CRH-MRNA REGULATION-- ROLE IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R01NS028912-10 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: adapted from applicant s ) The current proposal focuses on mechanisms and consequences of early-life seizures that are provoked by proconvulsant stressors such as fever (hyperthermia) and hypoxia. These non-genetic triggered seizures constitute the majority of developmental seizures. While the outcome of simple febrile seizures is generally benign, and the outcome of many developmental seizures depends on their etiology, emerging evidence in both human and animals indicates that prolonged febrile seizures and recurrent triggered seizures may be associated with neuronal injury. has demonstrated that the stress-activated neuropeptide, corticotropin releasing hormone (CRH), a well established key mediator of the CNS stress-response, acts as a powerful, age-specific convulsant in the developing brain and promotes injury of hippocampal neurons. Thus, CRH may play a role in the mechanisms by which triggered developmental seizures influence neuronal integrity. During the recent funding period, established the presence of a significant population of CRH-expressing interneurons in the developing hippocampus and the mechanisms by which CRH interacts with glutamate receptor activation to enhance hippocampal excitability. In addition, recent findings suggest that (1 ) pro-convulsant stressors may increase CRH expression in limbic regions and (2) excessive CRH-receptor activation during early-life may result in significant long-term consequences on hippocampal integrity and function. Therefore, the proposed research tests the hypothesis that proconvulsant stressors increase CRH levels in hippocampus resulting in augmentation by the peptide of excitotoxic mechanisms. to enhance neuronal injury and lead to long-term hippocampal dysfunction. Four experiments are proposed to test this hypothesis 1 ) studying-using in situ hybridization and immunocytochemistry- whether proconvulsant stressors enhance CRH-expression and levels in hippocampus. Studying the unique mechanisms by which CRH leads to hippocampal neuronal death using (2) in vivo and (3) in vitro dissociated hippocampal cell approaches, and, 4) Examining the significant long-term consequences of excessive CRH-dependent excitation during early life, focusing on hippocampal neuronal loss and hippocampal-dependent cognitive dysfunction. The significance of the proposed studies derives from their focus on mechanisms and consequences of early life provoked seizures that constitute the majority of developmental seizures, but remain relatively unstudied. The proposed studies, delineating age-specific mechanisms for seizure-related neuronal injury and its consequences should lead to the development of novel, age-appropriate, specific therapies to prevent these consequences.
Keywords: corticotropin releasing factor, epilepsy, febrile seizure, hormone regulation /control mechanism, newborn animal, physiologic stressor, cell death, convulsant, developmental neurobiology, genetic regulation, glutamate receptor, hippocampus, hormone receptor, hyperthermia, hypoxia neonatorum, interneuron, messenger RNA, neuroanatomy, neurotoxicology, pyramidal cell, receptor expression, immunocytochemistry, in situ hybridization, laboratory rat, tissue /cell culture
Project start date: 1992-03-01
Project end date: 2005-02-28
5R01NS028912-10 (2003): $300800
Sponsored Links Excellgen http://Excellgen.com
CRH-MRNA REGULATION--IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Children s Hospital Los Angeles Los Angeles, Ca 900276062
Grant 5R01NS028912-03 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: This project studies the regulation of CRH gene expression by glucocorticoids (GCs) in neonatal rats. It will test the hypothesis that the negative effect of GCs on CRH gene expression (present in adult rats) is not operative in neonates. CRH, an ENDOGENOUS convulsant, is more potent and rapid-acting in neonates, when the peptide s gene expression is low, compared to adults. The project tests the hypothesis that the low CRH gene expression in the neonate contributes to the enhanced convulsant potency of CRH in this age. A specific GC-receptor antagonist (RU-38486) will be implanted adjacent to the paraventricular nucleus of neonatal rats starting on the third postnatal day. CRH-mRNA abundance in implanted rats will be compared to littermate controls using semi-quantitative in situ hybridization (ISH), and the earliest age at which GC-blockade increases CRH gene expression will be determined. The abundance of GC-receptor gene expression, and the effects of Ru-38486 will be examined (using ISH). The effects of experimentally increasing CRH gene expression, via RU- 38486 implantation, on the convulsant responses of neonatal rats to CRH will be determined. Electrographic recording using bipolar electrodes from cortex, amygdala and hippocampus will allow precise definition and localization of the neuroanatomic origin of CRH- induced seizures. These studies will yield important information relevant to human neonatal epilepsy A better understanding of CRH gene expression and the epileptic properties of this ENDOGENOUS CONVULSANT in the neonate will help elucidate mechanisms of age-specific neonatal seizures, some of which respond to modulation of the CRH-GC feedback loop. In addition, it will provide insight into intrinsically important issues of neuropeptide regulation in the neonatal brain.
