Kim Seroogy - US grants

Primary sensory neurons located along the length of the spinal cord in structures known as spinal ganglia convey information about the body (somatosensory information; e.g. pain, temperature) to the central nervous system. Defining the anatomical, biochemical, and molecular characteristics of these sensory nerve cells is prerequisite to determining their function. Dr. Seroogy has recently discovered that substantial subpopulations of spinal ganglion cells contain the biosynthetic machinery for an enzyme called tyrosine hydroxylase, an enzyme crucial for the synthesis of a class of chemical messengers called catecholamines. This finding raises the possibility that catecholamines play a role in the transfer and coding of sensory information from the body. The primary goals of the proposed research are to thoroughly characterize the organization of tyrosine hydroxylase (and catecholamines) within spinal ganglia and to determine the specific parts of the body that may be associated with catecholamine signalling. Dr. Seroogy will accomplish this by using molecular biological and neuroanatomical techniques. The results of these studies will add significantly to our understanding of the functional organization of catecholamines in spinal ganglia and will serve as the basis for future correlations with physiological studies in order to understand the involvement of catecholamines in transmitting sensory information.

DESCRIPTION: In animal models of Parkinson's disease and in some Parkinsonian patients, neural and paraneural transplants of dopamine- rich tissue into the striatum have been shown to mediate functional recovery. Little is understood, however, of the mechanisms underlying the improvement of functional parameters. As an alternative to the traditional view that graft dopamine secretion accounts for the behavioral and neurochemical improvement, the trophic factor hypothesis of functional recovery following transplantation proposes that recovery occurs through graft-induced, trophic factor-mediated, modulation of injured host neural systems. The goal of the proposed research is to test aspects of this hypothesis by determining if neurotrophic factor production by tissue grafts or host mesostriatal system is a predictor of functional recovery in a rat model of Parkinson's disease. The studies will focus on the analysis of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), transforming growth factor-a TGFa), and glial cell line-derived neurotrophic factor (GDNF). These neurotrophic molecules have been shown to support dopaminergic neurons in vitro and in vivo, and are present within the mesostriatal system in vivo. Moreover, preliminary work from the applicant's laboratory indicates that mRNAs for BDNF and its receptor trkB are present within mesencephalic grafts subsequent to striatal implantation in normal rat. The first specific aim of these studies will examine neurotrophic factor expression in the 6-hydroxydopamine (6-OHDA)-lesioned rat subsequent to intrastriatal implantation of fetal mesencephalic grafts. The second two specific aims will directly test the hypothesis that trophic factors produced by the transplant ameliorate functional deficits by (a) implanting fetal midbrain tissue derived from recently developed "knockout" mice lacking a functional BDNF or NT-3 gene, or (b) by infusing trophic factors, into denervated rat striatum. In situ hybridization of cRNA probes will be used in all experiments to evaluate levels, regional distribution, and cellular localization of neurotrophic factor mRNAs in appropriate donor transplant tissue and in host striatum and ventral mesencephalon. Trophic factor expression will be correlated with amelioration of functional deficits as well as with neurochemical measures of dopamine metabolism. Overall, the proposed experiments should add significantly to our understanding of the properties of the mesostriatal system in 6-OHDA-lesioned rats. In particular, these studies will provide insight into processes underlying plasticity and regeneration associated with functional recovery following neural grafting and trophic factor administration. (From the Abstract)

This award supports participation of graduate and postdoctoral students to present their research at the Summer Neuropeptide Conference. Neuropeptides are molecular compounds that are known in many cases to have effects on modulating the activity of the brain and behavior. The meeting is not huge, and so it represents an excellent opportunity for young scientists to make important contacts with other scientists doing related work, to exchange the latest information on theories and techniques, and to develop new collaborations, including international ones. The NSF joins several other donors and agencies in giving partial support to this meeting, with an emphasis on the NSF mission of promoting infrastructure to develop the careers of young scientists. The travel awards will have a substantial impact on the careers of the young scientists who are able to attend.

Request is being made from the National Institute on Drug Abuse to sponsor the symposium titled "Neuropeptides and Drug Addiction: Recent Developments in Corticotropin-Releasing Factor Research" to be held as a part of the 1999 Summer Neuropeptide Conference to be held in Key West, Florida from June 27-July 1. The goal of the symposium is to bring together leaders in the fields of peptide and drug abuse research to discuss their latest findings of the role of the neuropeptide CRF in drug abuse. This symposium will provide important, timely information to aid in understanding the mechanisms of drug addiction and withdrawal, and will focus on neuropeptide and neuroendocrine systems, including the HPA axis, as mediators of reward and addiction. Specifically, we are requesting funds for meeting expenses for the five invited speakers in this symposium, and for several graduate student/predoctoral trainee travel awards, for a total request of $11,600. The Summer Neuropeptide Conference, now in its ninth year, has become one of the premier international meetings for neuropeptide research. The conference highlights major new advances in neuropeptide research and attracts a good mixture of senior and junior participants from academia and industry throughout the world. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The formal of the conference involves morning and evening symposia, a poster session, a conference banquet, and a plenary lecture by a distinguished scientist. The format, coupled with the informal setting, provides an ideal forum for the exchange of current information and the development of new collaborations among the participants.

