1985 — 1987 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mediating Controls of Cardiovascular Defense Response
There is little experimental information available on the mechanisms controlling the integration of the constellation of cardiovascular responses produced by average environmental stimulation. Although it is likely that cardiovascular adjustment occur in order to accomodate metabolic demands, the processes involved in the marked cardiovascular changes accompanying emotional states (e.g., anger, rage, fear) need to be elucidated. The present research plan proposes to study the neural control of cardiovascular responses in the rat exposed to a noxious exogenous stimulus complex. An evoked defense response will be produced by presenting an aversive stimulus complex consisting of tone/light and foot shock. The use of pulsed Doppler flow probe technology in the freely moving, awake rat will permit the quantification of hemodynamic changes on a second by second basis in a conrolled behavioral test situation. Using neurobiological and pharmacological methods the afferent, efferent and central mediating neural and humoral components of the response will be characterized. Also cardiovascular responsivity of the stimulus complex will be studied in conjunction with hypertensivogenic manipulations. The results of these experiments will provide fundamental new information on (1) the cardiovasculary dynamics accompanying aversivew stimuli, (2) the mechanisms (humoral and/or neural) mediating cardiovascular adjustments to such stimuli, (3) the role of the central nervous system in the coupling and modulation of somatic and autonomic responses and, (4) the role of the defense reaction in the pathogenesis of hypertension.
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1 |
1985 — 1988 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Early Salt Intake: Sympathetic Control of Blood Pressure
Evidence from epidemiological and experimental studies emphasize the significance of dietary salt intake in the development of hypertension. Several lines of evidence indicate that young animals are especially sensitive to excess sodium chloride intake. Because it has been repeatedly demonstrated that exogenous factors can have a prepotent effect on the organization of physiological systems if they are presented around the perinatal period, it is reasonable to suspect that inappropriately high sodium chloride intake in the neonate might have inordinate, deleterious effects on cardiovascular development. Unfortunately, systematic studies of the effects of salt intake on cardiovascular control systems during the immediate postnostal period have not been performed. One reason for this is that it has been difficult to manipulate sodium intake in a controlled manner in offspring that normally receive mother's milk as the total source of nutrition. Recently, a technique of infant feeding for the rat has been perfected. Neonatal animals are reared in a controlled environment without the present of a dam. The application of this technique has thus far been primarily to investigate brain and behavioral development. However, the method is ideally suited to investigate the long-term cardiovascular effects of altered dietary substances, such as sodium, during the neonatal period. The present proposal will use the artificial rearing technique to manipulate salt levels in the diet of neonates. Normotensive, genetically borderline hypertensive, spontaneously hypertensive, and renal compromised rats exposed to early salt feeding will subsequently be studied as juveniles (at the time of weaning) and as adults to evaluate the effects of such treatment on the sympathetic contribution to cardiovascular control. The results of these experiments will provide essential new information about the effects of early dietary sodium in the development of cardiovascular function.
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1 |
1988 — 1989 |
Johnson, Alan Kim |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Neurobehavioral Sciences Program |
1 |
1997 — 2001 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Parabrachial 5 Ht and Thirst and Salt Appetite
DESCRIPTION: (Adapted from the application) Body fluid homeostasis depends on reflexes which act to modulate the rate of renal water and sodium loss and on ingestive behaviors (i.e., thirst and salt appetite) that corrects deficits. Although renal mechanisms can slow fluid loss, the restoration of vascular volume depends on the ingestion of water and solute (e.g., sodium). The maintenance of extracellular volume requires that the CNS receives and processes information about the status of body water and sodium. Several visceral sensory systems are known to provide this afferent input but there is only a very limited understanding about how this information is handled by the CNS. The present proposal builds upon the investigator s prior studies on the central processing of afferent signals involved in body fluid and cardiovascular homeostasis. The proposed research will employ a model of rapid-onset sodium appetite in the rat. Because of its short latency of induction, this model of experimental sodium intake is especially appropriate for use in conjunction with a range of neurophysiological/pharmacological methods that permit the investigation of brain pathways and processes subserving extracellular fluid volume regulation. Experiments using the rapid-onset sodium appetite model will focus on defining the role of serotonergic mechanisms in the lateral parabrachial nucleus (LPBN) that we have implicated in the regulation of extracellular fluid volume. The proposed studies employing functional (behavioral), pharmacological, electrophysiological and neuroanatomical methods are designed to lead to converging experimental findings to increase our understanding of how the brain processes information necessary for maintaining body fluid and cardiovascular homeostasis. Such new information has relevance for the well-being of normal individuals exposed to physiological (exercise) and environmental (heat) challenges and for understanding mechanisms underlying pathological conditions related to fluid balance (e.g., hypertension, congestive heart failure, and renal disease).