Keywords: corticotropin releasing factor, gene expression, generalized seizure, hormone regulation /control mechanism, age difference, amygdala, corticosteroid receptor, hippocampus, inhibitor /antagonist, messenger RNA, neuroanatomy, paraventricular nucleus, receptor expression, dosage, electroencephalography, in situ hybridization, laboratory rat, newborn animal
Project start date: 1992-03-01
Project end date: 1996-02-28
5R01NS028912-03 (1994): $223175
5R01NS028912-02 (1993): $185627
CRH-mRNA Regulation: Role In Neonatal Seizure Potential
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Pediatricsuniversity Of California Irvine
irvine, Ca 926977600
Grant 5R01NS028912-14 from National Institute Of Neurological Disorders And Stroke IRG: DBD
Abstract: The overall goal of this proposal is to determine the role of the stress-neuromodulator corticotropin releasing hormone (CRH) in early-life neuroplasticity that contributes to neurological disease. Studies during previous funding periods have demonstrated that central administration of synthetic CRH to infant rats led to long-term deficits of hippocampus mediated cognitive function, similar to those described after severe early-life stress in human infants. We have also demonstrated the presence of the ´cellular machinery´ for endogenous CRH in immature hippocampus, i.e., substantial populations of CRH-expressing interneurons and abundant CRH receptors on hippocampal pyramidal cells innervated by these interneurons. Therefore, the current proposal aims to definitively test the hypothesis that enduring upregulation and excessive release of endogenous hippocampal CRH contribute crucially to the impaired functional integrity of the hippocampus following early-life adverse events such as chronic psychological stress or recurrent seizures. The driving hypothesis of this research is that certain stresses occurring during a period of heightened hippocampal plasticity elevate the ´set-point´ of hippocampal CRH expression, increasing the peptide´s levels in hippocampus longterm. Therefore, subsequent, acute stress at any point in life will evoke ´excessive´ release of CRH from hippocampal interneurons. Pathological levels of CRH provoke acute and long-term hippocampal neuronal dysfunction, associated with synaptic reorganization. This research proposal focuses on understanding this process at the synaptic, cellular and system levels, defining the means for interrupting the deleterious actions of excessive endogenous CRH on hippocampal function and integrity. Therefore, the proposal aims to (1) Investigate the effects of early-life (P2-P9) chronic ´psychological1 stress on hippocampal CRH expression long-term. (2) Delineate the unique synaptic machinery by which CRH (an excitatory neuropeptide), is stored in inhibitory interneurons, define the site of the postsynaptic elements mediating the peptide´s actions, and determine whether stress activates post-synaptic hippocampal pyramidal cells via the release of endogenous CRH. (3) Characterize the functional, electrophysiological and structural hippocampal changes induced by early-life chronic psychological stress in a novel model. (4) Determine whether these effects of early-life stress are abrogated by blocking the actions of endogenous, stress-released CRH; in other words, whether the endogenous peptide is a required, crucial mediator of the enduring, life-long adverse effects of early-life stress on hippocampal functional integrity. These studies address the impact of early-life chronic psychological stress, such as child abuse and neglect (and perhaps recurrent seizures), on critical learning & memory functions. By defining the role of the stress-activated neuropeptide, CRH, in the mechanisms of the established adverse effects of these early-life events, these studies will provide truly innovative and exciting targets for prevention of a tremendous loss of human potential
Keywords: corticotropin releasing factor, gene expression, genetic regulation, hippocampus, molecular psychobiology, neural plasticity, neuropsychology, neuroregulation, psychological stressor evoked potential, interneuron, long term potentiation, memory, messenger RNA, neural information processing, neuroanatomy, pyramidal cell, visual perception behavior test, immunoelectron microscopy, in situ hybridization, laboratory rat
Project start date: 1992-03-01
Project end date: 2009-08-28
5R01NS028912-14 (2008): $267506
5R01NS028912-13 (2007): $267506
5R01NS028912-12 (2006): $275496
CRH-MRNA REGULATION--ROLE IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R01NS028912-06 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: Applicant s ) The immature brain is more susceptible to seizures than the adult brain. This is particularly true for seizures induced by stressful environmental signals such as fever or trauma. Understanding the mechanisms underlying this age-dependent sensitivity is critical for development of treatments for seizures in infants and children. This proposal focuses on the effects of neuroendocrine stress mechanisms on seizure susceptibility in the infant. has developed models for studying the effects of corticotropin releasing hormone (CRH), a neuroendocrine mediator of stress, on seizure susceptibility in the infant animal. has shown that CRH promotes infant seizures; conditions which enhance the peptide s activity should augment seizure-induction. Therefore, the tested hypothesis states that cold stress increases CRH-mediated neurotransmission in limbic neurons of the infant rat. This occurs via enhanced CRH synthesis in the amygdala and/or via upregulation of one or both types of CRH receptors in amygdala and hippocampus, and leads to potentiation of limbic seizures, such as those induced by kainate. Four experiments are proposed to test this hypothesis i) Examination, using the established paradigms of cold stress and limbic seizures, whether cold facilitates kainate seizures in infant rats, and if this is blocked by CRH antagonists. ii) Confirmation and extension of pilot data that CRH facilitates kainate seizures. iii) Determination, using in situ hybridization, whether cold stress increases CRH synthesis and content in the amygdala of the infant rat, and augments synthesis of both novel types of CRH receptors in limbic target neurons. iv) Study of the regulation of CRH gene expression by stress-induced activation of the transcription factor, CREB, using gel-retardation assays and specific immunocytochemistry. This experimental approach is unique in focusing on the interface of environmental stress and epilepsy in the developing brain. The CRH paradigm will enhance the knowledge of the regulation and role of neuropeptides during a critical and little studied period of the developing brain, and may help clarify mechanisms of the enhanced seizure susceptibility at this age. These studies may shed light on mechanisms of human age-specific seizures such as febrile seizures and infantile spasms.
Keywords: cold temperature, corticotropin releasing factor, epilepsy, gene induction /repression, newborn animal, physiologic stressor, amygdala, cAMP response element binding protein, hormone receptor, kainate, neuropharmacology, nucleic acid probe, oligonucleotide, receptor expression, gel mobility shift assay, immunocytochemistry, in situ hybridization, laboratory rat
Project start date: 1992-03-01
Project end date: 2000-05-31
5R01NS028912-06 (1998): $200466
5R01NS028912-05 (1997): $197311
CRH-MRNA REGULATION-- ROLE IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R01NS028912-09 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: adapted from applicant s ) The current proposal focuses on mechanisms and consequences of early-life seizures that are provoked by proconvulsant stressors such as fever (hyperthermia) and hypoxia. These non-genetic triggered seizures constitute the majority of developmental seizures. While the outcome of simple febrile seizures is generally benign, and the outcome of many developmental seizures depends on their etiology, emerging evidence in both human and animals indicates that prolonged febrile seizures and recurrent triggered seizures may be associated with neuronal injury. has demonstrated that the stress-activated neuropeptide, corticotropin releasing hormone (CRH), a well established key mediator of the CNS stress-response, acts as a powerful, age-specific convulsant in the developing brain and promotes injury of hippocampal neurons. Thus, CRH may play a role in the mechanisms by which triggered developmental seizures influence neuronal integrity. During the recent funding period, established the presence of a significant population of CRH-expressing interneurons in the developing hippocampus and the mechanisms by which CRH interacts with glutamate receptor activation to enhance hippocampal excitability. In addition, recent findings suggest that (1 ) pro-convulsant stressors may increase CRH expression in limbic regions and (2) excessive CRH-receptor activation during early-life may result in significant long-term consequences on hippocampal integrity and function. Therefore, the proposed research tests the hypothesis that proconvulsant stressors increase CRH levels in hippocampus resulting in augmentation by the peptide of excitotoxic mechanisms. to enhance neuronal injury and lead to long-term hippocampal dysfunction. Four experiments are proposed to test this hypothesis 1 ) studying-using in situ hybridization and immunocytochemistry- whether proconvulsant stressors enhance CRH-expression and levels in hippocampus. Studying the unique mechanisms by which CRH leads to hippocampal neuronal death using (2) in vivo and (3) in vitro dissociated hippocampal cell approaches, and, 4) Examining the significant long-term consequences of excessive CRH-dependent excitation during early life, focusing on hippocampal neuronal loss and hippocampal-dependent cognitive dysfunction. The significance of the proposed studies derives from their focus on mechanisms and consequences of early life provoked seizures that constitute the majority of developmental seizures, but remain relatively unstudied. The proposed studies, delineating age-specific mechanisms for seizure-related neuronal injury and its consequences should lead to the development of novel, age-appropriate, specific therapies to prevent these consequences.
