1982 — 1985 |
Gall, Christine |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Hippocampal Enkephalin: Terminal Localization and Synaptic Function @ University of California-Irvine |
0.915 |
1985 — 1989 |
Gall, Christine M |
K04Activity Code Description: Undocumented code - click on the grant title for more information. |
Mossy Fiber Peptides: Involvement in Seizure Activity @ University of California Irvine
The hippocampal mossy fiber system has been proposed by many to be an ideal system for analyses of the function of opioid peptides. This anatomically well defined (and electrophysiologically accessible) axonal system has been found, by the applicant and others, to contain enkephalin (ENK)-, dynorphin (DYN)- and (in guinea pig and mouse) cholecystokinin (CCK)-like immunoreactivity. It is not known whether these peptides are colocalized or are present in distinct mossy fiber populations. There is evidence that mossy fiber ENK and, less certainly, DYN and CCK content is altered by seizure activity and a range of studies indirectly suggest that these peptides are involved in the regulation of epileptiform activity as well. It is the goal of the proposed research to further refine our understanding of the fine localization of ENK-, DYN-, and CCK-like immunoreactivities in the mossy fiber system through the application of immunoelectron microscopic techniques and to evaluate the recipricol interaction of these mossy fiber peptides with epileptiform activity. Specifically the latter studies propose to: 1) quantify the influence of seizure activity on DYN, ENK, and CCK immunoreactivities in hippocampus by radioimmunoassay; 2) evaluate the impact of the seizure-induced increase in mossy fiber terminal-contained ENK (and possibly DYN) immunoreactivity on opiate receptor binding patterns; and 3) use the in vitro hippocampal slice preparation and a penicillin-induced interictal-spike paradigm to evaluate the (positive or negative) epileptogenic effects of mossy fiber-contained peptides. The anatomical (EM and autoradiographic) studies should help clarify unresolved issues as to the 'place' of ENK, DYN, and CCK in hippocampal circuitry and thereby limit the range of considerations as to the local physiological role of these substances. It is hoped that data from the proposed studies will combine to advance our understanding of the involvement of hippocampal peptides in limbic seizure activity and, more generally, the interaction between physiological activity, terminal-contained peptide concentration, and peptide receptors throughout the CNS.
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1 |
1985 — 1988 |
Gall, Christine |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Localization, Ontogeny, and Seizure-Induced Changes in Mossyfiber Peptides @ University of California-Irvine |
0.915 |
1987 — 1989 |
Gall, Christine 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. |
Ornithine Decarboxylase &Seizure Activity in Brain @ University of California Irvine
Previous work in the applicants' laboratories demonstrated that seizures produced by focal lesions elicit a dramatic increase in enkephalin content and a concurrent decrease in dynorphon and cholecystokinin content in the hippocampal mossy fiber system of the adult rat and mouse. Additional work revealed that these effects are preceded by an increased transcription of mRNA for preproenkephalin, increased synthesis of enkephalin, and a massive but transient increase in ornithine decarboxylase (ODC) activity. Since ODC activity and polyamines have been linked to a variety of trophic responses in several types of cells, it was hypothesized that ODC induction and increased polyamine levels are responsible for the increased synthesis of enkephalin found after seizures. The proposed experiments will directly test this idea, identify the ananomical locus and biochemical nature of the ODC effect, and investigate the nature of the physiological events which trigger it. The specific goals of the proposed studies are as follows: 1) identify the hippocampal cells in which increased ODC activity occurs; 2) determine if physiological stimulation other than seizures can be used to induce ODC activity; 3) measure the effects of ODC Inhibition (and reduced polyamine levels) on seizure-induced changes in neuropeptides; 4) test the assumption that increased ODC activity is due to induction of the enzyme; and 5) examine the feasibility of using in vitro slices of hippocampus for further studies of ODC induction. Together these experiments will elucidate the process through which seizures, and possibly other physiological events, increase the activity of a potent trophic system (ODC) and test if this is responsible for alterations in the genomic machinery controlling neuropeptide levels.
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1 |
1989 — 1991 |
Gall, Christine 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. |
Physiological Regulation of Neuropeptide Expression @ University of California Irvine
Recent studies using a variety of neuronal systems strongly suggest that the expression of putative neurotransmitter / neuromodulatory substances is affected by physiological activity. The PI's work has demonstrated that recurrent limbic seizures differentially influence the regulation of three neuropeptides contained within the hippocampal mossy fiber system: enkephalin synthesis and concentration is increased whereas immunoreactivity for dynorphin is reduced and immunoreactivity for CCK is eliminated. Recent in situ hybridization studies indicate that seizure-induced increases in enkephalin transcription are broadly distributed across limbic forebrain and are associated, in at least some areas, with increased transcription of the proto-oncogene c-fos. There are four major goals to the proposed research. First, the regional distribution of seizure-induced alterations in the abundance of mRNAs for preproenkephalin A, preprocholecystokinin, and glutamic acid decarboxylase will be mapped in forebrain with particular interest in determining whether seizures have a consistent influence over each mRNA species in different brain areas and whether there is evidence for differential regulation in areas of colocalization. Second, in situ hybridization techniques will be used to test if there is good regional correspondence between the seizure-induction of c-fos and preproenkephalin A mRNA as would be expected if increased c-fos transcription is important for the later alterations in enkephalin expression. Third, the influence of repetitive afferent stimulation on the abundance of mRNAs for preproenkephalin A and the preprocholecystokinin will be examined in hippocampus and piriform cortex. The results of this experiment will be of considerable utility in evaluating the hypothesis that the effects triggered by seizures are exaggerated versions of events that occur under more normal physiological circumstances. Fourth, the influence of recurrent limbic seizures on the incidence of dentate gyrus granule cell somatic spines and soma-somatic junctions will be evaluated. These studies should contribute to the understanding of how the expression of messenger molecules is regulated in brain, provide data on the cellular consequences of recurrent seizures, and generate new information regarding the possibility that intense physiological activity effects long- lasting changes in the operation of brain circuities via alterations in genomic expression.
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1 |
1991 — 1997 |
Gall, Christine |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Faw: Activity-Regulated Trophic Factor Expression @ University of California-Irvine
With a Faculty Award for Women Scientists and Engineers from the National Science Foundation, Dr. Christine Gall will continue to elucidate the role of activity-dependent neuronal gene expression in shaping the functional properties of neuronal circuities in response to experience. By using a combination of sophisticated neuroanatomical and molecular biological techniques, Dr. Gall discovered that high frequency electrical stimulation in defined neuronal pathways alter the expression of genes encoding specific neuropeptides and neurotransmitters. For example, she has found that this activity induces changes in the genomic expression of a major subclass of glutamate receptors within the hippocampus, an area critical for the formation of memories. She is now beginning to unravel the clues about the mechanisms of neuropeptide regulation by examining more rapid, transcriptional events. With this award, she will concentrate on understanding how this physiological activity alters the regulation of immediate-early genes which then encode the proteins that mediate neuropeptide regulation. Moreover, she extend the anatomical work by developing electrophysiological approaches which enable her to examine the functional consequences of the change in gene expression within specific neuronal circuitry for neuropeptides, neurotransmitters and, more recently, neurotropic factors. Indeed this Award will permit her to explore the significance of her seminal finding that nerve growth factor is modulated in adult mammalian brain. This work leads to a more thorough understanding of the functional organization and the plasticity of the nervous system.
