1987 — 1994 |
Plotsky, Paul M |
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. |
Central Regulation of Adrenocorticotropin Secretion
Corticotropin releasing factor (CRF-4l)-producing perikarya in the hypothalamic parvocellular paraventricular nuclei (pPVN) play an integral role in regulation of adenohypophysial adrenocorticotropin (ACTH) secretion, pro-opiomelanocortin (POMC) gene expression and, thus, in the regulation of adrenocortical secretion. The secretory activity of CRF-positive neurons is modulated by humoral factors (glucocorticoids, glucose, etc) and by numerous afferent fibers conveying information about interoceptive and exteroceptive stimuli. CRF-41 neurons receive heavy innervation from medullary cell groups which, themselves, receive a diverse array of visceral and somatosensory inputs. Therefore they are excellent candidates for mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to a number of visceral (e.g. hypovolemia, hypotension) and somatic (e.g. pain) stimuli. Efferents from medullary regions are the major source of inputs containing norepinephrine (NE), epinephrine (EPI), neuropeptide Y (NPY), and a peptide with activin-like immunoreactivity (IbetaA-LI) to the CRF-rich pPVN. These putative transmitters generally facilitate CRF-41 secretion, although the nature of adrenergic receptor subtypes mediating catecholamine actions remain controversial. Ultimately, mechanisms must exist to ensure coordination of gene expression and secretion. In the present proposal, we will test the hypothesis that, individually or in combination, NE and IbetaA-LI (a member of the TGF-beta growth factor family) participate in the coordination of CRF-41 secretion and gene expression. Because of the biochemical diversity of these transmitters and the likelihood that their release occurs in a specific manner dependent upon the stimulus characteristics (modality, amplitude, frequency, duration), we hypothesize that these transmitters differentially affect secretion and gene expression in the target cells via multiple intracellular pathways. Neurotransmitter release evokes both rapid and slow responses in neurons, thus permitting an immediate response to the stimulus as well as longer-term adaptive plasticity. It has been suggested that induction of the c-fos gene, which encodes a nuclear phosphoprotein with DNA binding properties consistent that of a transcriptional regulator, is a component of the signaling cascade by which specific transmitters may modulate neuronal gene expression. Therefore, we will evaluate whether any of these neurotransmitters activate the c-fos gene and then determine whether or not C-fos activation is correlated with CRF-41 secretion and/or gene expression.
|
1 |
1994 — 2002 |
Plotsky, Paul M |
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 Experience Alters Adult Behavior and the Hpa Axis
DESCRIPTION (adapted from applicant's abstract): Both basic and epidemiological studies implicate psychosocial stressors and life events in the development of affective disorders. This stress diathesis model is partially based on the findings that a traumatic stressor often precedes the onset of affective episodes. Accumulating evidence strengthens the concept that the experience of early trauma serves as an important vulnerability factor in this sequelae. Dysfunction of one or more neuronal systems has been postulated in the etiology of major affective disorders, including the noradrenergic (NA) system, the serotonergic (5-HT) system, and the hypothalamic-pituitary-adrenal (HPA) axis. Clinical and animal studies have identified apparent dysregulation of the HPA axis in major depression and its experimental analogs. Dysregulation includes resistance to glucocorticoid negative feedback, elevated concentrations of corticotropin-releasing factor (CRF) in the CSF and/or in specific neuronal structures, and alterations in either peripheral and/or central glucocorticoid receptor density. In animals studies administration of exogenous CRF not only produces activation of the HPA axis, but is associated with many symptoms of depression. Given this burgeoning evidence for a major role for CRF in the pathogenesis of affective disorders coupled with the observed psychiatric impact of early trauma, the investigators hypothesize that early trauma such as that induced by maternal deprivation or abuse may modify hypothalamic and/or extrahypothalamic CRF neurons and may alter inputs to these CRF neurocircuits in such a way as to produce neurochemical, endocrine, and behavioral hyperresponsivity to stressors in adults. Their recent research utilizing neonatal maternal separation in rats has not only verified the existence of alterations in the function of central CRF systems of glucocorticoid receptor density associated with early traumatic experience, but has also uncovered evidence supporting the involvement of adrenergic, serotonergic and GABAergic/benzodiazapine (BZ) systems in either mediating and/or maintaining these maladaptive alterations. In the current application, the investigators propose to further characterize these changes, to elucidate the mechanisms underlying these changes and to evaluate the potential of pharmacological interventions to reverse these dysfunctions. Overall, this research will augment understanding of the role of perinatal life expereince in the development of individual differences in stress responsiveness as well as in identification of neural processes that define this vulnerability.