Keywords: corticotropin releasing factor, epilepsy, febrile seizure, hormone regulation /control mechanism, newborn animal, physiologic stressor, cell death, convulsant, developmental neurobiology, genetic regulation, glutamate receptor, hippocampus, hormone receptor, hyperthermia, hypoxia neonatorum, interneuron, messenger RNA, neuroanatomy, neurotoxicology, pyramidal cell, receptor expression, immunocytochemistry, in situ hybridization, laboratory rat, tissue /cell culture
Project start date: 1992-03-01
Project end date: 2004-06-30
5R01NS028912-09 (2002): $382016
5R01NS028912-08 (2001): $382016
Grants awarded to Tallie Z Baram
EPILEPSY RESEARCH TRAINING PROGRAM
Tallie Z Baram, Professor & Endowed Chair
University Of California Irvine, Irvine, Ca 92697-7600
Grant 2T32NS045540-06A1 from National Institute Of Neurological Disorders And Stroke
Abstract: This revised submission requests renewed support for an Institutional Postdoctoral Training Program, to enable recruitment and education of four Trainees per year for careers in research areas germane to the neurobiology, co-morbidities and cure of human epilepsy. The proposed training will take place in the laboratories of 12 preceptors from five departments, and will include Program-specific courses and clinical-translational field trips, as well as seminars, discussion groups and symposia. The first four years of this Program have been rewarding, as the eight Program graduates all remain in Academia Two are now Assistant Professors in the tenure track, one is a faculty instructor, two are faculty in partially-independent positions at UCI, and two are pursuing additional post-doctoral fellowships to round out their education in epilepsy research. Altogether, twelve excellent Trainees have been enrolled to date, including two of under-represented groups, one MD and seven women. These initial outcome data, together with the comprehensive restructuring of the Program, the addition of Program-specific courses and clinic-oriented field trips, and the recent availability of an MD trainee pool in the Department of Neurosurgery, will enable this Program to provide postdoctoral PhDs and MDs with a structured and nurturing training environment for careers in research relevant to epilepsy. Although epilepsy is the third most common chronic brain disorder, it remains relatively understudied, and the current Program is one of only two epilepsy-focused postdoctoral Training Programs in the U.S
Keywords: Epilepsy; Epileptic Seizures; Epileptics; Research Training; Seizure Disorder; Training Programs; epilepsia; epileptiform; epileptogenic
Project start date: 2003-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-06-468
2T32NS045540-06A1 (2009): $172150
Febrile Seizure Model - Neuronal Injury And Mechanisms
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 2R37NS035439-09A1 from National Institute Of Neurological Disorders And Stroke IRG: CND
Abstract: This revised competitive renewal proposal focuses on the mechanisms by which febrile seizures (FS), the most prevalent seizure type in infants and children, may lead to Epilepsy. has characterized an immature rat model of prolonged FS, those associated with subsequent development of limbic, temporal lobe epilepsy (TLE) in human studies. During the current award period, it was discovered that experimental prolonged FS lead to limbic epilepsy in approximately 35% of animals, establishing the paradigm as a valid model of developmental epileptogenesis. In addition, these seizures induced changes in the expression and co- assembly of specific ion channels, the hyperpolarization-activated, cyclic nucleotide gated (HCN) channels, that promoted hippocampal hyper-excitability. Remarkably, changes in the expression and in the relative abundance of the same members of the HCN channel family were found also in human hippocampus from individuals with TLE and a history of early-life seizures, confirming the relevance of molecular changes in these channels to clinical epileptogenesis. The current proposal aims to address important gaps in our understanding of the epileptogenic process bridging prolonged FS and limbic epilepsy 1) First, in vitro systems will be used to determine how these developmental seizures lead to down-regulation of the HCN1 isoform expression and increased expression of HCN2, by testing hypotheses about seizure-evoked, calcium-mediated cellular cascades influencing coordinate HCN isoform expression; 2) To determine how seizures evoke re-arrangements of HCN channel molecules into heteromeric channels that promote hyper-excitability the role of post-translational glycosylation of the channels in the expression of heteromeric channels will be studied in vitro; 3) Finally, in vivo experiments will investigate the parameters of the inciting FS that govern epileptogenesis, aiming to generate a more powerful model, where seizures elicit epilepsy in the majority of rats. Public health relevance (lay language) Epilepsy is the most common chronic brain disorder in young individuals. Temporal lobe epilepsy is the most refractory epilepsy, and is associated with early-life prolonged febrile seizures. Understanding the steps and the mechanisms by which febrile seizures convert a normal hippocampus to an epileptic one is a critical first step in intercepting the epilepsy-generating process resulting in temporal lobe epilepsy.
Keywords: febrile seizure, gene expression, hippocampus, membrane channel, pathologic process, developmental neurobiology, disease /disorder model, neural plasticity, neural transmission, infant animal, laboratory rat
Project start date: 1997-04-01
Project end date: 2010-06-30
2R37NS035439-09A1 (2006): $338153
5R37NS035439-12 (2009): $326392
3R37NS035439-11S1 (2009): $153628
5R37NS035439-11 (2008): $315649
5R37NS035439-10 (2007): $327768
Febrile Seizure Model: Neuronal Injury And Mechanisms
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R01NS035439-08 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: This proposal focuses on the mechanisms and consequences of febrile seizures, the most prevalent seizure type in young children. An immature rat model of prolonged febrile seizures, those associated with potential development of limbic epilepsy, has been characterized, and has already shed considerable light on the neuroanatomical basis of these seizures and on their functional consequences. Importantly, it was established that experimental prolonged febrile seizures lead to long-lasting enhanced hippocampal excitability. Surprisingly, this increased excitability was associated with persistent increase in GABA-mediated inhibition of CA1 pyramidal cells. A resolution to this apparent paradox derives from preliminary data showing functional changes in the Hyperpolarization-activated Cation-Nonselective channels (HCNs) in CA1 pyramidal cells of immature rats who had experienced experimental febrile seizures Slowed HCN channel kinetics permit increased Na+ entry, depolarizing the cell to promote action potential firing, essentially converting the potentiated inhibition to hyper-excitability. Importantly, slowing of HCN kinetics is consistent with a quantitative shift in the subunit make-up of these recently cloned channel molecules, and preliminary mRNA expression data support this notion. Therefore, this proposal will test the hypothesis that experimental prolonged febrile seizures modulate the expression of HCN channel molecules and disrupt their normal developmental expression patterns, leading to persistently enhanced excitability. Three experiments are proposed 1) To determine the developmental spatio-temporal expression profiles of the 4 HCN subunit isoforms in defined hippocampal cell populations and single neurons, providing the foundation for probing effects of the seizures; (2) To determine the effects of the seizures on HCN expression in defined individual cells and neuronal populations in vivo; 3) To use an in vitro organotypic hippocampal culture to determine the mechapisms for seizure-induced alteration of HCN isoform expression and the consequent ?neuroplastic? changes in hippocampal excitability. The proposed studies should provide novel and important insight into the remarkable age-and seizure-specific effects of prolonged experimental febrile seizures on the developing hippocampus, changes leading to enhanced excitability long-term. In addition, these studies should contribute to our understanding of fundamental aspects of the functional anatomy of these newly characterized ion channel molecules in developing hippocampus, leading to the definition of the roles of these pacemaker channels in the development of the synchronized hippocampal network.