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0.915 |
1992 — 1994 |
Gall, Christine 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. |
Odor Regulation of Neuronal Gene Expression @ University of California Irvine
Recent in situ hybridization studies in the applicant's laboratory show that regionally discrete changes in the expression of mRNAs for the immediate early genes (IEGs) c-fos and c-jun provide a unique map of cell activation in the odor-stimulated olfactory bulb. Moreover, although different odors stimulate regionally distinct increases in IEG mRNA content, the common vertical pattern of activation within a region (i.e., narrow in the glomerular layer and successively wider in the granule and mitral cell layers) suggests that presence of a basic functional/anatomical unit of odor representation in the olfactory bulb. The major goals of the proposed research are to test this possibility, to examine factors which may influence the spatial distributions of activation in the different bulb laminae, and to explore the possibility that in association with increased expression of transcriptional regulatory products encoded by IEGs, odors stimulate regional increases in the expression of transcriptional regulatory products encoded by IEGs, odors stimulate regional increased expression of transcriptional regulatory products encoded by IEGs, odors stimulate regional increases in the expression of neurotrophic factors. Five studies are proposed: (1) The spatial distribution and cellular localization of odor-elicited increases in mRNAs for c-fos, c-jun, and NGFI-A in main olfactory bulb will be evaluated to determine if there is a stereotypic vertical (columnar) pattern of activation that is independent of the particular odor used or region of bulb evaluated. (2) The influence of different durations and patterns of odor presentation on IEG expression will be evaluated to determine i) the threshold to induction, ii) the influence of stimulus duration on the spatial distribution of activation and iii) whether the IEG response of bulb neurons becomes refractory to repeated odor stimulation. (3) The influence of centrifugal afferents in shaping the fields of odor-elicited increases in IEG mRNA expression in the bulb will be evaluated in studies employing electrolytic and ibotenic acid lesions of afferent groups. (4) The influence of the NMDA receptor antagonist AP5 will be evaluated to test the hypothesis that this receptor type is involved in the odor stimulation of IEG expression by some, but not all, bulb cell types. (5) Finally, to test the hypothesis that olfactory stimulation, and odor-elicited increases in IEG expression, regulate the expression of neurotrophic factors, the influence of olfactory deprivation and of specific odor presentation on levels of mRNAs for nerve growth, brain derived neurotrophic factor, and insulin-like growth factor-I in olfactory bulb neurons will be examined. Throughout, in situ hybridization of 35S-cRNA probes will be used to evaluate levels, regional distribution, and cellular localization of mRNAs under analysis. The proposed studies should add significantly to our understanding of the functional organization of the olfactory bulb and may elucidate general principles of sensory representation in the CNS. Moreover, the studies of neurotrophic factor expression could reveal processes underlying the anatomical plasticity that goes on in the bulb throughout life.
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1 |
1992 — 1996 |
Gall, Christine M |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Neurotrophic Factor Regulation in the Cns @ University of California Irvine
This is a request for an ADAMHA Research Scientist Development Award, level II. The broad objectives of the research are to characterize the mechanisms which mediate activity-dependent changes in neurotrophic factor gene expression in the adult brain and to evaluate functional consequences of altered expression of the NGF-like neurotrophins following seizure activity. Prior studies by the applicant have demonstrated that seizures alter levels of mRNA for nerve growth factor (NGF) and the structurally related neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in adult rat brain. In the proposed studies, molecular biological techniques (in situ hybridization, S1 nuclease protection assay, run-on assay) will be used to determine i) if the different mRNAs are colocalized and differentially regulated within individual neurons, ii) if mRNA synthesis is altered following seizure, iii) if growth factor mRNA changes follow, and are dependent upon, increases in c-fos expression, iv) if activity-dependent increases in NGF mRNA and BDNF mRNA become refractory to repeated stimulation, v) if changes in NT3 mRNA are linked to changes in BDNF mRNA and NGF mRNA in a variety experimental paradigms, vi) if seizures stimulate increases in the expression of interleukin-1beta mRNA in forebrain that might play a role in later increases in NGF mRNA expression, and vii) if seizure-induced changes in NGF and BDNF mRNA lead to changes in trophic activity within the forebrain. The training goal for the applicant will be to learn and gain experience in the use of molecular biological techniques needed to support in situ hybridization procedures, to prepare, subclone, and characterize new cDNAs, and to assay levels of mRNA synthesis. This is to be accomplished through increased time working in the laboratory with collaborators on the U.C.I. campus. The long range goals of the research program are i) to further rely on these powerful technical capabilities to independently study the role of activity dependent neuronal gene expression in normal brain function and ii) to identify lines of trophic communication in brain which are necessary for normal function and might be manipulated to promote neuronal viability.
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1 |
1992 — 2000 |
Gall, Christine 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. |
Regulation of Neuronal Gene Expression--Neurotrophins @ University of California Irvine
BDNF gene expression is largely regulated by neuronal activity thereby implicating this regulatory process in the coordination of adaptive trophic responses to insult and in mechanisms of normal neuroplasticity. The applicant has demonstrated that activity dependent changes in BDNF mRNA content are suppressed by the adrenal hormones. Moreover, results indicate that BDNF transcripts I and II were co-regulated by activity and the adrenal hormones whereas BDNF transcripts III and IV were regulated by activity as immediate early genes. These findings suggest the hypothesis that, through the regulation of the different BDNF transcript forms, adrenal hormones have region specific effects on activity dependent BDNF expression and BDNF signaling. The goals of the proposed research are to test this hypothesis and predictions arising from it. Experiments are designed to evaluate the BDNF regulation at the level of mRNA expression, at the level of protein expression and trafficking, and at the level of trophic signaling. There are four specific aims. First, exon-specific in situ hybridization will be used to determine if adrenal hormones have cell- and transcript-specific effects on activity-induced increases in BDNF mRNA expression. Second, light and electron microscopic immunocytochemical techniques will be used to test the hypothesis that the newly expressed BDNF protein is preferentially anterogradely transported onto axonal and terminal arbors and depleted from those arbors by neuronal activity. Results from this study should indicate where increases in BDNF activity are expected to occur relative to regions of increased synthesis. Third, BDNF immunoassays will be used to test the hypothesis that adrenal hormones have region specific effects of seizure-induced increases in BDNF protein content. Finally, measures of tyrosine phosphorylation of the BDNF receptor trkB and NPY expression, thought to be regulated by BDNF following seizures, will be used to test the hypothesis that the adrenal hormones attenuate BDNF trophic signalling in a regional specific fashion.
