1988 — 1990 |
Urban, Janice H |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Sex Steroids and Brain Vasopressin Systems @ University of Washington |
0.955 |
1996 |
Urban, Janice H |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Npy Systems and Stress: Male/Female Comparisons @ Northwestern University |
0.942 |
1997 — 2000 |
Urban, Janice H |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Npy Systems and Stress--Male/Female Comparisons @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION (Adapted from applicant's abstract): Activation of neuropeptide Y1 (NPY1) receptors in limbic regions produces anxiolysis. It has been demonstrated that some NPY pathways exhibit a sexual dimorphism and modulation by steroids. Stress responses, as well as hormone responses to stress, also display a sex difference as well as a modulation by steroids in both animal and human studies. These findings are of importance since the clinical incidence of anxiety and panic disorders is highest within the female population. The long range objective of this grant proposal is to examine the involvement of central neuropeptide Y (NPY) systems in stress responses in both male and female rats. The specific aims of this proposal are to determine (1) whether a sex difference exists in the expression of NPY and NPY1 receptors in male and female rats, (2) whether male and female animals subjected to stress exhibit similar changes in NPY peptide or receptor expression, and (3) whether NPY receptors in the hypothalamus and amygdala are involved in the regulation of stress-induced behavior or corticosterone secretion. Receptor radioligand slice binding, radioimmunoassay and in situ hybridization will be used to measure changes in NPY receptor expression and NPY peptide and gene expression in the brains and pituitaries of male and female rats before and after stress. The third specific aim will be accomplished by examining changes in basal and stress-induced corticosterone secretion after injection of NPY and NPY1 agonists and antagonists into the hypothalamus and amygdala. These studies will elucidate some of the stress-induced neurochemical changes that occur with respect to NPY systems in male and female animals and contribute potentially important information on the influence of sex steroids in modulating the responses of central NPY systems to stress. These studies will provide insight to the etiology of sexually dimorphic stress responses and another mechanism by which anxiolytic drugs may act on the CNS.
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0.981 |
2002 — 2006 |
Urban, Janice H |
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. |
Neuropeptide Y Receptors and Hypothalamic Function @ Rosalind Franklin Univ of Medicine &Sci
DESCRIPTION (provided by applicant): Neuropeptide Y (NPY) receptors in the paraventricular nucleus of the hypothalamus (PVN) process information from NPY afferents relaying sensory, cardiovascular and endocrine information from the brainstem and hypothalamus. Any perturbation in this system, such as that perceived during stressful conditions, will alter the activity of the PVN. Y1 and Y5 receptor levels in the PVN are in part responsible for fine tuning these inputs and producing an efferent signal that will affect corticotropin releasing factor (CRF) secretion, cardiovascular and sympathetic tone. The long- range objective of this proposal is to examine the anatomical distribution and regulation of Y1 and Y5 receptor subtypes within the PVN as they relate to the regulation of stress hormone secretion. The hypothesis that Y1 and Y5 receptors are present on neuroendocrine neurons that regulate CRF and adrenocorticotropin (ACTH) secretion will be assessed. In addition, we will test the hypotheses that Y1 and Y5 receptor expressing neurons are activated during stressful conditions and that NPY regulates the expression of its own receptors. The following specific aims will be tested: 1. Determine whether NPY neurons projecting to the PVN and Y1 and Y5 receptor-containing neurons are activated during stress: 2. Determine the ultrastructural localization of NPY Y1 and Y5 receptors within the PVN: 3. Identify the phenotype and projections of hypothalamic Y1 and Y5 receptor immunoreactive neurons in the PVN: 4. Examine the regulation and processing of Y1 and Y5 receptors by elevated levels of NPY. This will be accomplished by using a combination of anatomical tracing methods combined with single and double label immunocytochemistry at the light and electron microscope levels to determine the projections and phenotype of Y1 and Y5 receptive neurons in the PVN. Different stressors (physical, psychological and nutritional) and chronic administration of NPY will be used to test the responsiveness and regulation of Y1 and Y5 receptors to these challenges. These studies will provide significant information on the distribution and neuroanatomy of Y1 and Y5 receptor expressing cells in the PVN and their potential role in integrating stress responses in the PVN. The identification of NPY receptors on neural pathways and hypothalamic neuropeptide neurons will provide important information regarding the regulation and integration of stress hormone secretion and food intake. Dysregulation of these systems may be implicated in the development of stress related illness such as depression and eating disorders.