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1 |
1998 — 2000 |
Johnson, Alan Kim |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Parabrachial Nucleus and Amygdala and Salt Intake
Body fluid homeostasis depends on reflexes which act to modulate the rate of renal water and sodium loss and on ingestive behaviors (i.e. thirst and salt appetite) that correct deficits. Although renal mechanisms can slow fluid loss the restoration of vascular volume depends on the ingestion of water and solute (i.e. sodium). The maintenance of extracellular volume requires that the CNS receives and processes information about the status of body water and sodium. Several visceral sensory systems are known to provide this afferent input, but there is only limited understanding about how this information is handled by the CNS. The present FIRCA proposal extends and builds upon the PI's prior studies on the central processing of afferent signals involved in body fluid and cardiovascular control and will couple the neuroanatomical expertise of Dr. de Olmos in Argentina with the functional studies of Dr. Johnson in the U.S. and Dr. Vivas in Argentina. The general goal of the study is to examine the role of the extended amygdala in the control of sodium appetite and body fluid control. The investigators will use the rapid-onset model of salt appetite and then perform a functional anatomical analysis of the extended amygdala. The F0S immunohistochemical technique will be employed to assess the effects of manipulations made to affect salt appetite, blood volume, blood pressure and 5-HT activity in the lateral parabrachial nucleus on neuronal activity in the extended amygdala. Such new information will advance our knowledge of how the brain processes information related to body fluid and cardiovascular homeostasis.
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1 |
1998 — 2002 |
Johnson, Alan Kim |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Targeted Modulation of Vasopressin in Brain Magnocellular Neurons by Gene Therapy
The potential to reliably and safety transfer genetic material into the central nervous system holds promise in providing gene therapy to treat both genetically-associated neuropathologies and pathologies where there is altered activity in identified neural systems that can be manipulated by modulation of genetic expression. To reach this goal, experimental strategies to optimize the delivery of genetic material must be studied in defined neuronal systems and in systems where functional actions are known and can be assessed. The vasopressin synthesizing magnocellular neurons of the hypothalamic- neurohypophyseal tract have served as an extremely valuable model for the discovery of basic principles in neurobiology. In addition, these cells play critical physiological roles in the maintenance of body fluid balance and in cardiovascular regulation. The focus of this proposal is to take advantage of our experience studying vasopressin neurons of the hypothalamic-neurohypophyseal tract. We will apply our knowledge of the basic neurobiology of this defined system to study and develop strategies for enhancing gene transfer into identified neurons, and then to test these optimized methods in pathological models where vasopressin has been implicated. Specifically, the studies in this proposal are directed at 1) devising methods to obtain maximum and specific gene transfer to the magnocellular neurons of the hypothalamic-neurohypophyseal tract, 2) inducing in magnocellular neurons the capacity to synthesize and secrete vasopressin in a genetic animal model of familial diabetes insipidus, the di/di Brattleboro rat, and 3) down-regulating the release of vasopressin in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR).