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1 |
1993 |
Gall, Christine 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. |
Regulation of Neuronal Gene Expression: Neurotrophins @ University of California Irvine
In the adult brain recurrent seizures induce distinct patterns of change in levels of mRNAs for members of the nerve growth factor (NGF) family of neurotrophins (NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 [NT-3]); these changes precede differential alterations in levels of mRNAs for various neuropeptides and at least one subunit of the non-NMDA glutamate receptor. These findings suggest that physiological activity modulates neurotrophin expression and, thereby, regulates the biosynthetic activities of trophin-responsive cells. The proposed projects address the first aspect of this hypothesis and, in particular, are designed to more funny characterize the dynamic properties of neurotrophin mRNA expression and to test predictions as to cellular mechanisms involved. There are five specific aims. (1) Through analysis of the colocalization of the neurotrophin mRNAs with each other and with glutamic acid decarboxylase mRNA it will be determined (la) if the neurotrophin mRNAs are colocalized and differentially regulated by activity in single cells and (lb) if neurotrophin expression by GABAergic neurons is unaffected by seizures. (2) Run-on assay and in situ hybridization to mRNA intron sequences will be used to determine if seizure-induced changes in neurotrophin mRNA content involve changes in mRNA synthesis. (3) Controlled stimulation of afferents to hippocampus and olfactory cortex will be used to determine the threshold and time courses of changes in activity-driven neurotrophin expression and if there are regional differences in the parameters of the neurotrophin mRNA response. This will include a test of the hypothesis that subseizure physiological activity regulates neurotrophin mRNA expression. (4) In vitro hippocampal explants will be used to determine whether depolarization-induced increases in NGF and BDNF mRNA are blocked by protein synthesis inhibition; this will test the hypothesis that increases in BDNF and NGF mRNA contents are immediate-early gene responses. (5) The last studies will explore the hypothesis that late changes in NGF mRNA expression after seizures are trophically induced. Exp. 5a will determine if seizures increase levels of mRNAs for acidic fibroblast growth factor (aFGF), basic FGF and interleukin-1beta prior to late increases in NGF mRNA content and Exp. 5b will determine if these cytokines increase the NGF mRNA content of hippocampal neurons in explant culture. Quantitative in situ hybridization and S1 nuclease protection assays will be used to quantify MRNA content. These studies should elucidate mechanisms that regulate the expression of brain neurotrophins thought to be critical for the survival of diverse populations of central neurons. Moreover, the results will indicate if activity dependent regulation of neurotrophin expression is an ongoing property of central neurons and, therefore, a likely mechanism through which activity influences the structure, function, and viability of the adult brain.
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1 |
1995 — 1999 |
Gall, Christine |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neurotrophic Factor Regulation in Brain Aging @ University of California Irvine
Brain aging is characterized by a gradual loss of some populations of neurons (e.g. forebrain cholinergic, monoaminergic) as well as decreases in excitatory synapses in cortical telencephalon. The proposed research will examine the possibility that disturpances in neurotrophic relationships contribute to these two classes age-associated effects. Results of colocalization studies conducted during the previous funding period suggest that acidic fibroblast growth factor (aFGF) and brain-derived neurotrophic factor (BDNF) are putative autocrine neurotrophic factors for forebrain cholinergic and midbrain dopaminergic neurons, respectively. The first set of experiments will test the hypothesis that age-related losses in the expression of these factors contribute to the reduced viability of cholinergic and dopaminergic neurons with age. Specific Aim 1 is to use in situ and solution hybridization techniques to determine if losses in aFGF and BDNF mRNA expression precede or accompany age-related losses in cholinergic and dopaminergic neurons, respectively, as expected if the former events contribute to the latter. The second group of studies is motivated by the discovery that insulin-like growth factor-I (IGF-1) expression is correlated with axon sprouting in adult brain and by the working hypothesis that IGF-1 plays a critical role in the regulation of reactive axonal growth and synaptic replacement throughout life. Specific Aim #2 will test if lesion-induced increases in IGF-1 expression are reliably correlated with the parameters of axonal growth in cortical telencephalon as would be expected if this factor regulates the growth response. Aims 2a and 2b are to determine if parameters of IGF-1 mRNA expression are delayed in association with the delayed time course of sprouting previously documented to be present (a) in aged rat and (b) in the C57BL/Ola mouse strain. Specific Aim 2c will determine if intraventricular infusion of antibody to IGF-1 interferes with lesion-induced sprouting of surviving septal and commissural/associational afferents to the partially deafferented rat hippocampus. Specific Aim 3 will examine the hypothesis that disturbances in IGF-1 expression are associated with disturbances in processes of axonal growth and synaptic replacement that are present in aged and Alzheimer's diseased (AD) hippocampus. Specifically, it will be determined if levels and patterns of IGF-1 mRNA expression are altered with increasing age and Alzheimer's disease and, in particular, if expression is increased in regions of pathological axonal growth. The proposed studies will determine if with increasing age and age-related disease there are disturbances in specific trophic relationships indicated to be important for neuronal survival and maintenance of innervation patterns in adult brain. Through the identification of chemistries that subserve neuronal viability and functional plasticity in adult brain, it should ultimately be possible to exploit these trophic mechanisms for the design of therapeutic strategies to optimize neuronal survival and function through aging and to counteract the deleterious effects of specific neurological diseases.
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1 |
1998 — 2001 |
Gall, Christine 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. |
Behaviorally Induced Neurochemical Plasticity @ University of California Irvine
DESCRIPTION (Applicant's abstract): The proposed research will use recently developed maps of regional activity patterns associated with behaviors that do and do not entail explicit learning, to test the hypothesis that proteolytic and synthetic chemistries linked to long term potentiation (LTP) are activated in situ during learning. Behavioral groups include rats at different stages in olfactory discrimination learning, recently engaged in copulation, or having received an IP saline injection; analysis will focus on subfields of hippocampus and amygdala. The first aim is to map cfos mRNA expression to identify regions activated during learning: the analysis will complete the evaluation of cfos expression in 8 behavioral groups. The second aim is to test the hypothesis that mRNA expression for the cytoskeleton-associated protein Arc increases in regions activated during behavior and that this effect will be greater in conditions associated with explicit learning as compared to conditions that are not. In addition, effects on Arc protein content will be evaluated. The third aim is to test the hypothesis that neurotrophin mRNA expression covaries with neuronal activity in a subset of areas that exhibit changes in c-fos expression, and most particularly in areas activated with learning as opposed to familiar behaviors. The fourth aim is to use antisera specific for spectrin fragments deriving from calpain activity to test the hypothesis that the protease is stimulated in dendritic spines in association with LTP and in select hippocampal and amygdala areas during learning. The chemistries to be evaluated (calpain activity, neurotrophin and Arc expression) are argued to be critical for certain forms of synaptic plasticity, and are candidates for involvement in memory encoding. The proposed work will provide a first test for their presence in regions engaged learning behaviors.
