1985 |
Kandel, Eric R |
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. |
Cellular Analyses of Behavior @ New York State Psychiatric Institute
The Division of Neurobiology and Behavior consists of seven independent laboratories: Mammalian neurophysiology, invertebrate neurobiology, neuropsychology, neurochemistry, biophysics, developmental neurobiology and morphology. The research of the Division is directed toward cellular analyses of behavior in selected vertebrates and in Aplysia. Because the brains of higher mammals contain trillions of nerve cells and the simplest behaviors involve actions of diverse cells with complex interconnections, our approach has been to reduce experimental preparations to manageable proportions. In mammals, complexity has been simplified by selecting particular brain systems for study. Thus, voluntary movements that depend on sensory clues being transformed into motor movement in just a few synaptic relays. In Aplysia, even complex behavior is mediated by only a small number of neurons. Because many of these cells can be identified individually by electrophysiological biochemical and morphological techniques, it is possible to correlate behavior and learning with neural function.
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0.894 |
1985 — 1986 |
Kandel, Eric R |
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. |
Learning Mechanisms in Abdominal Ganglion of Aplysia @ Columbia Univ New York Morningside
The program of research outlined in this proposal is designed to continue our attempts to develop a behavioral system in the marine mollusc Aplysia in which one can examine in appropriate cellular detail the mechanisms of a variety of short-term and long-term nonassociative and associative types of learning. Toward this end we plan in the proposed research to carry out three interrelated types of studies: 1) an analysis of the molecular mechanisms of two short-term nonassociative forms of behavioral modification habituation and sensitization, 2) an analysis of the relationships between a) short-term habituation and long-term habituation and b) between short-term sensitization and long-term sensitization, 3) an attempt to establish associative learning to analyze it on the cellular level.
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0.939 |
1990 — 1999 |
Kandel, Eric R |
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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Molecular Biological Approach to Ltp in the Hippocampus @ Columbia University Health Sciences
A critical feature of the dementia of the Alzheimer type is an interference with the formation of both short- and long-term memory. One clue that has emerged from a family of recent studies is that the hippocampus is involved in human memory and that damage to only the CA1 region is sufficient to impair the normal conversion of short- to long-term memory. Since LTP occurs in the CA1 region, it now becomes possible to begin to explore in cellular and molecular terms several elementary questions pertaining to normal memory storage. We have been exploring the mechanisms underlying memory in a simple invertebrate system, the monosynaptic component of the gill- and siphon-withdrawal reflex in Aplysia. We found that the proteins synthesized for long-term memory are utilized for two molecular mechanisms: 1) A transcriptionally-dependent persistence in the phosphorylation of the same substrate proteins phosphorylated in the short-term. This results from transcriptionally-dependent depression, perhaps by proteolytic cleavage, of the level of the regulatory subunit of the cAMP-dependent kinase, with the result that the catalytic subunit becomes constitutively active, in the absence of an elevated level of cyclic AMP. This persistence in kinase activity gives the long-term process its striking resemblance to the short-term process. 2) The activation of a growth process whereby new synaptic terminal are formed. This growth process is correlated with, and perhaps results from, the activated in mammalian cells in response to growth factors. The program outline in this proposal attempts to extend to the mammalian brain, and specifically to hippocampal LTP in the CA1 region the approach we have developed in our work on Aplysia. We now plan to explore in the hippocampus six interrelated questions: 1) What is the pattern of phosphorylation produced by LTP? How does the pattern established during the maintenance phase of LTP (2-3 hrs), compare to that of the induction phase (30-60 min)? 2) How does the pattern of phosphorylation, mediated by the C kinase, the Ca2+/calmodulin- dependent kinase or other known second messenger kinases compare to the pattern during initiation of LTP? 3) Does the maintenance of LTP involve persistent phosphorylation by one of these kinases? 4) Is this phosphorylation in the maintenance phase induced by second messengers, transcriptionally-dependent? 5) Does LTP depend on the synthesis of new proteins and mRNAs? 6) If so, what are the genes and proteins whose expression is changed following LTP?