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1 |
1998 — 2002 |
Johnson, Alan Kim |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Sensory Processing by Subfornical Organ in Body Fluid/Cardiovascular Homeostasis
Body fluid and cardiovascular homeostasis depends on ingestive behaviors and on reflexes acting to modulate renal water and sodium loss and to redistribute blood flow. In order for the appropriate effector mechanisms that maintain body fluid balance and cardiovascular function to be engaged, the brain must receive information about the current status of body hydration and blood pressure. Several visceral sensory systems provide this type of information to the central nervous system (CNS). This input is carried over afferent neural pathways and by the direct action of circulating factors on select brain regions which lack a blood-brain barrier. Three permeable areas of the brain receiving blood-borne signals have been described as sensory circumventricular organs (CVOs) and are typified by the subfornical organ (SFO). This proposal focuses on the SFO and its role in detecting circulating angiotensin II, how this information is handled within this structure and ultimately transferred into forebrain regions involved in the behavioral and reflex control of hydromineral balance and blood pressure. The present proposal builds upon our prior studies of the central sensing and processing of afferent signals involved in body fluid and cardiovascular homeostasis. The aims of this research are to investigate the mechanisms of sensory transfer and neural processing with the SFO in response to blood-borne ANG II and then to characterize the pathways which convey this information to specific forebrain nuclei involved in maintaining cardiovascular and body fluid homeostasis. The studies will employ both in vivo and in vitro methods to electrophysiologically, pharmacologically and anatomically characterize identified cells with the SFO. The cells will be analyzed to understand the mechanisms they use for both intra- and inter- cellular signaling. New information derived from studies on this important sensory structure that couples the systemic circulation with the CNS proper has relevance for understanding both normal physiology and pathophysiology associated with states of disordered body fluid and cardiovascular regulation, such as in hypertension.
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1 |
2002 — 2005 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Parabrachial 5-Ht in Thirst and Salt Appetite
DESCRIPTION (provided by the applicant): Body fluid homeostasis depends on reflexes which act to modulate the rate of renal water and sodium loss and on ingestive behaviors (i.e., thirst and salt appetite) that correct deficits. Although renal mechanisms can slow fluid loss, the restoration of vascular volume depends on the ingestion of water and solute (e.g., sodium). The maintenance of extra-cellular volume requires that the CNS receives and processes information about the status of body water and sodium. Several visceral sensory systems are known to provide this afferent input but there is only a very limited understanding about how this information is handled by the CNS. The present proposal builds upon our prior studies on the central processing of afferent signals involved in body fluid and cardiovascular homeostasis. Experiments using a rapid-onset model of sodium depletion accompanied by mild hypotension will focus on defining the role of serotonergic and cholecystokinergic mechanisms associated with the lateral parabrachial nucleus (LPBN) that we have implicated in the regulation of extracellular fluid volume. The proposed studies employing functional (behavioral), pharmacological, electrophysiological and neuroanatomical methods are designed to lead to converging experimental findings to increase our understanding of how the brain processes information necessary for maintaining body fluid and cardiovascular homeostasis. Such new information has relevance for the well-being of normal individuals exposed to physiological (exercise) and environmental (heat) challenges and for understanding mechanisms underlying pathological conditions related to fluid balance (e.g., hypertension; congestive heart failure; renal disease).
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1 |
2003 — 2007 |
Johnson, Alan Kim |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Depression and Heart Failure Associated Cardiovascular Pathology
Depression is both a debilitating psychological disorder and a condition that affects an individual's physical well-being. Depression is a recognized risk factor for heart disease. Research has demonstrated that depression predisposes an individual to myocardial infarction, sudden death, atherosclerosis, thrombosis and arrhythmias. While the behavioral and cognitive aspects of depression have been studied extensively, there has been much less research investigating the mechanisms responsible for the physiological consequences of mood disorders. Exposure of rodents to a series of chronic mild stressors (CMS) generates key behavioral characteristics of human depression that are observable and quantifiable. The CMS model of experimentally-induced depression (ID) mimics the reduced responsiveness to pleasurable stimuli (anhedonia)which is a pivotal diagnostic criterion seen in depression. In the CMSdD model, anhedonia is induced by presenting mild unpredictable stressors (e.g., paired housing, stroboscopic illumination, white noise) of varying durations. In rats,anhedonia is operationally defined as a decrease in responding for a previously demonstrated reinforcer (reward). Recently, we have begun to characterize cardiovascular function in rats with CMS-ID. We have found that rats exposed to CMS for 4 weeks showed anhedonia along with cardiovascular alterations. Similar to patients with depression and with heart failure,CMSgD rats had elevated resting heart rates and reduced heart rate variability. In addition, rats exposed to CMS have increased susceptibility to experimentally-induced premature ventricular contractions. In other studies investigating the behavioral consequences of heart failure, we have found evidence of anhedonia (i.e., experimental depression) in rats with experimental myocardial infarction. The proposed research program will extend our characterization of the cardiovascular changes that accompany experimentally-induced depression and investigate the role of brain serotonergic mechanisms that are hypothesized to be common in the mediation of cardiovascular alterations that accompany both experimental depression and experimental heart failure.