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1 |
1998 — 2007 |
Gall, Christine 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. |
Integrin Regulation and Functions in Adult Brain @ University of California Irvine
DESCRIPTION (provided by applicant): Integrin class adhesion receptors exert potent influences over trophic signaling and ion channels in various nonneuronal cells. Research in this program has shown that integrins are concentrated at synapses and influence neurotrophin expression, and glutamate receptor and ion channel properties in mature forebrain neurons. Specifically, the soluble integrin ligand peptide GRGDSP was found to up-regulate neurotrophin expression in an NMDA receptor (NMDAR)-dependent fashion. This led to the further discovery that GRGDSP treatment increases synaptic currents mediated by AMPA- and NMDA-class glutamate receptors and phosphorylation of the glutamate receptor themselves. The proposed work builds on these results and will test the hypothesis that synaptic integrins control local signaling cascades that regulate the functional properties of AMPA and NMDA receptors. There are 5 Specific Aims. In immunocytochemical studies of cultured hippocampal neurons, Aim 1 will identify integrin subunits and integrin signaling elements located in glutamatergic spine synapses. Studies will test if spines contain multiple integrins, if specific integrins and glutamate receptor proteins are co-distributed, and if the integrin signaling proteins FAK and Pyk2 are differentially distributed, in association with specific integrins, across glutamatergic spine synapses. In parallel studies to be conducted in acute hippocampal slices and synaptoneurosomes, Aim 2 will test the hypothesis that GRGDSP and native matrix ligands (fibronectin, vitronectin, laminin) activate synaptic integrin signaling leading to phosphorylation of AMPA and NMDA receptor proteins. Cotreatment with disintegrins and integrin neutralizing antisera will verify that effects are integrin-mediated and will identify the specific integrins involved. Aim 3 will test the hypothesis that native integrin ligands potentiate NMDAR- and AMPAR-mediated synaptic responses in electrophysiological studies of acute hippocampal slices; integrin function blocking antibodies will be used to identify integrins mediating these effects and to test if integrin effects are tonic or only occur with new ligand presentation. Aim 4 will test the hypothesis that treatment with integrin ligands alters specific AMPAR-scaffold associations and increases AMPAR surface expression in studies of acute hippocampal slices and cultured hippocampal neurons, respectively. Finally, Aim 5 will test the hypothesis that integrin signaling regulates neuronal gene expression through serial effects on NMDAR and VSCC function. Specifically, studies will test if integrin ligands trigger NMDAR-dependent phosphorylation of L-type VSCCs, will identify the specific integrins involved, and will use function blocking antibodies to test if integrin effects on neuronal gene expression are tonic or episodic (i.e., occur only with new ligand presentation). These studies will further characterize and identify novel interactions between adhesion and neurotransmitter receptors that influence both the potency of synaptic transmission and the regulation of neurotrophic factor expression in adult brain. As a consequence these findings are important for understanding basic mechanisms of neuronal communication and survival in the adult CNS.
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1 |
2003 — 2007 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bdnf Regulation: Roles in Plasticity and Neuroprotection @ University of California Irvine
DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) is neuroprotective, promotes axonal growth, and has been suggested to play roles in learning and counteracting depression. Increasing BDNF levels might, therefore, provide a means for treating various brain disorders. Recent work by the applicants discovered that positive modulators of AMPA-type glutamate receptors ('ampakines') induce BDNF expression. Ampakines cross the blood-brain barrier and have had minimal side effects in animal studies and clinical trials. Thus, they provide a plausible means for manipulating BDNF expression in brain. However, additional studies found that prolonged applications (24-48 h) cause BDNF induction to become refractory to treatment and led to a depression of fast excitatory responses suggesting that there may be a loss of glutamate receptor activity. Preliminary studies confirmed that prolonged ampakine treatment causes a loss of surface AMPA receptors. To obviate this problem, the applicants developed an on/off ampakine treatment regimen that sustains elevated BDNF levels (20-fold) for several days. The Program Project builds on these results and will address three broad objectives: 1) Identify cellular pathways through which ampakines up-regulate BDNF, induce refractoriness, and down-regulate fast, excitatory transmission; 2) Test if endogenous BDNF effects are similar to those of exogenous BDNF application; 3) Determine if up-regulation is neuroprotective. Project 1 will devise treatment regimens for optimally inducing BDNF, test if increased BDNF is associated with increased BDNF signaling and test the hypothesis that increased BDNF levels protect against ischemia. Project 2 will characterize the time course of ampakine-induced depression of synaptic responses and the hypothesis that this is due to a down regulation of AMPA receptors. Project 3 will compare the effects of exogenous BDNF with increases in endogenous BDNF on several physiological measures including transmitter release, synaptic plasticity, and cholinergically driven EEG rhythms. The possibility that BDNF interacts with integrin adhesion receptors to produce its effects will also be examined. Project 4 will use a mouse model pertinent to Alzheimer's disease (ApoE -/- mice) to test if endogenous BDNF counteracts age-related pathologies including neurofibrillary tangle formation and amyloid toxicity. Effects of BDNF on cholinergic innervation will also be examined. The four projects will use the same experimental preparations, treatments and core facilities. The program is expected to provide new insights into the regulation of excitatory receptors and neurotrophin expression. It could also provide foundations for a new therapeutic strategy for treatment of neuropsychiatric and neuropathological disorders.
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1 |
2003 — 2007 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Tissue Culture Core @ University of California Irvine |
1 |
2009 — 2012 |
Gall, Christine M Lauterborn, Julie C (co-PI) [⬀] |
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. |
Fragile X and Synaptic Plasticity @ University of California-Irvine
DESCRIPTION (provided by applicant): Efforts to identify causes of memory and cognition deficits in Fragile X Syndrome (FXS) led to the discovery of synaptic plasticity impairments in cortex of a knock-out mouse model (Fmr1-KO) of the disorder. The applicants have extended these results by showing that hippocampal long-term potentiation (LTP), induced by learning-related patterns of afferent activity, fails to stabilize in Fmr1-KO mice. Analysis of cytoskeletal changes required for lasting LTP pointed to the hypothesis that a critical FXS-defect involves failed stabilization of new actin filaments during the first few minutes after LTP induction. Preliminary results showing abnormal expression of several actin-associated proteins in the knockouts (KOs) support this argument. Objectives of the proposed studies are to (1) identify causes for the failure in filamentous (F) actin stabilization and LTP in Fmr1-KO mice, and (2) develop treatments for normalizing cytoskeletal changes and stable LTP. Pilot studies have shown that treatment with the mGluR5 antagonist MPEP, or with a positive AMPA receptor modulator (ampakine), can restore stable LTP to Fmr1-KO hippocampus. Further results indicate that both drugs also reverse measures of aberrant spine morphology in the KOs. The proposed research will build on these findings in 4 specific aims. Aim 1 will test the hypothesis that MPEP can normalize stabilization of spine F-actin and LTP in hippocampal slices from adult Fmr1-KO mice. Further studies will test if LTP impairments are offset by translation inhibitors and linked to aberrant signaling by integrin-associated tyrosine kinases. Aim 2 will test if abnormal basal levels of actin regulatory proteins in Fmr1-KO dendritic spines lead to aberrations in TBS- induced signaling to the actin cytoskeleton. Studies will employ deconvolution immunofluorescent techniques to test effects of theta burst afferent stimulation on levels of target proteins in spines of KO and WT mice. Aim 3 will use acute slices to test if MPEP and ampakine treatments have additive or synergistic effects in the rescue of hippocampal LTP in Fmr1-KO mice (3A). Follow on acute slice experiments will test if the treatments that rescue LTP also normalize (3B) pyramidal cell spine measures and (3C) levels and activity-induced changes in spine actin-regulatory proteins in hippocampal field CA1. Studies in Aim 4 complement those in Aim 3 to test if drugs that rescue hippocampal LTP also restore stable potentiation (4A) and spine measures (4B) in slices from somatosensory neocortex of Fmr1-KO mice. Aim 4C will then test if in vivo treatments with an ampakine, MPEP, or both, normalize spine measures in somatosensory cortex and hippocampal field CA1. Aims 3 and 4 will use Fmr1-KO and WT mice that constitutively express yellow fluorescent protein (YFP) in scattered pyramidal cells to provide a bright label of dendritic spines. These studies are expected to produce a specific explanation for why spine plasticity and structure are disturbed by the Fragile X mutation, and to generate potential therapies for correcting the defects. PUBLIC HEALTH RELEVANCE: Efforts to identify causes of mental retardation associated with Fragile X Syndrome led to the discovery of synaptic plasticity impairments in a mouse model of the disorder. The present studies will test the hypothesis that impairments are due to abnormal levels of actin regulatory proteins, which are critical for changes in synaptic function during learning. Studies will also test potential therapeutics for correcting these synaptic defects that might improve learning in this syndrome and other autism spectrum disorders.