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1 |
1994 — 1998 |
Kandel, Eric R |
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. |
Genetic Approaches to Neural Plasticity and Learning @ Columbia University Health Sciences
The main goal of this proposal is to establish a Center in Neuroscience Research designed to bring a variety of genetic approaches, including transgenic animals and gene transfer methodology, to bear on the study of how individual genes control behavior and learning in mammals. We propose to probe how changes produced by individual genes are reflected in behavior by examining the development of neuronal circuitry, the circuitry's signaling and plastic capabilities, and the circuitry's ability to be modified by experience. To accomplish this goal, the faculty of nine different laboratories at Columbia P&S will focus their efforts on six different projects involving three major themes. A. Neuronal Differentiation and Development: Project 1: Control of Neural Cell Identity and Pattern by Growth Factors. Project 2: Functions of Growth Factors and their Tyrosine Kinase Receptors in Mammalian Neural Development. B. Signal Transduction, Learning and Memory: Project 3: Initial Steps in the Induction of LTP and Spatial Memory: The Molecular Physiology of the NMDA Receptor. Project 4: Later Steps in the Induction of LTP and Spatial Memory: Activation of Second Messengers. C. The Regulation of Transmitter Release by Learning. Project 5: The Retrograde Signal and the Facilitation of Transmitter Release in LTP. Project 6: Role of Presynaptic Proteins in Transmitter Release and Synaptic Plasticity.
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1 |
1996 — 2002 |
Kandel, Eric R |
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. |
Genes, Aging, Learning and Dementia @ Columbia University Health Sciences
A critical feature of the dementia of the Alzheimer type is an interference with the formation of both short-and long term memory. One clue that has emerged from a family of recent studies is that the hippocampus is involved in human memory and that damage to only the CA, region is sufficient to impair the normal conversion of short- to long- term memory. Since LTP occurs in the CA, region, it now becomes possible to begin to explore in cellular and molecular terms several elementary questions pertaining to normal memory storage. Over the last several years, we have been exploring the mechanisms underlying short- and long term memory in a simple invertebrate system, the monosynaptic component of the gill- and siphon-withdrawal reflex in Aplysia. Specifically, we found that the proteins synthesized for long-term memory are utilized for two distinct molecular mechanisms; 1) A transcriptionally dependent persistence in the phosphorylation of the same substrate proteins phosphorylated in the short- term. This results from transcriptionally- dependent depression, perhaps by proteolytic cleavage of the level of the regulatory subunit of the cAMP-dependent kinase, with the result that the catalytic subunit becomes constitutively active, in the absence of an elevated level of cyclic AMP. This persistence in kinase activity gives the long-term process its striking resemblance to the short term process. 2) The activation of a growth process whereby new synaptic terminals are formed. This growth process is correlated with, and perhaps results from, the activation of a set of proteins that bear resemblance to the immediate early proteins activated in mammalian cells in response to growth factors. The program outline in this proposal attempts to extend to the mammalian brain, and specifically to hippocampal LTP in the CA, region, the approach we have developed in our work on Aplysia. We now plan to explore in the hippocampus six interrelated questions: 10 What is the pattern of phosphorylation produced by LTP? How does the pattern established during the maintenance phase of LTP (2-3 hrs), compare to that of the induction phase (30-60 min)? 2) How does the pattern of phosphorylation, mediated by the C kinase, the Ca2+/calmodulin-dependent kinase or other known second messenger kinases compare to the pattern during initiation of LTP? 3) Does the maintenance of LTP involve persistent phosphorylation by one of these kinases? 4) Is this phosphorylation in the maintenance phase inducted by second messengers, transcriptionally dependent? 5) Does LTP depend on the synthesis of new proteins and mRNAs? 6) If so, what are the genes and proteins whose expression is changed following LTP?
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1 |
1996 — 1998 |
Kandel, Eric R |
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. |
Ltp Induction Initial Steps--Second Messenger Activation
long term potentiation; memory; gene induction /repression; second messengers; NMDA receptors; learning; neural plasticity; genetic promoter element; enzyme induction /repression; hippocampus; gene expression; genetic recombination; developmental neurobiology; protein tyrosine kinase; calmodulin dependent protein kinase; in situ hybridization; genetically modified animals; laboratory mouse; electrophysiology;
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1 |
1999 — 2005 |
Kandel, Eric R |
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. |
Genetic Approaches to Neural &Behavioral Plasticity @ Columbia University Health Sciences
DESCRIPTION (Adapted from Applicant's Abstract): The main goal of this proposal is to bring a variety of approaches based on genetically modified mice to bear on the study of how genes control synapse formation, synaptic fine tuning, learning, memory, emotional state, and long-term synaptic plasticity. In so doing, we will be testing, in a number of different and synergistic ways, one central idea; that several, seemingly distinct and apparently unrelated biological processes - development, the fine tuning of a sensory representation in the brain, memory storage and stress related depressive states - reflect, to a large extent, a common set of molecular, genetic, and cellular mechanisms that are expressed in different contexts and in distinct neural circuits. Underlying and unifying these diverse processes is the central importance of long-term synaptic plasticity.