Keywords: febrile seizure, gene expression, hippocampus, membrane channel, pathologic process, developmental neurobiology, disease /disorder model, neural plasticity, neural transmission, infant animal, laboratory rat
Project start date: 1997-04-01
Project end date: 2006-07-04
5R01NS035439-08 (2005): $311328
5R01NS035439-07 (2004): $298728
5R01NS035439-06 (2003): $298728
2R01NS035439-05 (2002): $251536
Sponsored Links Excellgen http://Excellgen.com
MRI Predicts Epileptogenesis And Cognitive Deficits
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R21NS049618-02 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Abstract: The proposed research aims to validate a developmental model of epileptogenesis, and delineate surrogate markers for the epileptogenic process and for associated neuronal dysfunction. A major goal of Epilepsy Research, considered an Epilepsy Benchmark, is to intervene in the epileptogenic process and abort the development of epilepsy and of related cognitive dysfunction. This goal requires (1) validating models leading to epilepsy (spontaneous recurrent seizures) and (2) having reliable criteria or "markers" for progressive epileptogenesis. s have focused on the epileptogenic process culminating in temporal lobe epilepsy (TLE), and specifically on the potential causative role of prolonged febrile seizures (FS). An immature rodent model of prolonged FS has been characterized and has led to the discovery of molecular changes that promote hyperexcitability in the limbic circuit. Recent findings, using nocturnal video-EEG monitoring, indicate that a subset of adult animals that had experienced experimental prolonged FS early in life develop classical limbic seizures, with behavioral and EEG correlates. Therefore, the proposed research will test the hypotheses that the prolonged FS model can be used to predict TLE and hippocampal cognitive deficits, and that MRI lesions will serve as surrogate markers for epileptogenesis and/or hippocampal cognitive deficits. The project aims to (1) Determine the nature, distribution and time-course of abnormal MRI signals, (2) determine the value of MRI in predicting epileptogenesis, (3) determine the value of MRI in predicting the development of hippocampal neuronal dysfunction at the single cell and system levels. Based on exciting preliminary data, it is strongly believed that the outcome of this work will provide important data for future interventional strategies targeting mechanisms of disease processes - a major goal for this RFA.
Keywords: brain imaging /visualization /scanning, cognition disorder, epilepsy, magnetic resonance imaging, pathologic process, biomarker, disease /disorder model, febrile seizure, hippocampus, immature animal, memory, partial seizure, prognosis, temporal lobe /cortex disorder, behavior test, bioimaging /biomedical imaging, electroencephalography, laboratory rat, male, video recording system
Project start date: 2004-08-02
Project end date: 2007-04-30
5R21NS049618-02 (2005): $151932
1R21NS049618-01 (2004): $185792
CRH-mRNA Regulation: Role In Neonatal Seizure Potential
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 2R01NS028912-11A2 from National Institute Of Neurological Disorders And Stroke IRG: DBD
Abstract: The overall goal of this proposal is to determine the role of the stress-neuromodulator corticotropin releasing hormone (CRH) in early-life neuroplasticity that contributes to neurological disease. Studies during previous funding periods have demonstrated that central administration of synthetic CRH to infant rats led to long-term deficits of hippocampus mediated cognitive function, similar to those described after severe early-life stress in human infants. We have also demonstrated the presence of the cellular machinery for endogenous CRH in immature hippocampus, i.e., substantial populations of CRH-expressing interneurons and abundant CRH receptors on hippocampal pyramidal cells innervated by these interneurons. Therefore, the current proposal aims to definitively test the hypothesis that enduring upregulation and excessive release of endogenous hippocampal CRH contribute crucially to the impaired functional integrity of the hippocampus following early-life adverse events such as chronic psychological stress or recurrent seizures. The driving hypothesis of this research is that certain stresses occurring during a period of heightened hippocampal plasticity elevate the set-point of hippocampal CRH expression, increasing the peptide s levels in hippocampus longterm. Therefore, subsequent, acute stress at any point in life will evoke excessive release of CRH from hippocampal interneurons. Pathological levels of CRH provoke acute and long-term hippocampal neuronal dysfunction, associated with synaptic reorganization. This research proposal focuses on understanding this process at the synaptic, cellular and system levels, defining the means for interrupting the deleterious actions of excessive endogenous CRH on hippocampal function and integrity. Therefore, the proposal aims to (1) Investigate the effects of early-life (P2-P9) chronic psychological1 stress on hippocampal CRH expression long-term. (2) Delineate the unique synaptic machinery by which CRH (an excitatory neuropeptide), is stored in inhibitory interneurons, define the site of the postsynaptic elements mediating the peptide s actions, and determine whether stress activates post-synaptic hippocampal pyramidal cells via the release of endogenous CRH. (3) Characterize the functional, electrophysiological and structural hippocampal changes induced by early-life chronic psychological stress in a novel model. (4) Determine whether these effects of early-life stress are abrogated by blocking the actions of endogenous, stress-released CRH; in other words, whether the endogenous peptide is a required, crucial mediator of the enduring, life-long adverse effects of early-life stress on hippocampal functional integrity. These studies address the impact of early-life chronic psychological stress, such as child abuse and neglect (and perhaps recurrent seizures), on critical learning and memory functions. By defining the role of the stress-activated neuropeptide, CRH, in the mechanisms of the established adverse effects of these early-life events, these studies will provide truly innovative and exciting targets for prevention of a tremendous loss of human potential.