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1 |
2009 — 2010 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bdnf and Spine-Related Disorders of Memory and Cognition (P01). @ University of California-Irvine
Overall Program Abstract. Dendritic spines with abnormal morphology occur in various forms of mental retardation and are also found in psychiatric conditions associated with disturbances to memory and cognition. These widely reported observations raise the possibility that defects in the processes that regulate the spine actin cytoskeleton are a common final substrate for a broad array of learning disabilities. The present proposal, which is a revised application for renewal of PPG #P01NS045260, addresses this hypothesis and potential therapeutic strategies suggested by it. Work under the previous PPG award showed that the stabilization of long-term potentiation (LTP), a form of synaptic plasticity closely related to the encoding of lasting memory, is moderately to severely impaired in rodent models of five distinctly different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), early-life stress, and menopause. Evidence obtained with newly introduced light microscopic techniques indicates that LTP-related reorganization of the spine cytoskeleton is defective in at least three of these cases. Infusions of Brain-Derived Neurotrophic Factor (BDNF) rescued LTP in four of the models and restored activity-driven changes to the cytoskeleton in two so far studied. Increasing brain concentrations of BDNF, using daily drug regimens developed as one of goals the previous PPG, produces similar effects. The proposed studies have the following objectives: i) test the specific prediction that activity-driven cytoskeletal reorganization is abnormal in the different rodent models of memory impairment (this entails adding a mouse model of Angelman's Syndrome to those used in previous work);ii) identify reasons (enzyme, signaling abnormalities) contributing to cytoskeletal defects in the different models;and iii) test if chronic up-regulation of BDNF increases BDNF signaling at synapses and restores actin signaling in spines. There will be four subprojects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. A Core facility will make up the fifth subproject and will provide analytical, administrative, and animal services for the program. In all, the proposed studies are expected to test for the presence of a common neurobiological defect contributing to synaptic plasticity and memory disorders of different origin and to evaluate a clinically relevant strategy for normalizing spine plasticity and behavior. Project 1 Abstract (Christine M. Gall PI). In a number animal models of human cognitive impairment there are disturbances in activity-induced remodeling of the dendritic spine actin cytoskeleton and processes of long term potentiation (LTP) that depend upon it. Studies in this program have provided novel evidence that, for several models, Brain-derived neurotrophic factor (BDNF) can rescue both processes. These results suggest that processes of spine actin remodeling represent a final common path impacted in various conditions of cognitive dysfunction and that, through effects on this process BDNF might offset cognitive deficits of different origins. Project 1 will test the hypothesis that deficiencies associated with signaling in BDNF's TrkB receptor underlie LTP deficits in the Fmr1-knockout (KO) mouse model of Fragile-X Syndrome (FXS) (a mental retardation syndrome with susceptibility for autism spectrum disorder or ASD) and provide a first test of whether the LTP consolidation deficits exhibited by the Fmr1-KO mice are typical of other genetic disorders with high comorbidity for ASD. Specific Aim 1 will test the hypothesis that synaptic BDNF signaling through its TrkB receptor is regulated by neighboring receptor systems and enhanced by increased levels of endogenous BDNF. Subaims will test if the frequency sensitivity of TrkB activation depends on mGluR5 and NMDA receptors and if levels of TrkB activation are elevated with in vivo BDNF protein content is increased. Specific Aim 2 will identify deficits in TBS-induced signaling contributing to deficiencies in spine F-actin stabilization in Fmr1-KOs and, in particular, if there are impairments in the effects of theta burst afferent stimulation on signaling through TrkB and its downstream effectors Src, MAP kinase and the Rho-GTPase Rac1. Aim 3 will test if TBS-induced LTP and aspects of spine actin remodeling that are perturbed in Fmr1-KO mice, are similarly impaired in murine models of other autism associated disorders;to this end BTBR T+ tf/J mice will be evaluated. These studies will identify mechanisms underlying deficits in LTP stabilization in FXS model mice and therefore targets for therapeutics designed to improve cognitive function in autism associated disorders. Project 2 Abstract (Gary Lynch PI). The abnormal spine morphology found in disorders of memory and cognition is suggestive of defects in the local cytoskeleton. Evidence that signaling pathways controlling the organization of actin networks are disturbed in several instances of retardation accords with this idea. The proposed work uses recent advances in immunofluorescence microscopy and image reconstitution to test if activity-driven reorganization of the spine cytoskeleton is defective in rodent models of human conditions in which memory is impaired. The project involves two sets of experiments. Aim One will define signaling pathways used by normally present neuromodulatory factors [Brain-Derived Neurotrophic Factor (BDNF), estrogen] to potently influence the assembly and stabilization of actin filaments within spines following the induction of long-term potentiation (LTP). Changes in the availability of both BDNF and estrogen have been implicated in the failure of LTP to consolidate (stabilize) in the animal models. Aim Two will use the results from Aim One to identify LTP and learning-related defects in spine actin signaling in rodent models of middle-age, early stage Huntington's Disease (HD), and surgical menopause. Additional work addresses the prediction that BDNF will both normalize actin signaling in these cases and, for the HD model mice, will slow the progression of neuropathology in the neostriatum. The proposed work will substantially increase our understanding of how diverse memory disorders disrupt the final steps in consolidating synaptic changes and memory, and lay the groundwork for rigorous testing of a mechanism-based, pharmacologically plausible strategy for correcting such disruptions. Project 3 Abstract (Michel Baudry PI). The general model of LTP motivating the proposed PPG involves three, inter-related categories of events set in motion within dendritic spines by theta burst afferent stimulation (TBS): 1) proteolysis of key structural proteins and transmembrane receptors by calpain;2) reorganization and re-stabilization of the cytoskeletal network;and 3) local protein synthesis. According to the model, each of these elements is modulated by a number of agents, including Brain-Derived Neurotrophic Factor (BDNF), released during TBS. It is further proposed that disturbances to the model's components, or to the modulatory factors, are responsible for a broad array of memory and cognitive disorders. The first broad goal of SubProject 3 for the next two years is to test and expand the protein degradation argument of the general hypothesis. This will involve testing whether calpain activation is a necessary step for TBS-induced actin signaling/polymerization within dendritic spines. It will also involve testing the hypothesis that calpain activation is a consequence of ERK-mediated phosphorylation triggered by BDNF release. The second broad goal makes use of the results from the above experiments, and from other projects in the program, to investigate the causes and potential treatments for spine defects in a mouse model of Angelman Syndrome, a retardation disorder involving a ubiquitin ligase (E6-AP) targeting several elements intimately related to cytoskeletal reorganization. Specifically, Aim 3 will test if local protein synthesis and actin signaling are aberrant in the Ube3a knockout mouse model of Angelman Syndrome. In all, Project 3 addresses fundamental questions regarding spine mechanisms of synaptic plasticity and applies this knowledge to investigate possible causes of, and treatments for, synaptic and cognitive disorders associated with Angelman syndrome. Project 4 Abstract (Tallie Z. Baram, PI). Chronic stress during early postnatal life (ES) results in enduring deficits of learning and memory that become prominent during middle age, associated with profound disturbances in LTP and structural defects of apical dendrites and spines in hippocampal fields CA1 and CA3. ES persistently up-regulates the expression of the stress-activated neuropeptide CRH in hippocampus, and CRH damages spines and dendrites in domains that are impaired after ES, suggesting that CRH may be involved in an ES-provoked cascade of events that eventually leads to synaptic dysfunction. Selective disturbances to synaptic plasticity and dendrite/spine integrity are shared among ES and several disorders discussed elsewhere in this application, and preliminary work suggests that common mechanisms are involved. This project will test the hypothesis that, acting via CRH-CRH receptor signaling, ES leads to two types of disturbances of actin organization in dendritic spines: (1) ES interferes with basal actin polymerization resulting in spine loss;(2) In common with other disorders discussed in this project, ES deranges activity-driven assembly and stabilization of the spine actin-skeleton. Accordingly, the first aim of this 2 year ARRA-supported proposal is to test if actin stabilization mechanisms known to be defective in various rodent models of memory disorders are impacted by CRH-CRH-receptor signaling, and to define the responsible mechanisms. The second aim is to determine the role of endogenous CRH, which is pathologically elevated in ES graduates, in both activity-induced and basal derangements of actin dynamics in spines of middle-aged ES graduates. Collectively, these studies will significantly increase our understanding of why early-life stress leads to cognitive dysfunction in adulthood and set the stage for testing pharmacologically plausible strategies for ameliorating this clinically important neuropsychiatric problem. Project 5, Core, Abstract (C.M. Gall, PI). An advantage of conducting research within a coordinated Program Project is the ability to create core facilities to (i) efficiently and economically share resources and administration support, (ii) provide infrastructure for the scientific objectives of the program, (iii) provide mechanisms for disseminating results and facilitating discussions within the group, and (iv) coordinate interactions with outside investigators to obtain critical evaluation, technical advice and intellectual input to keep the work on track and at the cuing edge of technologies in the field. To this end an Analytical, Administrative and Animal Core (Core A) will be created and directed by Dr. Christine Gall. Core A will address 6 specific aims. Aim 1 is to establish a facility within the Core, for Deconvolution Microscopy-Image analysis, Electrophysiology, Behavioral Assays and BDNF Protein Assays to provide for shared analytical needs of the various subprojects, to ensure that data obtained within the program can be reliably compared across projects, and to make most the economical use of resources and technical support;this will include training and oversight of technical personnel. Facilities for Microscopy and Electrophysiology will be established in years 1 and 2, respectively. Aim 2 is to oversee animal purchase and maintenance costs, genotype mice for the program, and establish a video-monitored system for behavioral studies. Aim 3 is to provide ampakine drugs and neurotrophin reagents (BDNF peptides and antagonists) to subprojects;this includes contracting the synthesis of ampakines from outside sources. Aim 4 is to coordinate collaborations and integration of research results among subproject laboratories through meetings of all program investigators and smaller collaborative groups. Aim 5 is to coordinate interactions with outside investigators to provide review and oversight, technical advice, and outside intellectual input to program investigators: formal internal and external advisory board have been created to help meet these goals. Aim 6 is to provide administrative support and computer assistance for all program investigators. "
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1 |
2011 — 2013 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bdnf and Spine-Realted Disorders of Memory and Cognition @ University of California-Irvine
DESCRIPTION (provided by applicant): Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment; ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models; iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo; and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.
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1 |
2011 — 2015 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bdnf and the Restoration of Synaptic Plasticity in Fragile X and Autism @ University of California-Irvine
In animal models of human cognitive impairment there are disturbances in activity-induced remodeling of the dendritic spine actin cytoskeleton and processes of long term potentiation (LTP) that depend upon it. Our program has shown that Brain-derived neurotrophic factor (BDNF) can rescue both processes in several models. This suggests that spine actin remodeling is a final common path impacted in various conditions of cognitive dysfunction and that, through effects on this process, BDNF can offset cognitive deficits. Project 1 will test this for the Fmr1-KO mouse model of Fragile-X Syndrome (FXS) (a mental retardation syndrome with susceptibility for autism). The Fmr1-KOs have abnormal LTP threshold and stabilization. We find they also lack of normal activity-induced Rac GTPase > p21 activated kinase (PAK) signaling proposed to mediate F-actin and LTP stabilization, but BDNF infusion can still stabilize potentiation in the mutants. Proposed studies will use acute hippocampal slices and in vivo preparations to understand deficiencies in F-actin regulation, and to test an ampakine-BDNF strategy for restoration of function in Fmr1-KOs. Aim 1 will test if failed Rac activation accounts for signaling and LTP impairments in the KOs and if this is secondary to changes in synaptic integrin function. Aim 2 will test if BDNF infusion restores spine signaling through PAK or drives other systems to effect stabilization of spine F-actin and LTP in the KOs. Aim 3 will then test if in vivo treatments (ampakine or ampakine+MPEP) that increase BDNF protein content similarly restore actin regulation and LTP as assessed ex-vivo. Aim 4 will use an unsupervised learning paradigm to test if upregulating BDNF leads to heightened signaling through BDNF's TrkB receptor and a normalization of exploratory behavior and learning in the mutants; these studies will also test if the topography of synapse activation is abnormal in the mutants and normalized in association with increases in BDNF signaling. Finally, Aim 5 will test if TBS-induced LTP, and steps in actin signaling that are perturbed in the Fmr1-KO mice, are disturbed in other animal models of autistic phenotype and corrected by BDNF: this work will evaluate effects in the BTBR T[+] tf/J mice and Tuberous Sclerosis complex model mice. Together these studies will identify mechanisms underlying deficits in LTP stabilization in FXS model mice, determine if the same processes are disturbed in other mouse strains with features of autism, and test if increasing endogenous BDNF is an effective therapeutic strategy for correcting impairments in the cellular mechanisms of learning and memory in models of cognitive conditions associated with autism.