|
1 |
1999 — 2002 |
Plotsky, Paul M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Core--Rat
The Rat Model Core (Core B) of the Emory University Silvio O. Conte Center~f6r the Neuroscience of Mental Disorders (CCNMD) represents an integral component of the overall Center. Core B will serve as the source of all rodents used by the individual preclinical Research Projects. In specific, Core B will produce and characterize a rat epigenetic early life stress (ELS) model associated with vulnerability to the development of a depression-like syndrome. Core B personnel will breed rodents, provide high quality animal care and uniformly applied neonatal manipulation protocols necessary to generate the ELS model, characterize the phenotype of all animals, ascertain the stage of the estrus cycle in adult female animals, and provide experimental manipulations as required by individual preclinical Research Projects within the Center. This epigenetic ELS model consists of Long Evans rats which are exposed to different rearing conditions from postnatal days (PND) 2-14, including: (1) animal facility reared (AFR) colony controls, (2) brief handling plus 15 min maternal separation (HMS 15) handling controls, (3) brief handling plus 180 min maternal separation (HMS 180). All individual Research projects will assess these animals for gender specific effects. Comparison of data obtained from these standardized rearing conditions among the various basic Research projects of this CCNMD will permit identification of central neurocircuit and intracellular mechanisms which are impacted by early life stress and which give rise to depressive-like syndrome; furthermore, since the animal models will be standardized, regression modeling can be used to elucidate interactions among these CNS systems in the genesis of this condition. Furthermore, the efficacy of various treatments (antidepressant, antisense, corticotropin releasing factor antagonist) in reversing aspects of depressive-like syndrome will be tested in these models. To this end, Core B will characterize the behavioral and HPA axis stress responsiveness of each animal, provide phenotypic screening for anhedonia, anxiety4fear-like behavior, as well as pr6viding surgical services such as chronic jugular catheterization, CNS guide cannula implantation, Alzet minipump preparation and implantation, resident intruder social defeat exposure, and other protocols as required by the Research Projects. Core B will provide characterized rats or will provide brain tissue, other tissue (adrenal, pituitary, etc), blood, or CSF from the HMS rats to the individual Research Projects. This organization has the advantage of maintaining consistency in animal handling and implementation of all protocols so that each preclinical Research Project receives identically characterized and treated animals for study.
|
1 |
1999 — 2002 |
Plotsky, Paul M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Crf and Urocortin Systems
The Emory University Silvio O. Conte Center for the Neuroscience of Mental Disease (CCNMD) brings together a group of expert basic and clinical investigators to study several animal models and clinical models relevant to the pathophysiology of depression. Considerable research has established a possible link between major depression and central corticotropin-releasing factor (CRF) containing neural circuits. CRF is the..major physiological regulator of the ~yp0thalamic~pituitary~adrenal (HPA) axis. A burgeoning database has accumulated which clearly suggests that CRF- and urocortin-producing neuronal systems integrate not only the Organism's endocrine response to stress, but also their autonomic, immunologic, and behavioral responses to stress as well. Moreover, hyperactivity of both hypothalamic and extrahypothalamic CRF neurons appears to be involved in the pathophysiology of both mood and anxiety disorders. We propose to compare the function of central CRF/urocortin systems in rat and primate models of early life stress-related depressive- like syndrome. The rat model of neonatal maternal separation and the primate model of variable foraging demand have both been shown to alter central CRF neurocircuit activity. We postulate that early life stress during some critical period of vulnerability modifies hypothalamic and extrahypothalamic CRF neurons as well as altering inputs to these CRF neurocircuits in-such a way as to produce ne\1rochemical, endocrine, and behavioral hyper-responsivity to stressors in adults. Preliminary data in these animals sh6ws alterations in noradrenergic, serotonergic and dopaminergic systems that may modify CRF neuronal function or may be modified as a result of altered CRF neuronal function. We will test whether these models of "environmental programming" have similar neurobiological underpinnings in the Long Evans rat strain and the rhesus macaque monkey. In all of these studies, we will also evaluate whether there are gender-related differences to the consequences of early life stress. In the current pr6posal we will: (1) characterize the state of CRF and urocortin neural systems in these rat and primate models at different ages, (2) assess the responsivity of these systems to acute and chronic stressors in adult animals, (3) evaluate the ability of mechanistically distinct antidepressants to modify these systems when administered to adult animals or during the period of early life stress exposure, and (4) determine whether selective targeting of the CRF1 versus CRF2alpha receptor subtype modifies the biological and behavioral actions of early life stress,. Overall, by utilizing and being guided by findings from the other projects in this Center, these studies will seek to elucidate the neurobiological basis of how early life environmental influences lead to a vulnerability to psychiatric morbidity in adults that is already supported by clinical and epidemiological data.