Keywords: corticotropin releasing factor, gene expression, genetic regulation, hippocampus, molecular psychobiology, neural plasticity, neuropsychology, neuroregulation, psychological stressor, evoked potential, interneuron, long term potentiation, memory, messenger RNA, neural information processing, neuroanatomy, pyramidal cell, visual perception, behavior test, immunoelectron microscopy, in situ hybridization, laboratory rat
Project start date: 1992-03-01
Project end date: 2009-02-28
2R01NS028912-11A2 (2005): $304334
SPECIFIC RECEPTOR MEDIATION OF CRH-INDUCED SEIZURES
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Neurocrine Biosciences, Inc. 12790 El Camino Real San Diego, Ca 92130
Grant 1R41HD034975-01 from National Institute Of Child Health And Human Development IRG: ZRG1
Abstract: The neuropeptide, corticotropin releasing hormone (CRA), is the key coordinator of the neuroendocrine, behavioral and autonomic responses to stress. The principal investigator has shown that infusion of CRH into the cerebral ventricles of infant rats produces severe age- dependent limbic seizures. Multiple CRH-induced seizures result in selective neuronal death in amygdala and hippocampus. The seizures, like other CRH effects, are mediated via specific receptors. Two distinct members of the CRH-receptor family have been characterized CRF1 and CRF2. Both receptor types are found in amygdala, site of origin of CRH-induced seizures, and may therefore mediate this effect of CHR. The availability of ligands specific for one receptor type permits determination of the receptor mediating CRH-induced seizures. The goal of this collaborative proposal is to test the hypothesis that 1) CRH induced seizures are mediated by CRF, and 2) that the seizures alter CRF1 (but not CRF2) gene expression. Selective non-peptide CRF1 antagonists will be administered by the P1 to infant rats prior to the infusion of CRH. Their ability to abolish the seizures induced by CRH will be compared to the established effects of non-selective peptide compounds, using both behavioral and EEG criteria. Brains of animals with CRH-induced seizures (and control brains) will be analyzed in the principal investigator s laboratory for messenger RNA levels of CRF1 and CRF2, using in situ hybridization, focusing on limbic regions. Authoradiographic studies will determine alterations in CRH-binding capacity of each receptor type in defined brain regions. This project builds on the strengths and expertise of the collaborators, it establishes CRH-induced seizures in infant rats as a reliable in vivo paradigm for testing candidate compounds as CRH receptor blockers. In essence, this Phase I project sets the stage for the commercial development of novel CRH receptor blockers as anti convulsants for selected seizure types.
Keywords: convulsion, corticotropin releasing factor, epilepsy, hormone receptor, receptor expression, behavior, inhibitor /antagonist, neuropharmacology, receptor binding, autoradiography, electroencephalography, in situ hybridization, infant animal, laboratory rat
Project start date: 1997-04-01
Project end date: 1998-03-31
1R41HD034975-01 (1997): $99604
Epilepsy Research Training Program
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Pediatricsuniversity Of California Irvine
irvine, Ca 926977600
Grant 5T32NS045540-05 from National Institute Of Neurological Disorders And Stroke IRG: NST
Abstract: The Epilepsy Research Training Program will provide intensive conceptual and technical research training to postdoctoral trainees, in research topics and cutting-edge techniques germane to the understanding of the Epilepsies. These areas include the neurobiology of neuronal and network hyperexcitability, plasticity and repair, and the Genetic/Genomic, Cellular and Molecular mechanisms involved in the generation and maintenance of the epileptic state. The program is designed for individuals who have recently completed their MD or PhD training, and will engage them in basic and translational research approaches, to fulfill the need for research to Cure Epilepsy, as highlighted in the NIH strategic plan. The Program´s goal is to create the next generation of Epilepsy Researchers, who will not only utilize methods and concepts currently in place, but will be prepared to carry them forward. The Research training will be provided by an apprenticeship under the immediate sponsorship of one or more faculty preceptor, with guidance and oversight of an Individual Training Committee. This research training will be complemented by active participation in the program´s structured training seminars, as well as in journal clubs, clinical/research symposia and specialized training courses, including the ethical conduct of research. The program is located at the UCI Research Campus, and includes faculty in several Neuroscience departments and in the multi-disciplinary Research Centers for Human Genome, Biomedical Engineering and Computational Modeling, Neuronal Death and Regeneration and Aging and Dementia. Thus, the program´s setting is a community rich in both, Basic Neuroscience as well as in research approaches to Clinical Disorders, including Epilepsy. The preceptors of this program include basic scientists with expertise in key aspects and methods, which are crucial to the study of Epilepsy, as well as physician-scientists who offer a critical clinical perspective. The program will thus provide focused yet multi-dimensional research training to generate the next cadre of researchers in the Neurobiology, Genetics, Cellular and Molecular mechanisms of the Epilepsies
Project start date: 2003-07-01
Project end date: 2009-06-30
5T32NS045540-05 (2007): $207902
5T32NS045540-04 (2006): $186189
5T32NS045540-03 (2005): $223251
5T32NS045540-02 (2004): $206187
1T32NS045540-01 (2003): $100908
FEBRILE SEIZURE MODEL--NEURONAL INJURY AND MECHANISMS
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 5R01NS035439-04 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Abstract: Seizures induced by fever are common in the infant and young child. Whether they result in neuronal death and subsequent temporal lobe epilepsy is controversial. Experimental models for febrile seizures used to date have involved older animals, or were unsuitable for long-term studies. Work by has established an infant rat paradigm of hyperthermia-induced seizures which is age-appropriate and suitable for long-term studies. This model will be used to test the following hypotheses (1). Hyperthermic seizures result in injury of select limbic neurons, particularly in the central and lateral amygdaloid nuclei. (2). This neuronal injury is mediated by the neuroexcitatory peptide, corticotropin releasing hormone (CRH). To define the distribution and characterize the types of neurons injured, brains will be examined at several time-points following the induction of hyperthermic seizures. Neuronal injury will be determined based on altered staining properties of affected cells. Concurrent experiments will test the hypothesis proposed for the mechanism of this neuronal injury If neuronal injury produced by hyperthermic seizures is mediated by CRH then i). these seizures should increase the levels of CRH in the involved brain regions and ii). the injury should be prevented by the administration of CRH antagonists. Furthermore, the long-term effects of hyperthermic seizures during infancy on the development of spontaneous seizures (epilepsy) in adulthood will be determined. The proposed studies establish a long-term model for the study of febrile seizures in the infant, a model which had been pursued by investigators focusing on Developmental Epilepsy Research for close to two decades. These studies should yield fundamentally important information regarding the pathogenesis of non-genetic human developmental epilepsies, of which febrile seizures are the most prevalent. The results of the proposed studies may have significant implications for the current management of these seizures in human infants, and could lead to a more aggressive approach to febrile seizures.