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1 |
2011 — 2015 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Analytical, Administrative and Animal/Reagent Support @ University of California-Irvine
An advantage of conducting research within a coordinated Program Project is the ability to create core facilities to (i) efficiently and economically share resources and administration support, (ii) provide infrastructure for the scientific objectives of the program, (iii) provide mechanisms for disseminating results and facilitating discussions within the group, and (iv) coordinate interactions with outside investigators to obtain critical evaluation, technical advice and intellectual input to keep the work on track and at the cutting edge of technologies in the field. To this end an Analytical, Administrative and Animal/Reagent Core (Core A) will be created and directed by Dr. Christine Gall. Core A will address 4 specific aims. Aim 1 will be to maintain an Analytical Core for Microscopy, Electrophysiology, Behavior and Assay functions. Studies within Projects 1-4 entail analyses of long term potentiation (LTP) in hippocampal slices, localized signaling to actin, modulating endogenous BDNF protein content, and evaluation of treatment effects on unsupervised learning. This will be accomplished using Analytical Core facilities and personnel for microscopy-image analysis, electrophysiology, behavioral analysis (unsupervised learning) and protein assays. Aim 2 will be to support Animal and Reagent functions. Core personnel will coordinate purchases of reagents and ampakines, support mouse colonies employed for UCl Projects, and perform genotyping. Aim 3 will be to manage collaborations and integration of research among Project laboratories, and provide input from internal and external advisory boards (Administration). This includes coordinating both research activities among the projects for access to key analytical facilities (e.g., microscopic, electrophysiological and behavioral facilities and staff) and Program Project collaborative meetings. The Core will also convene meetings with Internal and External Advisory Boards, and seminar speakers. Aim 4 is to provide general administrative support and computer assistance for all program investigators (Administration). This includes general administrative support for grants management, coordinating seminars, oversight of animal use in Core A, supervision of Core personnel, and maintenance of computer servers for Program activities. Overall the Core facilities and functions will provide critical integration of research within the Projects and will support technical platforms that are critical for reaching project goals.
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1 |
2013 — 2017 |
Crawley, Jacqueline N Gall, Christine M Lynch, Gary S (co-PI) [⬀] |
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. |
Convergent Synaptic Mechanisms in Neurodevelopmental Disorders @ University of California At Davis
DESCRIPTION (provided by applicant): Diverse genetic mutations cause different neurodevelopmental disorders, yet many syndromes share similar intellectual impairments. The overarching aim of this multidisciplinary project, enabled by specific expertise from three principal investigators, is to discover fundamental mechanisms responsible for cognitive impairments across genetic mouse models of diverse neurodevelopmental disorders. We hypothesize that various upstream genetic abnormalities converge on common downstream mechanisms to produce learning disabilities across syndromes. Synaptic activation of small GTPases drives remodeling of the dendritic spine actin cytoskeleton, a far-downstream mechanism which underlies enduring synaptic plasticity, learning and memory. We will test the hypothesis that failure to properly reorganize the subsynaptic cytoskeleton is a shared endpoint across neurodevelopmental disorders, employing established mouse models of Fragile X (Fmr1), Rett (Mecp2), Down (Ts65Dn) and Angelman (Ube3a) syndromes. Aim 1 will use theta burst stimulation and three learning paradigms to test the hypothesis that the four mutant lines all exhibit deficits in synaptic GTPase activation and actin remodeling in cortex and hippocampus. We further propose that normalizing these signaling dysfunctions will restore cognitive functions. Our preliminary data indicate that changing the spacing of afferent activity rescues hippocampal long-term potentiation (LTP), and changing the spacing of cognitive training rescues one form of learning. Aim 2 will test the hypotheses that newly identified timing rules for LTP will engage the impaired actin regulatory cascades and facilitate synaptic potentiation in the mutants, and that analogous spaced training regimens in three different cognitive tasks will restore synaptic GTPase activation and learning. We discovered that impairments in actin regulation, LTP and learning in Fmr1 and Ube3a mice are rescued by increasing the availability of BDNF, which facilitates signaling to restore actin stabilization. Ai 3 will employ these same downstream endpoints for preclinical evaluation of pharmacological rescues. Two compounds that lower the threshold for GTPase activation in the wildtypes will be tested for efficacy in (1) reversing defects in signaling leading to actin stabilization, (2) restoing LTP, and (3) improving cognitive performance in the four models. Investigations of novel, broad spectrum behavioral and pharmacological interventions which enhance the activation of downstream mechanisms, and which can be readily implemented clinically, will address a fundamental neurobiological hypothesis with unifying translational implications for improving cognitive abilities in multiple neurodevelopmental disorders.
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0.981 |
2014 — 2015 |
Gall, Christine M |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Bdnf and Spine-Related Disorders of Memory and Cognition @ University of California-Irvine
DESCRIPTION (provided by applicant): Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment; ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models; iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo; and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.
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1 |
2016 — 2020 |
Gall, Christine M Lynch, Gary S [⬀] |
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. |
Loss and Rescue of Endocannabinoid-Dependent Ltp and Memory in Fragile-X Model Mice @ University of California-Irvine
Memory for the ?what?, when? and ?where? of serial events, termed ?episodic memory?, is a critical element in human cognition and is particularly disturbed in conditions of congenital intellectual disability (ID) including autism spectrum disorders (ASDs). The encoding of episodic-like memory depends upon the entorhinal cortex with medial (MEC) and lateral (LEC) fields supporting processing of spatial and non-spatial memories, respectively. With the goal of understanding the neurobiological processes contributing to ID in autism disorders and other forms of congenital cognitive dysfunction, we have evaluated mechanisms of transmission and enduring synaptic plasticity in LEC projections to hippocampus in the Fmr1 KO mouse model for Fragile-X Syndrome (FXS), the most common inherited form of ID which is also co-morbid for autism. Our results show that Fmr1 KOs have particularly severe deficits in the expression of Long-Term Potentiation (LTP) in the LEC- hippocampal connection (the lateral perforant path, LPP) and fail to learn episodic memory tasks that, in wild type (WT) mice, depend upon the LPP. Proposed studies build on these results with goals to identify mechanisms underlying the failure of LTP in Fmr1 KOs and to test manipulations predicted to rescue both potentiation and episodic memory. The project takes advantage of our recent discovery that LTP in the LPP involves novel substrates: LPP potentiation is induced postsynaptically but expressed presynaptically, via increased transmitter release, with the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) as the critical retrograde messenger. The presynaptic adjustments underlying this eCB-dependent LTP (ecLTP) involve CB1 ?mediated signaling and cytoskeletal reorganization within LPP terminals. Collectively, the results suggest that encoding episodic memories depends upon an unusual, pathway specific-form of synaptic plasticity. The three specific aims will test the hypothesis that mechanisms of this ecLTP are severely impaired in Fmr1 KO mice, thus (i) accounting for disturbances in episodic memory and (ii) identifying therapeutic targets to improve learning in this and potentially other forms of ID associated with autism. Aim 1 will identify postsynaptic processes required for ecLTP that are defective in Fmr1 KOs: this aim builds upon preliminary results indicating that on-demand production of 2-AG is impaired in Fmr1 KO mice. Aim 2 will test if presynaptic events that regulate the expression of ecLTP are impaired in the KOs and, in particular, if there are disturbances in the regulation of 2-AG breakdown and CB1 signaling to actin. Finally, Aim 3 will test if in Fmr1 KOs ecLTP, and episodic memory that depends upon it, are rescued by manipulations that enhance 2-AG levels. These studies use a new learning paradigm that tests the `what' component of episodic memory for which WT learning depends on the LPP and Fmr1 KO encoding is severely impaired. Together, results will provide unique insights into the bases of disturbances in episodic memory with congenital ID and identify novel therapeutic targets, and candidate treatments, for enhancement of this specific component of cognition.