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0.981 |
2009 |
Urban, Janice H |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Neuropeptide Circuits and Stress Regulation in the Basolateral Amygdala @ Rosalind Franklin Univ of Medicine &Sci
Stress responses in all species are the result of the culmination of sensory and memory information processed by different brain regions, each of which is designed to handle a set of unique inputs. The ultimate goal of a properly executed stress response is to assess the danger and either confront or avoid the threat. In some cases, repeated stress or exposure to extreme stresses, such as combat, puts undue pressure on the individual resulting in continued anxiety which can manifest as anxiety-related stress disorders such as panic disorder, posttraumatic stress disorder (PTSD) or depression. Conversely, some individuals thrive in the face of continued stress and are resistant to the adverse effects of stress. The mechanisms underlying individual differences in stress responses have not been elucidated and the description of which is in its scientific infancy. Neuropeptide Y (NPY) has received considerable attention as an endogenous anxiolytic compound. Recent studies describe an inverse correlation between NPY and the incidence of PTSD in combat veterans. Our preliminary data demonstrate that administration of NPY in the basolateral amygdala (BLA) decreases stress responses in rats and produces persistent stress resilience. We also found that a conditioned fear (emotional) stress increases NPY expression within the BLA, an area critical for the generation of emotional stress behaviors and memories. These proposed studies are designed to examine the contribution of NPY receptor activation to stress resilience and to elucidate the cellular and molecular mechanisms underlying NPY receptor signaling in the BLA. The following aims will be addressed: 1) Identify the source(s) of NPY fibers innervation neurons of the BLA and the neurochemical phenotype of neurons expressing NPY receptors;2) Determine the cellular responses to administration of NPY and NPY receptor selective ligands;and 3) Examine the cellular and molecular mechanisms that are associated with anxiolysis and stress resilience in animals treated with injections of NPY in the BLA. A multidisciplinary approach using anatomical, behavioral, electrophysiological and molecular biological methodologies will be employed in the performance of this research. The results from this work will be of importance in understanding the circuitry underlying the generation of stress resilience.
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0.981 |
2010 — 2014 |
Urban, Janice H |
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 Underlying Stress Resilience @ Rosalind Franklin Univ of Medicine & Sci
DESCRIPTION (provided by applicant): Stress is a major causal factor in the etiology of a number of psychiatric-related disorders. Individuals exposed to life-jolting, traumatic events, such as natural disasters, war or personal injury, may develop post- traumatic stress disorder (PTSD), a condition which results in the individual's inability to function in everyday life. However, through it all, there are those individuals that remain stress resilient and persevere in the face of intense stress. Currently, there is very little known about the mechanisms underlying the production of stress resilience. The long-term goal of this research is to elucidate the pathways and mechanisms in the brain involved in the generation of stress resilience which will be useful for preventive and therapeutic treatment of anxiety-related disorders. The basolateral nucleus of the amygdala (BLA) is a brain region that is essential for the integration and processing of sensory and memory information into stress responses and emotion. BLA activity is reflective of the balance of inhibitory and excitatory tone which is modulated, in part, by neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF). In the BLA, NPY not only buffers the actions of CRF, but produces long term stress resilience. The overarching hypothesis is that NPY decreases the output of the BLA by reducing the excitability of glutamatergic output neurons via acute and chronic downregulation of HCN (hyperpolarization-activated, cyclic nucleotide-gated) channel function which carries Ih. Preliminary studies demonstrate that NPY and CRF receptors present on glutamatergic cells in the BLA, exert opposing physiological actions on an important ion channel, (Ih), which governs the excitability of the BLA. That both of these peptides affect Ih makes this molecule a nexus for two different stress signals in modulating the activity of principal neurons of the BLA. Our central hypotheses are that: 1) acutely, NPY produces anxiolysis by decreasing BLA output through inhibition of the tonically-active H-current (Ih) in BLA pyramidal neurons, and that 2) repeated treatment with NPY results in a prolonged reduction in expression of the postsynaptic HCN channels which carry Ih; and that 3) stressful stimuli, via CRF, increases HCN activity and ultimately expression in BLA output cells. The identification of the HCN channels as potential targets of neuronal plasticity in this model of induced resilience is exciting and such information is crucial for the development of pharmacopoeia that could aid those individuals exposed to stressful environments.