Keywords: disease /disorder model, febrile seizure, neuron, amygdala, corticotropin releasing factor, hormone receptor, hyperthermia, inhibitor /antagonist, neuropharmacology, synapse, electroencephalography, in situ hybridization, infant animal, laboratory rat
Project start date: 1997-04-01
Project end date: 2001-12-14
5R01NS035439-04 (2000): $199090
Sponsored Links Excellgen http://Excellgen.com
5R01NS035439-03 (1999): $193293
5R01NS035439-02 (1998): $187663
1R01NS035439-01A1 (1997): $203784
EFFECTS OF EARLY-LIFE EXPERIENCE: ROLE OF CRH
Tallie Z Baram, Professor & Endowed Chair
University Of California Irvine, Irvine, Ca 92697-7600
Grant 5R01MH073136-08 from National Institute Of Mental Health
Abstract: Early-life experience influences neuroendocrine and behavioral responses to stress long-term, with profound implications for emotional health throughout life, but the molecular mechanisms of this effect remain unclear. Studies during the current award period found that reduced expression of the stress neuromodulator corticotrophin releasing hormone (CRH) in hypothalamus was an early event in experience-evoked ´programming´ of the hypothalamic pituitary adrenal (HPA) system CRH mRNA was downregulated already on postnatal day 9 in daily handled pups, preceding the onset of attenuated stress responses and the life-long enhancement of hippocampal glucocorticoid receptor (GR) mRNA and stress-´coping´ behaviors. The goal of the current proposal is to investigate the mechanisms of this stress-response neuroplasticity after handling-evoked alterations of maternal care, by testing systematically several mechanistic hypotheses (1) An early phase of ´handling´-evoked HPA axis neuroplasticity in rat pups involves coordinated transient activation of neuronal transcription factors in stress-regulating sensory integration regions. This effect is evoked by a ´burst´ of maternal care elicited by the return of ´handled´ pups to the cage. (2) Recurrence of this neuronal activation, particularly in ´stress-memory storage regions´ is required for enduring downregulation of hypothalamic CRH gene transcription and steady state expression. (3) Reduction of hypothalamic CRH expression is necessary and sufficient to promote the attenuated neuroendocrine stress responses and enduring elevation of hippocampal GR expression and ´coping´ behaviors characteristic of high maternal care early in life. (4) CRH acts via the CRF1, receptor to ´program´ HPA responses long-term, so that selective CRF1 antagonists will convert hippocampal GR expression and long-term stress responses to those seen in early-life ´handled´ rats. (5) The mechanisms by which reduced CRH levels and decreased activation of CRH receptors alter hippocampal GR expression and stress responses long-term involves modulation of plasma glucocorticoid levels, so that ´clamping´ these levels will prevent handling-evoked HPA axis programming. The proposed experiments will delineate the spatiotemporal onset and progression of the protein effects of early life experience (and maternal care) on the immature HPA system, and use molecular and pharmacological means to define the responsible mechanisms. These studies should help clarify the molecular and neuroanatomical basis for early-life plasticity of the HPA system. In addition, they should yield mechanistic, targeted therapy for reversing the HPA hyperactivity consequent to deficient early-life experience that characterizes, and perhaps underlies, certain human affective and anxiety disorders
Keywords: 21+ years old; ACTH-Releasing Factor; ADRGND; ARHGEF5; ARHGEF5 gene; Adrenal Glands; Adrenals; Adult; Affect; Affective; Ammon Horn; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Attenuated; Award; Beds; Behavior; Behavioral; Blood Plasma; Boxing; Brain region; CNS plasticity; CREB; CREB1; CREB1 gene; CRF receptor type 1; CRF-41; CRF-R1; CRF1 receptor; CRH; CRH-1; Caring; Caspase 1, Apoptosis-Related Cysteine Protease; Caspase 1, Apoptosis-Related Cysteine Protease (Interleukin 1, Beta, Convertase); Caspase-1; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Cells; Characteristics; Chemotherapy-Hormones/Steroids; Common Rat Strains; Condition; Coping Behavior; Cornu Ammonis; Corticoliberin; Corticotropin Releasing-Factor Receptors; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Corticotropin-Releasing Hormone-41; Crh1 receptor; Critical Period; Critical Period (Psychology); Daily; Data; Development; Double-Stranded RNA; Down-Regulation; Down-Regulation (Physiology); Downregulation; EC 3.4.22.36; ENPT; Elevation; Emotional; End Point; EndPointCode; Endocrine Gland Secretion; Endpoints; Event; FOS gene; Figs; Figs - dietary; Foundations; Future; G0S7; GEF5; Gene Action Regulation; Gene Expression; Gene Expression Regulation; Gene Products, RNA; Gene Regulation; Gene Regulation Process; Gene Transcription; Genes; Genetic Transcription; Globin; Glucocorticoid Receptor; Glucocorticoids; Goals; HPA; Health; Heterogeneous Nuclear RNA; Hippocampus; Hippocampus (Brain); Hormonal; Hormones; Hour; Human; Human, Adult; Human, General; Hyperactive behavior; Hyperactivity; Hyperactivity, Motor; Hyperkinesia; Hyperkinesis; Hyperkinetic Movements; Hypophysis; Hypophysis Cerebri; Hypothalamic structure; Hypothalamus; ICE Protease; IL-1 beta Convertase; IL-1 beta-Converting Enzyme; IL-1b Converting Enzyme; IL1B-Convertase; IL1BC; Immediate-Early Genes; Infusion; Infusion procedures; Interleukin 1-B Converting Enzyme; Interleukin 1-Beta Convertase; Interleukin-1 Beta Converting Enzyme; Interleukin-1 Converting Enzyme; Interleukin-1beta Converting Enzyme; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Investigation; Lead; Life; Life Experience; Light; Link; Mammals, Rats; Man (Taxonomy); Man, Modern; Maps; Maternal Behavior; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Memory; Messenger RNA; Molecular; Mothers; Nature; Nerve Cells; Nerve Unit; Nervous System, Pituitary; Neural Cell; Neurobiology; Neurocyte; Neuroendocrine; Neuroendocrine System; Neuromodulator; Neuronal Plasticity; Neurons; Neurosecretory Systems; Nucleus; P 23; P23; P45; P60; Paraventricular Nucleus of Thalamus; Pathway interactions; Pattern; Pb element; Performance; Phase; Phenotype; Phosphorylation; Photoradiation; Physiologic; Physiological; Pituitary; Pituitary Gland; Pituitary-Adrenal System; Plasma; Population; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Pre-mRNA; Process; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; Proteins; Protooncogene FOS; Pump; Quelling; RNA; RNA Expression; RNA Interference; RNA Silencing; RNA Silencings; RNA, Double-Stranded; RNA, Messenger; RNA, Non-Polyadenylated; RNAi; Rat; Rattus; Receptors, CRF; Receptors, CRH; Receptors, Corticotropin-Releasing Hormone; Recurrence; Recurrent; Reticuloendothelial System, Serum, Plasma; Ribonucleic Acid; Role; Scheme; Sensory; Sequence-Specific Posttranscriptional Gene Silencing; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Stress; Stress and Coping; Structure of paraventricular nucleus of