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2005 — 2009 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurobehavioral Control of Body Fluid Balance in Mouse
DESCRIPTION (provided by applicant): Body fluid homeostasis depends on reflexes that modulate the rate of renal water and sodium loss and on ingestive behaviors (i.e., thirst and salt appetite) that correct homeostatic deficits. Although renal mechanisms slow fluid loss, the restoration of vascular volume depends on the ingestion of water and solute (e.g., sodium). The maintenance of extracellular volume requires that the central nervous system (CNS) receives and processes information about the status of body water and sodium. Several visceral sensory systems provide this afferent input, but there is only a very limited understanding about how this information is handled by the CNS. The present proposal builds upon our prior studies that have been directed at defining the nature of interactions of afferent signals involved in body fluid and cardiovascular homeostasis and at understanding the CNS processing mechanisms of such afferent information. Recently, we have used the mouse to investigate several issues related to body fluid and cardiovascular homeostasis. Use of this species was prompted by the potential of new experimental models derived by manipulation of the mouse genome. Several of our initial studies have adapted and validated many of the conventional experimental manipulations used to study thirst and salt appetite in rat. The results indicate that there are many important similarities between mouse and other experimental species, and also provocative differences. We propose studies in normal mice that allow us to clarify understanding of the control of thirst and salt appetite in this species. In addition we propose studies that take advantage of currently available mouse models to generate important new information about the basic neurobiology of thirst and salt appetite. Specifically, we will study the interaction of the systemic and brain renin-angiotensin-aldosterone systems and blood pressure in the control of their behaviors that contribute to body fluid homeostasis. Initial studies will employ methods and knowledge derived from studying wild type mice to further understanding of the role of body and brain renin-angiotensin systems in the behavioral control of body fluid balance. Other studies will make use of a mouse transgenic model developed at the University of Iowa that over-expresses angiotensin type 1 receptors in brain and in sensory circumventricular organ neurons. Information generated from these studies will be relevant to the well-being of normal individuals exposed to physiological (e.g., exercise) and environmental (e.g., heat) challenges. These studies will be especially important for understanding mechanisms underlying pathological conditions such as hypertension and congestive heart failure where excess thirst and sodium intake have been documented.
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2008 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Circumventricular Organs: Gender and Hypertension
DESCRIPTION (provided by applicant): Sex differences in the development of hypertension and cardiovascular disease have been well described in humans and in animal models. Low dose AngII infusion is known to induce a neurogenic hypertension via CNS actions on circumventricular organs in the brainstem and hypothalamus. An increasing body of evidence has shown that Angll central and peripheral effects involve activation of reactive oxygen. Similarly, central peripheral studies with estrogen and testosterone have shown that many of their cardiovascular related effects may be related their modulation of the generation of reactive oxygen species (ROS) and nitric oxide (NO). Recent data from our laboratory have shown that low-dose infusion of AngII results in hypertension WT male mice but not in intact WT females. Further, we have new preliminary data showing that AngII induced hypertension in males is blocked by central infusions of the adrogen receptor flutamide and by central infusion of the superoxide dismutase (SOD) mimetic tempol and that males show greater levels of intracellular ROS in CVO neurons following Ang II long-term infusion than females. This proposal will use brainstem slices of circumventricular organs key to AngII hypertension, state-of-the-art imaging techniques, real-time RT-PCR, adeno-vector gene transfer and telemetry measurements of conscious blood pressure recordings to test the general hypothesis that sex and sex steroids modulate the central actions of Angll via interactions with free radical and NO generating pathways within the circumventricular organs of the brainstem and hypothalamus. This hypothesis will be tested with 4 specific aims: Specific Aim 1. Determine the roles of nNOS and SOD on AngII induced increases in [Ca++]i in the brainstem and forebrain CVO brain slices from male and female mice. Specific Aim 2: Determine the effects of sex and sex steroids on AngII induced release of intracellular ROS in the brainstem and forebrain CVOs of male and female mice. Specific Aim 3: Determine the effects of sex and sex steroids on expression of SOD, nNOS and AT1 receptors in the brainstem and forebrain CVOs of males and females mice. Specific Aim 4: Determine the role of SOD and nNOS in AngII induced hypertension in WT males and females.