DESCRIPTION: (Verbatim from the Applicant's Abstract) Request is being made from the National Institute of Mental Health to sponsor the symposium title "Peptides and Posttraumatic Stress Disorder" to be held as a port of the 1999 Summer Neuropeptide Conference to held in Key West, Florida from June 27-July 1. The goal of the symposium is to bring together leaders in the field of mental health research to discuss their latest findings of the relationship of specific neuropeptides to posttraumatic stress disorder (PTSD). This symposium will provide important, timely information to aid in understanding the pathophysiology and neurochemical basis of anxiety disorders, such as PTSD. Specifically, we are requesting funds for meeting expenses for the five speakers in this symposium, for several student/postdoctoral trainee travel awards, and for partial travel expenses of the keynote speaker, for a total request of $12,500. The Summer Neuropeptide Conference, now in its ninth year, haw become one of the premier international meetings for neuropeptide research. The conference highlights major new advances in neuropeptide research and attracts a good mixture of senior and junior participants from academia and industry form throughout the world. Active participation by graduate and postdoctoral trainees, as well a by women and minority scientist, is strongly encouraged. The format of the conference involves morning and evening symposia, a poster session, a conference banquet, and a plenary lecture by a distinguished scientist. This format, coupled with the informal setting, provides an ideal forum for the exchange of current information and the development of new collaborations among the participants.

DESCRIPTION (From the applicant's abstract): Parkinson's disease is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons in the ventral midbrain. Although the basic underlying mechanisms of this debilitating movement disorder remain unknown, considerable efforts have centered on developing effective strategies for halting the neurodegenerative process and restoring normal function. One promising approach involves the use of neurotrophic factors, proteins that promote the survival and proper functioning of select populations of neurons. Preliminary findings from our laboratory show that receptor mRNA and protein for a relatively novel group of trophic factors called neuregulins are synthesized within the dopaminergic nigrostriatal system in rodents and primates. We find that supranigral administration of neuregulin induces increased dopamine overflow in the striatum, indicating functional effects upon the dopaminergic nigrostriatal system. Our recent data also indicate that neuregulin treatment protects dopaminergic cells against neurotoxin-induced degeneration in vivo, and against both oxidative and metabolic insults in vitro. In the proposed research, we will expand upon these findings to test the overall the hypothesis that neuregulins are neuroprotective and/ or neurorestorative for midbrain dopaminergic neurons upon selective neurotoxic damage. Specific Aim #1 will determine the extent to which neuregulin receptors are expressed by dopaminergic cells in the ventral mesencephalon of normal and neurotoxin-lesioned rat and monkey using single- and double-labeling in situ hybridization and immunocytochemical techniques. Specific Aim #2 will use a well-characterized rat model of Parkinson's disease coupled with specific neuregulin treatment regims to test if infusion of neuregulins (I) protects dopaminergic neurons from subsequent neurotoxic damage or (ii) promotes functional recovery of the injured nigrostriatal system after neurotoxic damage. Morphological, behavioral and neurochemical approaches will be used to analyze the extent of protection and/or functional restoration afforded by neuregulin treatment. Specific aim #3 will (I) determine if neuregulin receptor expression is spatially or temporally deficient in the rat and monkey nigrostriatal system in aged animals, and (ii) using intracerebral microdialysis, evaluate the responsiveness of the dopaminergic nigrostriatal system to neuregulin administration in young, middle age and old rats. Specific aim #4 will assess the potential mechanisms by which neuregulin protects dopaminergic cells from insults relevent to Parkinson's disease. Overall, these studies will assess the therapeutic value of neuregulin trophic factors for the treatment of Parkinson's disease and other neurodegenerative disorders of the nigrostriatal system.

