment 1 will employ (a) behavioral tests relevant to depression, (b) continuous recording of autonomic and cardiac parameters, and (c) measures of circulating and central nervous system hormones and peptides, to test the hypothesis that social isolation induces behavioral and physiological responses relevant to depression and cardiovascular disease (Specific Aim 1). Experiment 2 will employ (a) chronic administration of oxytocin and (b) administration of an oxytocin antagonist, to test the hypothesis that oxytocinergic mechanisms underlie specifically the behavioral, autonomic, and neuroendocrine responses to social isolation (Specific Aim 2). This research proposes a novel mechanism by which the social environment impacts behavior, physiology, and brain function, which can promote the development of more comprehensive treatments for patients with depression and cardiovascular disease. There are important interactions among behavior, brain function, and the cardiovascular system; one such example of these interactions is the association between depression and heart disease. The current research project will investigate directly the link between these conditions by studying in an animal model the behavioral, endocrine (hormones), autonomic (control of cardiovascular function), and brain processes involved in mediating mood and cardiovascular function. This research can lead to the development of more effective treatments for patients with depression and heart disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This research will investigate the effects of an environmental treatment (environmental enrichment), for preventing the negative emotional and cardiovascular consequences of social isolation in the context of depression and heart disease. There is a bidirectional association between depression and heart disease, and this relationship is especially important for people with specific vulnerabilities such as aging populations or individuals who lack beneficial social experiences. Psychological and physiological responses to social stressors and isolation play an important role in the development of affective symptoms and cardiovascular dysfunction. However, current treatments for individuals with depression and heart disease are significantly limited. The present project will use a rodent model, the socially monogamous prairie vole, to study behavioral, autonomic responses to a social stressor (social isolation), and potential molecular mechanisms that underlie environmental enrichment as a treatment for these negative consequences. Preliminary findings, from our laboratory and others, indicate that environmental enrichment - involving increased stimulation from the environment in the form of inanimate objects and physical activity - has beneficial effects on several central nervous system functions, and can improve emotional reactivity and behaviors associated with depression. The prairie vole is a valuable model system for studying responsiveness to social experiences and neurobiological mechanisms related to mood and cardiovascular function. This species displays several unique social behaviors that mimic those of humans, including living in extended families and forming enduring social bonds; and also exhibits autonomic regulation of the heart similar to humans. Using the prairie vole model, Specific Aim 1 will employ behavioral tests of depression and continuous recording of cardiovascular variables including blood pressure, heart rate, heart rate variability, and autonomic balance, to test the hypothesis that environmental enrichment is an effective treatment for behavioral and cardiovascular consequences of social isolation. Specific Aim 2 will employ measures of central nervous system genes including delta-FosB immunoreactivity, to investigate the hypothesis that long-term alterations in cortical, limbic, and autonomic brain regions underlie the positive effects of environmental enrichment in animals that are socially isolated. This research proposes a novel mechanism by which the social environment impacts behavior, physiology, and brain function, and will promote the development of more comprehensive treatments for patients with depression and cardiovascular disease. PUBLIC HEALTH RELEVANCE: The association between depression and heart disease is bidirectional, and is significantly influenced by the social environment. The current research project will investigate, in an animal model, the ability of an environmental treatment to protect against negative behavioral, cardiovascular, and brain processes associated with mood and cardiovascular dysfunction. This research will lead to the development of more effective treatments for patients with depression and heart disease.

Project Summary/Abstract This research will investigate central nervous system mechanisms underlying exercise as a strategy to promote resilience to social stressors, and is specifically designed to provide a training environment for undergraduate students. Exposure to social stressors significantly reduces quality of life, contributing to emotion-related disorders such as depression, physiological disorders such as heart disease, and premature mortality. However, our understanding of the mechanisms underlying social stressors and potential sex differences in stress vulnerability and resilience is limited. Therefore, strategies designed to promote resilience to social stressors in both sexes will improve public health. The present project will use a rodent model ? the socially monogamous prairie vole ? to investigate behavioral, autonomic, and endocrine reactivity to long-term social isolation (Specific Aim 1), and potential molecular and neuropeptide mechanisms that underlie exercise as a prevention strategy against social isolation (Specific Aim 2). The prairie vole is a valuable model system for studying responsiveness to social experiences and neurobiological mechanisms underlying stress-related disorders. This species displays several unique social behaviors that mimic those of humans, including living in extended families, forming enduring social bonds, and displaying behavioral, physiological, and neural changes as a function of social stressors. Voluntary exercise may serve a protective role against some depression-relevant behaviors and endocrine responses in socially isolated prairie voles; however the mechanisms underlying these benefits are not clear. Therefore, using male and female prairie voles, Specific Aim 1 will employ continuous recording of autonomic variables (e.g., heart rate, heart rate variability), repeated corticosterone measurements, and behavioral tests of depression and stress reactivity to test the hypothesis that exercise is an effective strategy to promote resilience to behavioral and physiological effects of social isolation in a sex-specific and activity level-specific manner. Specific Aim 2 will employ measures of central delta-FosB and neuropeptide immunoreactivity, to investigate the hypothesis that long-term alterations in cortical, limbic, and autonomic brain regions underlie the protective effects of exercise. We hypothesize that exercise will, in a sex-specific manner: (a) prevent long-term autonomic and endocrine consequences of isolation; (b) improve behavioral and physiological reactivity to stressors; and (c) improve neural activity in regions of the brain relevant to social behavior, stress, and autonomic and endocrine processes including the medial prefrontal cortex, hypothalamus, hippocampus, amygdala, bed nucleus of the stria terminalis, medullary structures, and dorsal vagal complex. This research proposes novel mechanisms through which exercise can protect against behavioral and physiological consequences of social isolation. The findings from this project will facilitate realistic strategies to promote resilience to social stress in both women and men.