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2008 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Baroreceptor Afferent Transmission
[unreadable] DESCRIPTION (provided by applicant): There is both functional and anatomical evidence for the presence of several VGCC subtypes (N, P/Q, L, R) in the cell bodies of aortic baroreceptor afferents, with the N-type being the predominant current. It has been in general inferred that VGCC present at the terminals in approximately similar proportions to the soma and calcium currents of the cell bodies reflect calcium currents at the synapse. However, recent preliminary findings from our laboratory suggest that different population of the VGCCs may play specific roles during different levels and stages of synaptic activation. Using currently available fluorescent imaging techniques, the proposed studies will test the general hypothesis that extended, high frequency baroreceptor activation shifts the primary inward calcium channel flux responsible for exocytosis from the N-type calcium channel to other available calcium channels within the baroreceptor terminal. Further, we will test the hypothesis that different subsets of calcium channels are responsible for baroreceptor exocytosis from the different synaptic vesicle pools found in synaptic terminals. We will use in vitro imaging of synaptic vesicle turnover and intraterminal calcium and imaging of intraterminal calcium in brainstem slices to address are 4 major and distinct aims: 1) To evaluate the contribution of different VGCC subtypes to stimulation evoked vesicle exocytosis at different frequencies. 2) To determine the contribution of different VGCC subtypes to stimulation induced increases in intraterminal calcium. 3) To determine the role of different VGCC in vesicle pool mobilization. 4) To evaluate the effects of sustained hypertension on frequency induced increases in intraterminal calcium and the contribution of the different VGCC subtypes to these changes. Results from these studies are expected to yield novel information that will provide an important advances in our understanding of the cellular mechanisms regulating of baroreceptor neurotransmission. [unreadable] [unreadable]
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1 |
2010 — 2013 |
Johnson, Alan Kim Xue, Baojian |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Control of the Circulation: Sex and Hypertension
DESCRIPTION (provided by applicant): Sex differences in the prevalence and pathogenesis of hypertension are well documented in humans and in animal models of cardiovascular disease. Recent findings from our laboratory indicate that infusions of low doses of angiotensin II or of aldosterone into mice and rats produce markedly greater hypertension in males than in females. In addition, we find that ovariectomy (OVX) abolishes these female-related antihypertensive effects and that administration of estrogen or estrogen receptor agonists selective for estrogen receptor a (ERa) or for estrogen receptor b (ERb) into the brain restores protection in OVX females. Central administration of estrogen prevents experimentally-induced hypertension in males. In other preliminary studies we have found that either decreasing reactive oxygen species (ROS) or increasing nitric oxide (NO) in the brains of rodents attenuates hypertension induced by systemic treatment with angiotensin II or aldosterone. The present proposal will extend these unique findings by addressing the following questions: 1) Where does estrogen act in the brain to evoke its antihypertensive protection? 2) What brain estrogen receptor subtype(s) is/are necessary for this antihypertensive protection? and 3) What are the roles of [Ca2+]i and of altering the balance between ROS and NO in the cellular mediation of estrogen's protective effects? Methods to be used in conducting experiments to answer these questions include: chronic telemetric measurements of blood pressure and heart rate in rats and mice, in vitro imaging of rat paraventricular nucleus neurons to determine the effects of estrogen on angiotensin II- and aldosterone-induced changes in [Ca2+]i and [ROS]i in anatomically identified ("tagged"), putative premotor sympathetic neurons, pharmacological methods, small interference RNA to selectively attenuate expression of estrogen receptor subtypes in the brain, and genetically manipulated mice to selectively remove (knockout) ER1 or ER2. A full understanding of cellular and brain mechanisms underlying the effects of sex estrogen receptor subtypes, and sex steroids in the pathogenesis of hypertension is critical for the continued development of therapies to treat cardiovascular disease in both men and women. PUBLIC HEALTH RELEVANCE: Hypertension is a major risk factor for heart disease, stroke, atherosclerosis, renal disease and blindness. There is a substantial body of evidence indicating that females of child bearing age in comparison to males are protected against high blood pressure and new evidence indicates that part of this protection results from the action of estrogen on the central nervous system Understanding the role of estrogen on the brain to prevent high blood pressure is likely to lead to new methods for prevention and treatment of this disorder.