|
1 |
2004 — 2008 |
Plotsky, Paul M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Laboratory Rat Core
The Rat Model Core (Core 9001) of the Emory University Silvio O. Conte Center for the Neuroscience of Mental Disorders (CCNMD) represents an integral component of the overall Center. This Core will serve as the source of all rodents used by individual preclinical Research Projects 1-4. This Core will produce and characterize variants of a rat early life stress (ELS) model associated with vulnerability to the development of an anxiety-and depression-like syndrome. Personnel will purchase or breed rodents, provide high quality animal care and uniformly applied neonatal manipulation protocols necessary to generate the ELS model, characterize the phenotype of all animals, ascertain the stage of the estrus cycle in adult female animals, and provide experimental manipulations as required by individual preclinical Research Projects within the Center. This ELS model consists of Long Evans rats which are exposed to different rearing conditions from postnatal days (PND) 2-12, including: (1) animal facility reared (AFR) colony controls, (2) brief handling plus 15 min maternal separation (HMS15) handling controls, (3) brief handling plus variable maternal separation (HMS180+). Comparison of data obtained from these standardized rearing conditions among the various basic Research projects of this CCNMD will permit identification of central neurocircuits and intracellular mechanisms which are impacted by early life stress and which give rise to this anxiety- and depression-like syndrome; furthermore, because the animal models will be standardized, regression modeling can be used to elucidate interactions among these CNS systems in the genesis of this condition. In addition, the efficacy of various manipulations or treatments on aspects of the anxiety- and depression-like syndrome will be tested in these models. An important aspect of these animals is comparison with the phenotype and other measures in the nonhuman primate model as well as in the human studies. To this end, Core 9001 will characterize the behavioral and HPA axis stress responsiveness of animals, provide phenotypic screening for anhedonia, anxiety-/fear-like behavior, as well as providing surgical services, resident intruder social defeat exposure, and other protocols as required by the Research Projects. This organization has the advantage of maintaining consistency in animal handling and implementation of all protocols so that each preclinical Research Project receives identically characterized and treated animals for study.
|
1 |
2004 — 2008 |
Plotsky, Paul M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Neuroregulators
Project 0001 of the Emory University Silvio O. Conte Center for the Neuroscience of Mental Disorders (CCNMD) represents an integral component of the overall Center. We have proposed four studies that in concept or data generated are interrelated to one another and to other basic and clinical projects in this Center proposal. The primary focus is on early life stress induced alterations in neurocircuits and their function. Briefly, the first study (Investigator: Paul M. Plotsky, PhD) extends our knowledge of sensitive periods in development and the sequence of neurocircuits that change in response to an unstable early environment using variations on the rat neonatal maternal separation paradigm. The studies will use behavioral, neuroendocrine (HPA axis function) and CNS gene expression as endpoints. We seek to clarify the relationship between behavioral alterations, HPA axis changes, and adaptations of other central circuits. The second study (Investigators: Kerry Ressler, MD, PhD, & Paul M. Plotsky, PhD) will directly address the role of early life stress induced up-regulation of extra-hypothalamic CRF systems and the locus coeruleus NE system using targeted retrovirus-mediated gene transfer of the rat CRF or tyrosine hydroxylase (TH) genes during different neonatal periods or in adulthood. The third study (Investigators: Donald Rainnie, Ph.DI, & Paul M. Plotsky, PhD)will address important functional issues by assessing how early life stress may alter the balance of signaling in the bed nucleus of the stria terminalis (BNST) such that stress-induced 5-HT input to this region shows a reversal from a stimulatory to inhibitory pattern resulting in a potentially maladaptive response to subsequent stressors. The fourth study (Investigators: M. Mar Sanchez, PhD, & Paul M. Plotsky, PhD) will begin postmortem analyses of gene expression and receptor binding in a sampling of rhesus monkey brains from our existing cohorts (see Conte Monkey Core 9003). Together, these components provide a multifaceted investigation of the long-term consequences of early life stress on neurocircuits in the rat and rhesus models. These data will be important for comparison and interpretation of imaging data obtained in the human studies. Furthermore, they may hold important theoretical implications and clinical relevance. The convergence of excellent animal models, sophisticated scientific questions, cutting edge techniques, and extraordinary expertise among the participants of this project and the Conte Center permit us to address the question of how early life stress affects selected neurocircuits and subsequent behavioral and neuroendocrine in a systematic way.
|
1 |