DESCRIPTION (Provided by applicant): On behalf of the American Summer Neuropeptide Conference, request is being made from the National Institute on Aging to sponsor the symposium titled A1zheimer's Disease to be held as a part of NEUROPEPTIDES 2001, the 2nd Joint Meeting of the European Neuropeptide Club and the Summer Neuropeptide Conference. This joint international meeting will be held in Jerusalem and Tel Aviv, Israel, from May 7-12, 2001. The goal of the symposium is to bring together leaders in the fields of peptides and aging disorders research to discuss their latest findings on the relationship of neuropeptides to Alzheimer's disease. This symposium will provide important, timely information to aid in understanding the pathophysiology and neurochemical basis of Alzheimer's disease. Neuropeptide-related topics will range from basic molecular mechanisms to potential therapeutics of neuropeptides in the treatment of the debilitating aging disorder. Specifically, we are requesting funds for meeting expenses for several invited speakers in this symposium, and for several graduate student/postdoctoral trainee travel awards, for a total request of $12,600. The Summer Neuropeptide Conference, now in its eleventh year, and its counterpart the European Neuropeptide Club, also in its eleventh year, have become the premier international meetings for neuropeptide research. The conferences highlight major new advances in neuropeptide research and attract a good mixture of senior and junior participants from academia and industry from throughout the world. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The format of the present joint conference involves morning, afternoon and evening symposia, poster sessions, conference dinners, and special lectures by distinguished scientists. This format, coupled with the informal setting, provides an ideal forum for the exchange of current information and the development of new collaborations among the participants.

On behalf of the Summer Neuropeptide Conference, request is being made from the National Institute on Drug Abuse to support several competitive student travel awards to the 2002 Summer Neuropeptide Conference to be held June 29-July 3, 2002 at Marco Island, Florida. Specifically, we are requesting funds in the amount of $4,750 to help defray meeting expenses of several graduate student and postdoctoral trainees who will participate in the conference and interact with established leaders in fields related to the mission of the National Institute on Drug Abuse. The title of the NIDA-related symposium at the meeting is "Neuropeptides and Drug Addition", and includes investigators whose research is currently funded by NIDA. This symposium is designed to present the latest state-of-the-art research on the role of neuropeptides in mechanisms of drug addiction and withdrawal. This will be an invaluable opportunity to expose student and junior neuroscience researchers to senior scientists actively engaged in NIDA-related research. The Summer Neuropeptide Conference, now in its twelfth year, has become one of the premier international meetings for neuropeptide research. The conference highlights major new advances in neuropeptide research and attracts a good mixture of senior and junior participants from academia and industry from throughout the world. A significant focus of recent meetings is to include sessions related to peptides and drug abuse, and this has been done again for the 2002 conference. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The format of the conference involves morning and evening symposia, a poster session, a conference banquet, and a plenary lecture by a distinguished scientist. This format, coupled with the informal setting, provides an ideal forum for the exchange of current information and the development of new collaborations among the participants.

DESCRIPTION (provided by applicant): On behalf of the American Summer Neuropeptide Conference request is being made from the National Institute on Aging to partially sponsor the symposium titled "Alzheimer's Disease" to be held as part of NEUROPEPTIDES 2003, the 3rd Joint Meeting of the American Summer Neuropeptide Conference and the European Neuropeptide Club. This joint international meeting will be held in Montauk, New York, USA from June 8-12, 2003. The goal of the symposium is to bring together leaders in the field of peptides and aging disorders to discuss their latest findings on the roles of neuropeptides in Alzheimer's disease. This symposium will provide important, state-of-the-art research on the pathophysiology and biochemical basis of AIzheimer's disease in the context of neuropeptides. Topics will range from basic molecular mechanisms to potential neuroprotective and therapeutic applications of neuropeptides in neurodegenerative disorders, with an emphasis on Alzheimer's disease. Specifically, we are requesting funds to help defray meeting expenses of several invited speakers in this symposium and of several graduate student and postdoctoral trainees who will participate in the conference and interact with established leaders in fields related to the mission of the National Institute on Aging. The total amount requested is $11,650. The American Summer Neuropeptide Conference, now in its thirteenth year, and its counterpart the European Neuropeptide Club. The conferences highlight major new advances in neuropeptide research and attract a good mixture of senior and junior participants from academia and industry from throughout the world. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The format of the present joint conference involves morning, afternoon and evening symposia, poster sessions Club, also in its thirteenth year, have become the premier international meetings for neuropeptide research, an award ceremony and conference banquet, and special lectures by distinguished international scientists. This format, coupled with the informal setting, provides an ideal forum for the dissemination and exchange of current information and the development of new collaborations among the participants.

DESCRIPTION (provided by applicant): On behalf of the American Summer Neuropeptide Conference, request is being made from the National Institute on Drug Abuse to support several competitive young investigator awards to NEUROPEPTIDES 2003, the 3rd Joint Meeting of the American Summer Neuropeptide Conference and the European Neuropeptide Club. This joint international meeting will be held in Montauk, New York, USA from June 8- 12, 2003. Specifically, we are requesting funds in the amount of $4,500 to help defray meeting expenses of several graduate student and postdoctoral trainees who will participate in the conference and interact with established leaders in fields related to the mission of the National Institute on Drug Abuse. In the NIDA related symposium at the meeting, "Neuropeptides in the Pathogenesis and Control of Pain", leading scientists in the field will present the latest state-of-the-art research on the role of neuropeptides in the etiology and maintenance of pain. This will be an excellent vehicle by which promising graduate student and postdoctoral trainees are exposed to senior scientists actively engaged in NIDA-related research in an intimate setting. The American Summer Neuropeptide Conference, now in its thirteenth year, and its counterpart the European Neuropeptide Club, also in its thirteenth year, have become the premier international meetings for neuropeptide research. The conferences highlight major new advances in neuropeptide research and attract a good mixture of senior and junior participants from academia and industry from throughout the world. Active participation by graduate and postdoctoral trainees, as well as by women and minority scientists, is strongly encouraged. The format of the present joint conference involves morning, afternoon and early evening symposia, poster sessions, an award ceremony and conference banquet, and special lectures by distinguished international scientists. This format, coupled with the informal setting, provides an ideal forum for the dissemination and exchange of current information and the development of new collaborations among the participants.