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2010 — 2012 |
Johnson, Alan Kim |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neural Processing in the Lamina Terminalis in Long-Term Regulation of Blood Press
Acetylcholine; Acute; Address; Affect; Aldosterone; Amygdaloid structure; Angiotensin II; Angiotensins; Animals; Area; basal forebrain; Behavior; Behavior Control; Blood; Blood Circulation; Blood Pressure; blood pressure regulation; Body Fluids; Brain; Brain region; Cardiovascular Physiology; Cardiovascular system; Cations; Cell Nucleus; Cells; Chronic; copper zinc superoxide dismutase; Equilibrium; extracellular; Fluid Balance; Generations; Homeostasis; Hormonal; Hypertension; Hypotension; Hypothalamic structure; indexing; information processing; Investigation; Laboratories; Lamina Terminalis; Lesion; Liquid substance; Medial; Mediation; Mineralocorticoid Receptor; Molecular and Cellular Biology; NADPH Oxidase; neural information processing; Neuraxis; Neurobiology; Neurons; Osmolar Concentration; Output; paraventricular nucleus; Physiological; Process; Program Research Project Grants; Prosencephalon; Protocols documentation; Reactive Oxygen Species; receptor; receptor expression; Reflex action; Regulation; relating to nervous system; Renin-Angiotensin System; Research; Resources; Role; Saline; Signal Transduction; Structure; Superoxide Dismutase; System; Testing; Third ventricle structure; Tissues; Vanilloid; Work
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2010 — 2014 |
Johnson, Alan Kim |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Stress of Chronic Disease: Mineralocorticoid Mediation of Mood
DESCRIPTION (provided by applicant): Stressors exert an exacting toll when they are prolonged or varied and do not permit their target to mobilize appropriate or sufficient resources to attenuate the challenge. A characteristic of many chronic diseases is that throughout their prolonged course they generate neurohumoral signals intended to compensate for compromised physiological function, but they paradoxically generate additional disorders. The high incidence of the co-morbidity of heart failure and psychological depression may provide an example of how the product of the chronic physiological stress produced by a disease state gets translated into a second disorder. Recently we have been addressing the question of why there is such a high incidence of psychological depression accompanying heart failure. The results from several converging lines of evidence lead us to hypothesize that adrenal mineralocorticoids released in the course of attempting to maintain the cardiac output of a failing heart are depressivogenic through their action on the central nervous system. The present application proposes to test this hypothesis by studying the co-morbidity of heart failure and anhedonia, a cardinal sign of depressed mood, and by investigating the role of mineralocorticoids generated during heart failure in inducing the attenuated experience of pleasure. In addition, the role of mineralocorticoids themselves as depressivogenic agents will be investigated. The three specific aims to be achieved by the proposed research are to: 1) test experimental myocardial infarction-induced heart failure as a model for the co-morbidity of heart failure and depression, 2) investigate the role and mechanisms of mineralocorticoids in heart failure-induced depression, and 3) determine the role and mechanisms of mineralocorticoids as depressivogenic agents. Protocols employing methods from behavioral neuroscience, preclinical psychopharmacology, experimental cardiology, and cardiovascular physiology will be used to answer a series of key experimental questions. In the course of these studies a better understanding will be achieved of the 1) value of prophylactic use of selective serotonin reuptake inhibitors beginning early after myocardial infarction on heart failure-related depression, 2) likelihood that mineralocorticoids have a depressivogenic action on their own, and 3) potential antidepressant actions of mineralocorticoid receptor antagonists. Importantly, this preclinical research will test the feasibility of using a clinically approved mineralocorticoid receptor antagonist as an antidepressant pharmacotherapeutic.