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0.981 |
2014 — 2018 |
Rosenkranz, Jeremy E Urban, Janice H |
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. |
Sex Differences in Amygdala Function @ Rosalind Franklin Univ of Medicine & Sci
Project Summary Despite a higher incidence of mood and anxiety disorders in females, and sex differences in the expression of symptoms, the neurobiological underpinnings of sex differences in affective behaviors are not well understood. Dysfunction of the amygdala contributes to these disorders, yet it is unknown whether there are sex differences in amygdala neuronal function, or in amygdala susceptibility in psychopathology. Targeting of sex differences in amygdala pathology is expected to provide a novel therapeutic approach for the treatment of affective disorders. The objective of this project is to test whether differences exist in amygdala physiology and function in females and males, and whether a stress model that shares features with mood disorders exerts sex-dependent effects on the amygdala. This project will test the central hypothesis that the basolateral amygdala (BLA) in females is more responsive than the BLA in males, that this difference is specific for subcircuits of BLA neurons, and that stress decreases neuronal excitability and function of the BLA in females, but exerts opposite effects on BLA function in males. This project will test the contribution of ion channels that regulate BLA neuronal excitability to the sex differences, and key enzymes that modulate the function of these ion channels. In addition, this project will also test whether pharmacological manipulation of these novel ion channel and enzymatic targets reverses the behavioral impact of stress. The rationale for these studies is that the mechanism for sex differences in amygdala-dependent behaviors and the impact of stress on these behaviors is not known. These issues need to be understood to determine the role of the amygdala in sex differences in mood disorder symptomology. The Aims of this proposal are to test if sex differences in BLA neuronal excitability is specific for BLA subcircuits, if the effects of repeated stress on BLA function are sex dependent, and if the effects can be reversed in a sex-dependent manner. This will be tested using in vivo and in vitro electrophysiological approaches, combined with biochemical and behavioral approaches. These Aims are expected to demonstrate sex differences in the physiology of the BLA, the effects of repeated stress on BLA physiology and function, and that pharmacological targeting of the effects of stress will reverse impairments in a sex-dependent manner. This can lead to novel insight into the cause of sex differences in mood and anxiety disorders, and lead to a novel sex-dependent therapeutic approach for rapid treatment of mood disorders.
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0.981 |
2017 — 2018 |
Colmers, William Francis (co-PI) [⬀] Urban, Janice H |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Maternal Experience and Stress Resilience in Females @ Rosalind Franklin Univ of Medicine & Sci
PROJECT SUMMARY Within the general population, women are at increased risk for developing anxiety-related disorders. Many of these mental health disorders are linked to times of hormonal fluctuations (puberty, pre-menstrual disorder, pregnancy, menopause). However, some of these life events (reproductive experience/pregnancy/child rearing) may be beneficial, producing persistent decreases in stress responsiveness that far outlast the post-partum and weaning periods. While much research is focused on mechanisms that cause stress-related disorders, few studies have examined the neural circuits associated with resilience. The long-term goal of this research is to elucidate the brain pathways and mechanisms involved in the establishment and maintenance of stress resilience. While our research team has advanced the understanding of how neuropeptide Y (NPY) works as an anxiolytic compound in the basolateral amygdala (BLA) of male rats, the assessment of stress resilience cannot be complete without identifying the generation of resilience in females. The studies outlined here focus on the role of NPY in establishing stress resilience in females both via injection of the peptide into the amygdala and through endogenous release in a naturally-occurring model of resilience (reproductive experience; RE). We postulate that administration of NPY into the BLA will induce behavioral stress resilience in naïve female rats and that this will be accompanied by alterations in BLA neuronal excitability, decreases in ion channel expression and altered BLA neuronal morphology associated with decreased anxiety; a cellular ?signature? that was observed in male rats. To examine whether NPY participates in physiologically-induced resilience, we will use a model of RE (uniparous females rearing one litter), a life experience that increases stress resistance, to assess anxiety-related behaviors and properties of BLA neurons in ex vivo slice preparations. We will also examine gene expression of ion channels and neuropeptide receptors associated with stress resilience, as well as whether blockade of NPY Y5 receptors inhibits the generation of this resilience. The work proposed here will expand the stress resilient role of NPY, and the effects of RE on similar mechanisms (alteration of H currents) to produce stress resilience. While these studies examine mechanisms underlying resilience, the results can also inform future studies of postpartum depression and sex differences in treatment of anxiety disorders. The contribution of the Y5R subtype to the generation of resilience in two different models will be particularly informative in identifying a mechanism and novel target for anxiety treatment.
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0.981 |