DESCRIPTION (provided by applicant): Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quality of life than the debilitating motor symptoms. Although the etiology of depression in PD is unknown, understanding the potential pathophysiological processes and deleterious consequences of these co-morbidities is of high importance, and may lead to the development of novel treatment therapies. Currently, models aimed at deciphering the complex neurobiological interactions of PD and depression are lacking. In the proposed studies, we will combine the unilateral 6-hydroxydopamine rat model of PD with a widely accepted rat model of stress-induced depression symptomology (chronic variable stress model), to test the hypothesis that experimental depression exacerbates the neurodegeneration and associated dysfunction of the injured mesostriatal dopaminergic system as evaluated by functional, morphological, neurochemical, and gene expression analyses. SPECIFIC AIM #1 will determine if stress-induced depression either following, preceding, or flanking neurotoxin lesioning exacerbates behavioral symptoms and dopaminergic neuronal degeneration and related behavioral and neurochemical sequelae in the injured mesostriatal system. SPECIFIC AIM #2 will assess whether antidepressant treatments improve or hinder midbrain dopaminergic neuron survival and associated parameters in the combined PD/chronic stress-induced depression model. SPECIFIC AIM #3 will determine if experimental induction of depression exacerbates behavioral and neurochemical dysfunction and dopaminergic neuronal degeneration to a greater extent in the injured mesostriatal system of old vs. young animals. To test a potential mechanism of action, SPECIFIC AIM #4 will use a glucocorticoid receptor antagonist currently in clinical trials for treatment of depression to determine if endogenous glucocorticoids released during stress mediate the deleterious effects of stress-induced depression in the injured mesostriatal system. In the context of the dopaminergic mesotelencephalic system, each of these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immunohistochemistry, HPLC analysis of dopamine and its metabolites, and in situ hybridization for dopamine- associated neurotrophic factors and apoptotic factors. The overall goal of this project is to gain functional, morphological and mechanistic insight into the co-morbidity of PD, stress and depression. Moreover, this research may lead to future therapies that alleviate affective as well as motor symptoms of PD. PUBLIC HEALTH RELEVANCE: Almost half of all patients with Parkinson's disease, the second-most common neurodegenerative disease in the US, experience coexisting major depression. The present research will investigate whether having depression worsens motor symptoms and hastens brain cell death in PD. This work will help us understand the underlying brain circuits, chemicals and mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.

Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quaUty of life than the debilitating motor symptoms. Although the etiology of depression in PD is unknown, understanding the potential pathophysiological processes and deleterious consequences of these co-morbidities is of high importance, and may lead to the development of novel treatment therapies. Currently, models aimed at deciphering the complex neurobiological interactions of PD and depression are lacking. In the proposed studies, we will combine the intrastriatal 6-hydroxydopamine rat model of PD with a widely accepted rat model of stress-induced depression symptomology (chronic variable stress model), to test the hypothesis that experimental depression exacerbates the neurodegeneration and associated dysfunction of the injured nigrostriatal dopaminergic system via deleterious glucocorticoid mechanisms as evaluated by functional, morphological, neurochemical, and gene expression analyses. To test potential mechanisms by which depression may increase nigrostriatal vulnerability, SPECIFIC AIM #1 will evaluate the necessity and sufficiency of glucocorticoids in dopaminergic degeneration and motor dysfimction, and determine plausible molecular correlates contributing to the enhanced degeneration. In the context of the dopaminergic mesotelencephalic system, these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immimohistochemistry, unbiased stereology, HPLC analysis of dopamine and its metabolites, and custom PCR arrays. The overall goal of this project is to gain functional, morphological and mechanistic insight into the co-morbidity of PD, stress and depression. Moreover, this research may lead to future therapies that ameliorate alTective as well as motor symptoms of PD. RELEVANCE (See instmctions): Almost half of all patients with Parkinson's disease experience coexisting major depression. The present research will investigate whether having abnormal levels of stress hormones is a mechanism by which depression worsens motor symptoms and accelerates nerve cell death in PD. This work will help us understand the underlying mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.