thalamus; Swimming; TIM; TIM1; Technology; Testing; Thalamic Nucleus, Paraventricular; Therapeutic Glucocorticoid; Therapeutic Hormone; Therapeutic Intervention; Time; Time Study; Transcription; Transcription, Genetic; Transducers; Work; adult human (21+); amygdaloid nuclear complex; attenuation; base; biological adaptation to stress; biological signal transduction; c fos; c-fos Gene; c-fos Proto-Oncogenes; coping; corticotropin releasing hormone; corticotropin-releasing factor receptor 1; critical developmental period; day; dsRNA; experience; experiment; experimental research; experimental study; gene product; heavy metal Pb; heavy metal lead; hippocampal; hnRNA; hypothalamic; hypothalamic-pituitary-adrenal (HPA) axis; hypothalamic-pituitary-adrenal axis; hypothalmus-pituitary-adrenal axis; implantation; imprint; improved; intervention therapy; interventional strategy; mRNA; neural plasticity; neurobiological; neuronal; neuroplasticity; p-Globin; pathway; pituitary adrenal axis; postnatal; prevent; preventing; programs; pup; reaction; crisis; receptor expression; research study; response; restraint stress; sensory integration; social role; spatiotemporal; stress response; stress; reaction; suprarenal gland; transcription factor; v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog
Project start date: 1999-12-01
Project end date: 2010-07-31
Budget start date: 1-AUG-2008
Budget end date: 31-JUL-2010
5R01MH073136-08 (2008): $0
5R01MH073136-07 (2007): $210862
5R01MH073136-06 (2006): $217481
9R01MH073136-05A1 (2005): $244272
5R01NS039307-04 (2003): $259527
5R01NS039307-03 (2002): $247230
5R01NS039307-02 (2001): $222508
Sponsored Links Excellgen http://Excellgen.com
1R01NS039307-01A1 (2000): $247763
CRH IN STRESS-INDUCED HIPPOCAMPAL NEUROPLASTICITY
Tallie Z Baram, Professor & Endowed Chair
University Of California Irvine, Irvine, Ca 92697-7600
Grant 2R01NS028912-15A2 from National Institute Of Neurological Disorders And Stroke
Abstract: Chronic stress early in life (ES), including neglect, abuse, loss of parent and severe poverty, affects the majority of the world´s children (UNESCO report, 2004). This is of major clinical importance because chronic childhood stress is associated with cognitive (and psychiatric) disorders later in life. Because elimination of global ES is not feasible, effective therapies that can be given post hoc to prevent the effects of ES on mid- life cognitive decline are necessary. Having defined a rodent model of ES which results in enduring deficits of hippocampus-dependent cognitive function and LTP, together with dendritic atrophy, we found that post hoc blocking of the receptor (CRFR1) of the stress-activated neuropeptide, corticotropin releasing hormone (CRH) immediately after the ES period, abrogated these deficits. Whereas these data are encouraging, major gaps in our knowledge require study in order to translate these experimental findings into therapies for children. In this revised continuation proposal, we propose (1) to test if pathological activation of central or of peripheral CRFR1 is responsible for ES-provoked learning and memory defects and dendritic atrophy; (2) to distinguish between the hypothesis that ES leads to enduring changes in hippocampal structure and function that are irreversible after a "critical period" of development, and the possibility that ES initiates hippocampal derangements that progress throughout life. In the latter case, therapeutic interventions in young adult ES graduates will still prevent the cognitive and structural deficits; (3) Because the structural changes provoked by ES-dendritic atrophy and synapse/spine loss--underlie the cognitive deficits, the mechanisms of dendritic atrophy will be studied, focusing on the role of hippocampal CRH-CRFR1 signaling; (4) Because dendritic atrophy derives from chronic loss of dendritic spines, the mechanisms by which stress, via CRFR1 activation, provokes dendritic spine collapse will be examined. The proposed studies, spanning in vivo and in vitro systems, will provide insight into the mechanisms by which ES impacts neuronal integrity, synaptic plasticity and cognitive function long-term. Because ES affects the majority of the world´s children, these studies address a problem of paramount importance, which is strikingly understudied. The proposed studies will identify a novel mechanism, CRH-CRFR1 signaling, as pivotal in the disturbances provoked by ES. Because the proposed studies will demonstrate the potential for post hoc intervention, and because compounds targeting CRFR1 are under clinical development, the results of these studies have tremendous translational potential. This project studies how chronic stress early in life impacts our brain. The United Nations has found that more than half of the world´s young children grow up under chronic stress (e.g., hunger, war, loss of parent). It is also known that early-life stress is associated with impairments of memory and other cognitive functions subserved by the brain´s hippocampus region, and that these deficits persist during adulthood and worsen with age. We plan to test the possibility that a brain-specific stress hormone (CRH) contributes in a major way to the adverse, long-lasting effects of early stress on memory during adulthood and middle-age, and find out how this happens. Our studies will identify new therapies (blocking the actions of CRH) for prevention and/or reversal of the severe impact of early stress on cognitive function- a major advancement in world health
Keywords: 0-11 years old; 21+ years old; ACTH-Releasing Factor; Actins; Address; Adult; Affect; Age; Age-Months; Ammon Horn; Atrophic; Atrophy; Blood - brain barrier anatomy; Blood Plasma; Blood-Brain Barrier; Brain; Brain Ventricle; Brain region; CNS plasticity; CRF-41; CRH; Cell Communication and Signaling; Cell Signaling; Cerebral Ventricles; Chemotherapy-Hormones/Steroids; Child; Child Youth; Childhood; Children (0-21); Chronic; Chronic stress; Clinical; Cognition Disorders; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive deficits; Cognitive function abnormal; Cornu Ammonis; Corticoliberin; Corticotropin Releasing-Factor Receptors; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Corticotropin-Releasing Hormone-41; Critical Period; Critical Period (Psychology); Data; Defect; Dendrites; Dendritic Spines; Development; Disturbance in cognition; Dose; Dysfunction; Effects, Longterm; Encephalon; Encephalons; Endocrine Gland Secretion; Excitatory Synapse; Exposure to; Functional disorder; Glucocorticoid Receptor; Glutamate Receptor; Health; Hemato-Encephalic Barrier; Hippocampus; Hippocampus (Brain); Home; Home environment; Hormones; Hour; Human, Adult; Human, Child; Hunger; Image; Impaired cognition; In Vitro; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Knowledge; Learning; Length; Life; Life Stress; Location; Long-Term Effects; Long-Term Potentiation; Mediating; Memory; Memory Deficit; Memory impairment; Mental disorders; Mental health disorders; Modeling; Molecular; Motion; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neuronal