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1 |
2018 — 2021 |
Gall, Christine 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. |
Ical: Impact of Cannabinoids Across Lifespan: Pilot Project Core @ University of California-Irvine
PROJECT SUMMARY: PILOT CORE The proposed NIDA Center of Excellence, entitled Impact of Cannabinoids Across the Lifespan (ICAL), will test the hypothesis that non-physiological activation of the endocannabinoid system in adolescence ? caused by exposure to THC or one of its synthetic mimics ? initiates a reprogramming of the genetic and epigenetic processes that govern this system?s molecular structure, neuroanatomical architecture, and synaptic functions, ultimately producing persistent abnormalities in cognition and motivated behavior. To test this hypothesis, ICAL will deploy a vertically integrated strategy combining molecular, neuroanatomical, electrophysiological, and behavioral approaches. ICAL?s scientific and programmatic objectives will yield many opportunities for neuroscience and addiction researchers to explore exciting new avenues of research. ICAL?s Pilot Core is designed to fulfill two major objectives of the Center: (1) to foster innovative research that aligns with the Center?s scientific mission and maximizes use of its research resources; and (2) to provide high-quality career development activities and mentorship for junior investigators and/or investigators new to cannabinoid research. The Pilot Core will achieve these objectives via its annual competition for pilot funding. The Core Director, Christine Gall, PhD, is Professor and Chair of the Department of Anatomy & Neurobiology and Professor of Neurobiology & Behavior at UCI. Dr. Gall will supervise the recruitment of projects and oversee their progress in consultation with the Center director and co-director, the internal Steering Committee (SC) and External Advisory Group (EAG). The Center?s Administrative Core will provide clerical support for this Core. Junior investigators and/or investigators new to the field who receive ICAL pilot funding will be paired with senior faculty members who will provide mentorship during the pilot project funding period and after research is completed. In addition, pilot grantees will have access to the leadership and expertise of the SC and the EAG. The Pilot Core will serve as a conduit for the exploration of new ideas as well as an important venue for mentoring junior investigators and those new to the field. The Core?s leadership will work to ensure that the potential for each individual project and project investigator is fully realized. !
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1 |
2018 — 2021 |
Gall, Christine 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. |
Ical: Impact of Cannabinoids Across Lifespan: Cellular Project @ University of California-Irvine
Project 2 Summary The incidence of cannabis use in the US population has been on the rise over the last decade and with legalization is likely to increase even further in coming years. This includes increases in the prevalence of use in adolescence both as a therapeutic and in social settings. Adolescent use presents special risks as brain networks are still developing and malleable. In this context, evidence that cannibis disturbs cognitive function and can impair learning and memory is a particular concern. Controlled studies with defined doses and outcome measures are clearly needed to understand these cognitive disturbances, and neurobiological processes underlying then. Studies in rodent have shown that exposure to cannabinoids (either ?9- tetrahydrocannabinol (THC), the psychoactive ingredient in cannabis, or a synthetic mimic) alters brain levels of components of the endocannabinoid (ECB) system and impairs specific forms of learning and memory. Less effort has been devoted to analysis of specific forms of synaptic plasticity thought to form the neurobiological substrate for memory or to projection-specific effects. Project 2 will evaluate both of these issues. Aim 1 will use electrophysiological (brain slice) techniques to determine if daily THC treatment of adolescent (ado) and young adult mice (both sexes) influences, and specifically impairs, synaptic transmission and activity-induced long-term potentiation (LTP) for three systems involved in memory encoding: (1) the lateral perforant path (LPP) afferents to hippocampus which we have found exhibits an ECB-dependent form of LTP, (2) Schaffer- commissural afferents to hippocampal field CA1 for which LTP is very well characterized and does not depend on ECB function, and (3) excitatory afferents to medial/prelimbic frontal cortex. Preliminary results indicate that THC effects are indeed projection specific: in male mice, daily ado-THC treatment eliminates the ECB- dependent form of LTP in the LPP. The same THC treatments impair, but do not eliminate non-ECB dependent field CA1-LTP but disturb processing of gamma-frequency afferent input to this region. Aim 1 studies will further determine if ado-THC effects on synaptic transmission persist into middle age, and are greater than effects of similar THC treatments applied to young adults. Aim 2 then will focus on hippocampal systems to test specific hypotheses as to the neurobiological processes underlying disturbances in synaptic plasticity and memory with ado-THC exposure: three sets of studies will test if changes in plasticity are associated with compartment-specific changes CB1R expression and CB1R signaling and if manipulation of ECB levels can offset impairments in synaptic function otherwise induced by ado-THC exposure. These studies have been designed to complement activities in other components of ICAL to provide an extensive vertical analysis of disturbances in substrates that underlie effects of THC on behavioral measures to be assessed in Project 3. Together this work will determine if mnemonic systems in the adolescent brain are particularly vulnerable to THC exposure and if levels of use in real world settings have enduring effects on higher cognitive function. !
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2021 |
Gall, Christine M Lynch, Gary S (co-PI) [⬀] |
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. |
Postnatal Oxytocin Treatment and Cognitive Function in Fragile X @ University of California-Irvine
Autism Spectrum Disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder with high co- morbidity for intellectual disability. This includes difficulties forming episodic, personal narrative, memories that are critical for orderly thinking and organizing future behaviors. Episodic memory deficits are thus thought to be major contributors to cognitive difficulties associated with autism. Many brain changes underlying abnormalities in ASD appear in childhood suggesting the possibility for effective therapeutic strategies targeting brain maturation. One candidate therapeutic is the hypothalamic peptide Oxytocin (OXT). Postnatal OXT treatment improves social behavior in animal models of ASDs and recent work indicates that treatment in childhood improves social interactions in autistic individuals. OXT acutely facilitates forms of synaptic plasticity, but there has been little experimental consideration of possible enduring effects of postnatal OXT treatment on learning and no analyses of effects on episodic memory. We examined this possibility using intranasal OXT (iOXT) treatment in the Fmr1 KO mouse model of Fragile X Syndrome, and novel paradigms for analyses of `What, When and Where' encoding. Our preliminary results show that in Fmr1 KOs iOXT treatments during the second postnatal week (P7-13) fully rescue hippocampal field CA1 long-term potentiation, object location memory, object identity (What) learning, and social recognition as assessed in adulthood (i.e., >40d after the last treatment). These findings raise the exciting possibility that a limited period of early life OXT treatment can effect a life-long rescue of a critical element of cognitive function in ASD. They also raise questions as to the breadth of effects iOXT has on behavior and the mechanisms involved; these questions will be addressed in the proposed studies. Aim 1 studies will test if postnatal iOXT treatment of male and female Fmr1 KO mice rescues encoding for the three major components of episodic memory, social recognition and stereotypic behavior as assessed in adulthood, and if effects depend on native OXT efflux. We will also determine if there is a critical period for enduring iOXT effects on behavior. Aim 2 will use electrophysiological recordings of evoked responses and network activity, analyses of synaptic proteins and signaling, and measures of neuronal arbors to test if postnatal iOXT treatment normalizes neurobiological processes in the distinct hippocampal subdivisions related to episodic memory encoding. Finally, Aim 3 will test the hypothesis that early life iOXT leads to activation of synaptic trophic factor receptors (EGFR, TrkB) in hippocampus, thereby suggesting a direct route for OXT effects on maturational changes in the structure. Overall, the proposed studies will greatly expand our current knowledge of OXT actions in the young brain, including potentially critical roles in regulating hippocampal development and synaptic function. Moreover, the results will lay the groundwork for designing novel, early life regimens to optimize hippocampal maturation and function, and to rescue the encoding of episodic memories in ASD and related developmental disorders.
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