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1 |
1999 — 2002 |
Kandel, Eric R |
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. |
Genetic Dissection of Memory Storage and Retrieval @ Columbia University Health Sciences
DESCRIPTION: In this project the investigators propose to take advantage of recent advances from Center laboratories in the temporal and spatial regulation of transgene expression to address questions about the role of the medial temporal lobe system of mammals in the storage and retrieval processes of memory. Questions to be addressed include identification of the function of different medial temporal lobe regions in explicit memory, determining whether different sites are functionally similar or specialized. If subregions are specialized, how are they specialized and do they participate in different types of memory tasks--- spatial, contextual, object memory or olfactory memory, or do they participate in the different types of operations of explicit memory initial consolidation and storage, retrieval. There are two specific aims. For the first aim, the investigators will determine to what degree the different areas of the medial temporal lobe system contribute preferentially to one or another type of explicit memory tasks: spatial, contextual, object recognition, or olfactory. For a second specific aim, the investigators will determine whether memory retrieval can be disassociated from initial storage. If this is possible, they will attempt to identify the molecular nature of retrieval. They will attempt to determine whether different regions of the hippocampus are specialized for different memory operations such as consolidation and retrieval.
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1 |
2000 |
Kandel, Eric R |
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. |
Minibrain Gene in Down's Syndrome/ Alzheimer's Diseas @ Columbia University Health Sciences
During the past five years we have carried out studies, as part of this Center, that allowed us to defined and characterize the late phase of long- term potentiation (L-LTP). We have found that L-LTP appears to map onto long-term memory formation and we have characterized several molecular components necessary for memory formation. We then went on to show that age-related memory loss in mice is associated with an impairment of L-LTP and that drugs that act on this phase and reserve the physiological defect also reverses the age-related memory loss. To study more effectively the roles of genes in memory formation and memory disorders, we have developed methods for directing and regulating transgene expression in mouse brain, and for brain region specific ablation. We now propose to use these methods for generating new mouse models for Down's Syndrome (trisomy 21). In particular, we want to study the role of minibrain kinase (mnbK)- a gene in the critical Down's syndrome region of chromosome 21-in the cognitive defect of Down's syndrome. We plan to generate mice with regulated expression, in the hippocampus, of the minibrain kinase transgene, as well as mice with hippocampal specific knockout of the minibrain gene In so doing we plan to examine the role of the minibrain kinase in the memory defect, the developmental time course during which expression of the kinase produces, the physiological consequences of minibrain expression in the brain, as well as possible pharmacologic approaches to blocking the action of the kinase. We also propose to use a mouse model to explore the role of the minibrain kinase in the early onset of Alzheimer's disease seen in patients with Down's syndrome. As potential links to Alzheimer's disease we propose. to explore potential substrates for the minibrain kinase.
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1 |
2000 — 2004 |
Kandel, Eric R |
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. |
Molecular Biological Approaches: Ltp in the Hippocampus @ Columbia University Health Sciences
A great deal of work has focused on synaptic plasticity and to the relation of synaptic plasticity to learning and memory. However, changes at the level of the synapse represent only one of several ways of modulating neurons. The input/output functions of a cell and the network to which it belongs also can be altered by changes in the other, nonsynaptic, properties of the neuron. In particular, the rhythmic firing properties of neurons can generate states which profoundly affect that cell's response to a given synaptic input. The recent cloning in our laboratory of genes (HCN-1 and HCN-2) encoding subunits of the Ih channel provides an opportunity to study the role of nonsynaptic mechanisms on both the dynamic and plastic properties of neurons and on the contribution of these properties to behavior. The Ih current contributes to nonsynaptic mechanisms because of its role in the "pacemaker" activity of neurons, enabling the cell to fire rhythmically, and by its ability to change the electrical properties of the membrane. Thus, a lesion of the molecular components of this current would be likely to change both the intrinsic firing properties of individual neurons and the rhythmic network oscillations (such as the theta rhythm) which impinge upon the neuron's response to synaptic input. With these goals in mind, we propose to generate whole animals and CA1-specific knockouts of these genes and to examine how HCN-1 and HCN-2 contribute to the theta rhythm of the hippocampus, to basic cellular and synaptic properties of the CA1 pyramidal cells, and to complex spike bursting and to LTP in these cells, as well as to hippocampal-based memory and to the properties of hippocampal place cells.