Plasticity; Neurons; Neuropeptides; Parents; Peripheral; Physiopathology; Plasma; Poverty; Prevention; Process; Proteins; Psychiatric Disease; Psychiatric Disorder; Pyramidal Cells; Receptor Activation; Receptor Protein; Receptors, CRF; Receptors, CRH; Receptors, Corticotropin-Releasing Hormone; Reporting; Reticuloendothelial System, Serum, Plasma; Rodent Model; Role; Serum, Plasma; Signal Transduction; Signal Transduction Systems; Signaling; Skeleton; Spinal Column; Spine; Stress; Structure; Synapses; Synaptic; Synaptic plasticity; System; System, LOINC Axis 4; Testing; Therapeutic Hormone; Therapeutic Intervention; Time; Translating; Translatings; UNESCO; United Nations; Unspecified Mental Disorder; Vertebral column; War; World Health; abuse neglect; adult human (21+); adult youth; backbone; base; biological signal transduction; children; cognitive disease; cognitive disorder; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; corticotropin releasing hormone; critical developmental period; critical period; dendrite spine; depolymerization; depression; effective therapy; experiment; experimental research; experimental study; gene product; hippocampal; imaging; in vivo; insight; intervention therapy; interventional strategy; language translation; mental illness; mid life; mid-life; middle age; middle aged; midlife; neglect and abuse; neural plasticity; neuronal; neuroplasticity; novel; osmotic minipump; pathophysiology; pediatric; postnatal; prevent; preventing; psychological disorder; public health relevance; receptor; research study; social role; trafficking; two-photon; young adult; youngster
Relevance: This project studies how chronic stress early in life impacts our brain. The United Nations has found that more than half of the world´s young children grow up under chronic stress (e.g., hunger, war, loss of parent). It is also known that early-life stress is associated with impairments of memory and other cognitive functions subserved by the brain´s hippocampus region, and that these deficits persist during adulthood and worsen with age. We plan to test the possibility that a brain-specific stress hormone (CRH) contributes in a major way to the adverse, long-lasting effects of early stress on memory during adulthood and middle-age, and find out how this happens. Our studies will identify new therapies (blocking the actions of CRH) for prevention and/or reversal of the severe impact of early stress on cognitive function- a major advancement in world health
Project start date: 1992-03-01
Project end date: 2014-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2010
PFA/PA: PA-07-070
2R01NS028912-15A2 (2009): $311500
CRH-MRNA REGULATION-- ROLE IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Pediatricsuniversity Of California Irvine
irvine, Ca 926977600
Grant 2R01NS028912-07A2 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: adapted from applicant´s ) The current proposal focuses on mechanisms and consequences of early-life seizures that are provoked by proconvulsant´stressors´ such as fever (hyperthermia) and hypoxia. These non-genetic ´triggered´ seizures constitute the majority of developmental seizures. While the outcome of simple febrile seizures is generally benign, and the outcome of many developmental seizures depends on their etiology, emerging evidence in both human and animals indicates that prolonged febrile seizures and recurrent triggered seizures may be associated with neuronal injury. has demonstrated that the stress-activated neuropeptide, corticotropin releasing hormone (CRH), a well established key mediator of the CNS stress-response, acts as a powerful, age-specific convulsant in the developing brain and promotes injury of hippocampal neurons. Thus, CRH may play a role in the mechanisms by which triggered developmental seizures influence neuronal integrity. During the recent funding period, established the presence of a significant population of CRH-expressing interneurons in the developing hippocampus and the mechanisms by which CRH interacts with glutamate receptor activation to enhance hippocampal excitability. In addition, recent findings suggest that (1 ) pro-convulsant stressors may increase CRH expression in limbic regions and (2) excessive CRH-receptor activation during early-life may result in significant long-term consequences on hippocampal integrity and function. Therefore, the proposed research tests the hypothesis that proconvulsant stressors increase CRH levels in hippocampus resulting in augmentation by the peptide of excitotoxic mechanisms. to enhance neuronal injury and lead to long-term hippocampal dysfunction. Four experiments are proposed to test this hypothesis 1 ) studying-using in situ hybridization and immunocytochemistry- whether proconvulsant stressors enhance CRH-expression and levels in hippocampus. Studying the unique mechanisms by which CRH leads to hippocampal neuronal death using (2) in vivo and (3) in vitro dissociated hippocampal cell approaches, and, 4) Examining the significant long-term consequences of excessive CRH-dependent excitation during early life, focusing on hippocampal neuronal loss and hippocampal-dependent cognitive dysfunction. The significance of the proposed studies derives from their focus on mechanisms and consequences of early life provoked seizures that constitute the majority of developmental seizures, but remain relatively unstudied. The proposed studies, delineating age-specific mechanisms for seizure-related neuronal injury and its consequences should lead to the development of novel, age-appropriate, specific therapies to prevent these consequences
Keywords: corticotropin releasing factor, epilepsy, febrile seizure, hormone regulation /control mechanism, newborn animal, physiologic stressor cell death, convulsant, developmental neurobiology, genetic regulation, glutamate receptor, hippocampus, hormone receptor, hyperthermia, hypoxia neonatorum, interneuron, messenger RNA, neuroanatomy, neurotoxicology, pyramidal cell, receptor expression immunocytochemistry, in situ hybridization, laboratory rat, tissue /cell culture
Project start date: 1992-03-01
Project end date: 2004-06-30
2R01NS028912-07A2 (2000): $363400
3R01NS028912-07A2S1 (2000): $43616
SHORT-TERM TRAINING STUDENTS IN HEALTH PROFESSIONAL SCHO
Tallie Z Baram, Danette Shepard Professor Of Neurologica
Pediatricsuniversity Of California Irvine
irvine, Ca 926977600
Grant 5T35GM008630-04 from National Institute Of General Medical Sciences IRG: ZRG2
Project start date: 1997-08-01
Project end date: 2002-04-30
5T35GM008630-04 (2000): $30955
5T35GM008630-03 (1999): $30218
5T35GM008630-02 (1998): $42924
1T35GM008630-01 (1997): $42107
CRH-MRNA REGULATION--ROLE IN NEONATAL SEIZURE POTENTIAL
Tallie Z Baram, Danette Shepard Professor Of Neurologica
University Of California Irvine Irvine, Ca 926977600
Grant 2R01NS028912-04A2 from National Institute Of Neurological Disorders And Stroke IRG: NLS
Project start date: 1992-03-01
Project end date: 1999-05-31
2R01NS028912-04A2 (1996): $191984