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2014 — 2018 |
Johnson, Alan Kim |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Sites and Mechanisms of Cns Neuroplasticity in the Sensitization of Hypertension
One-third of individuals over the age of 20 in the United States have hypertension. High blood pressure is a major risk factor for coronary heart disease and strpke. t h e estimated burden of the effects of hypertension in the U.S. during 2010 was estimated to be $93.5 billion due to health care costs and missed work. The causes of the onset and the progressive increase in blood pressure over time are not known for most cases of hypertension. In recent studies in rats we have discovered that initial challenges with low, non-pressor doses of either angiotensin II or aldosterone wilf sensitize the pressor response to subsequent hypertension-inducing stimuli. Additional evidence indicates that these sensitized pressor responses are a result of sustained changes in the central nervous system. Similar types of neuroplasticity have been observed and studied in neural networks controlling many behavioral and physiological response systems. However, as ofthe present time, there has been little appreciation ofthe role that changes in information processing in the nervous system as a result of experience-induced sensitization may have in the pathogenesis of hypertension. Therefore, the principal hypothesis to be tested in this proposal is that physiological and environmental challenges act to sensitize the pressor response to hypertension-inducing stimuli by inducing neuroplasticity within speciflc components of the brain's neural netwprk controlling blood pressure. An important corollary of this hypothesis to be tested in that components of the brain renin-angiotensin-aldosterone system act in conjunction with other neuroplasticity-associated signaling systems to produce long-term modifications of the brain and a sensitized hypertensive response. To address an evaluation of these hypotheses, three speciflc aims will be pursued that will employ functional, cellular and molecular methodologies to analyze where in the central nervous system and in what cell types neuroplasticity occurs to effect sensitization of hypertension. The results of these studies will provide important new information and insights into the pathogenesis of high blood pressure. RELEVANCE (See Instructions): The nervous system plays a major role in the regulation of blood pressure and has the capacity to adjust cardiovascular function over the course of time through the processes involving neuroplasticity. Understanding how physiological or exogenous stimuli, present eartier in life, can modify brain function to produce a predisposition for an enhanced hypertension to a subsequent cardiovascular challenge is likely to identify targets and strategies for intervening in the pathogenesis of high blood pressure.
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1 |
2018 — 2021 |
Johnson, Alan Kim Xue, Baojian |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Hypertensive Response Sensitization and Perinatal Programming of Hypertension
PROJECT SUMMARY Work from our laboratory discovered that mild physiological and environmental challenges encountered earlier in adulthood produce sustained sensitization of the hypertensive response to subsequent hypertensinogenic challenges. Our recent studies indicate that the adult male offspring of dams with angiotensin II-produced gestational hypertension or eating a high-fat diet during the perinatal period also display sensitization of the hypertensive response. Accompanying this exacerbation of the hypertensive response is increased expression of components of the brain renin-angiotensin-aldosterone system, proinflammatory cytokines and activation of microglia in forebrain structures controlling sympathetic tone and blood pressure. Importantly, we find that administering a converting enzyme inhibitor to the sensitized offspring for six weeks between weaning and early adulthood abrogates gestational hypertension-induced sensitization of the hypertensive response. The present proposal builds on these findings with experiments that will determine: 1) the critical perinatal period when the hypertensive response can be sensitized by maternal gestational hypertension, 2) if maternal gestational hypertension alters mother-offspring behaviors to induce hypertensive response sensitization, 3) whether inhibitors of microglial activation and proinflammatory cytokines and other blockers of the renin-angiotensin- aldosterone system will reverse the sensitizing effects of maternal gestational hypertension and maternal perinatal high-fat diet intake, 4) why young females are protected against hypertensive response sensitization, 5) if maternal gestational hypertension or high-fat diet intake induces sensitized responses to identified hypertension risk factors related to dietary obesity, sodium intake and what factors are responsible of maintaining a sensitized response. This information will be obtained by using telemetry to measure blood pressure in freely moving rats and pharmacological methods to test mechanisms mediating hypertensive response sensitization. In addition molecular expression methods be used to characterize changes in mRNA and protein expression in key CNS regions controlling blood pressure. Completion of the proposed experiments will result in the delivery of important new information on how fetal programming results in increasing the likelihood of expression of enhanced hypertension later in life and measures that can be used to prevent it.
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