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1 |
2004 — 2008 |
Kandel, Eric R |
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. |
Mouse Models of Da and Glutamate Dysfunction @ New York State Psychiatric Institute
The unifying theme of this Center is that schizophrenia reflects an impaired interaction between the dopaminergic and glutamatergic systems of the striatum and the PFC. In addressing this theme this project of this Center will test the idea that many of the symptoms of schizophrenia can be traced to three specifc defects: 1) Striatal dopaminergic hyperactivity 2) Cortical dopaminergic dysregulation and 3) Cortical glutamatergic hypofunction. The hypotheses will be tested using genetically engineered, selective molecular alterations that are both regionally and temporally specific. The objective is to establish specific cause-effect relationships that may help to explain symptoms of schizophrenia. Hypothesis 1 is tested in mice with increased striatal DA D2 receptor expression (aim 1). Hypothesis 2 is investigated in mice with increased neocortical DA D1 receptor expression and decreased DA prefrontal innervation (aim 2) and hypothesis 3 is tested in mice expressing mutant NMDA receptors selectively in D1 receptor positive cells of the neocortex (aim 3). All three mouse models will be used to study a) the behavioral consequences of the genetic modifications with emphasis on: cognitive impairments such as deficits in working memory and behavioral flexibility by the physiological Consequences that may explain Cognitive impairments, c) how cortical and subcortical glutamatergic and dopaminergic systems interact and d) whether there are chronic effects of these modifications that:may lead to neurodevelopmentai abnormalities. Point a) wili be addressed using behavioral methods, point b) using functional imaging and electrophysiological techniques, poim c) using microdiatysis and electrophysiological techniques and point d) using structural brain imaging, stereological measurements and various molecular and biochemical methods including gene expression analysis. First results obtained with mice that over-express DA D2 receptors selectively in the striatum show deficits in working memory tasks. This has two important implications. First, it suggests that subcortical striatal D2 receptors may affect the function of the PFC and second, it suggests that the striatum and its D2 receptors may be more critical for cognitive impairments of schizophrenic patients than it has generally been assumed. The results of the proposed studies will lead to the development of clinical hypotheses that can be subsequently tested in patients.
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0.894 |
2006 — 2010 |
Kandel, Eric R |
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. |
The Role of Neuronal Integration in Working Memory @ Columbia University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): Problem solving and other higher cognitive functions depend on working memory, a short-term memory typically lasting seconds, which is required to maintain and organize an active representation. Studies of learning and memory have tended to focus on the importance of long-term synaptic plasticity for long-term memory storage. Much less is known about how a neuron's non-synaptic integrative properties and excitability influence its ability to modify or translate synaptic changes into an output that can influence behavior. Similarly, relatively little is know about the cellular and molecular mechanisms of short-term explicit memory processes especially working memory. Such an understanding is not only important for the biology of memory storage, but is of great clinical importance as the organization of working memory processes is impaired in many psychiatric diseases, for example it is disordered in schizophrenia and in attention deficit disorders. Here we propose to investigate the cellular mechanisms of short-term explicit memory. We will focus on the role of neuronal integration and excitability and probe them by perturbing neuronal function in the prefrontal cortex and the hippocampus using restricted deletion of the gene encoding the HCN1 (hyperpolarization-activated cyclic nucleotide-gated, non-selective cation) channel. To achieve this aim, we will address three specific questions: 1) Does HCN1 modulate explicit short-term memory processes? 2) How does HCN1 knockout affect the physiological properties of circuits involved in short-term memory both in the prefrontal cortex? 3) Does HCN1 influence the 'on-line' neural representation of information during working memory? [unreadable] [unreadable]
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1 |
2007 — 2012 |
Kandel, Denise B Kandel, Eric R Levine, Amir |
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. |
A Molecular Analysis of the Gateway Hypothesis in Mice @ Columbia University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): The overall goal of the research is to test an epidemiological hypothesis, the Gateway Hypothesis, in molecular terms. The hypothesis describes the sequence of steps whereby use of one class of drug, e.g. cigarettes (nicotine), precedes the use of other drugs, such as cocaine. We propose to test the Gateway Hypothesis at the molecular level using a mouse model. Our approach is further based on the evidence that addiction shares molecular steps and molecular logic with long-term memory. We will address four specific aims: (1) To determine on a behavioral and transcriptional level whether there is the sequential order between nicotine and cocaine predicted by the Gateway Hypothesis, whether this sequence is unidirectional (from nicotine to cocaine) or bidirectional (from cocaine to nicotine), and whether nicotine can also enhance the response to drugs of abuse other that cocaine, such as morphine. (2) To determine the molecular mechanisms by which nicotine primes an animal to the effects of cocaine, we propose to use gene-chip analysis to selected target regions to survey patterns of mRNA in the striatum, particularly the nucleus accumbens, and the amygdala. We will use pharmacological analysis to dissect any possible signal transduction pathway that may mediate the priming effects, and genetically modified mice to explore some of the selected candidate genes emerging from the screen. (3) To identify molecular mechanisms that might contribute to maintaining the gateway effect, we will examine persistent histone acetylation focusing on promoters of FosB and c-Fos, using chromatin immunoprecipitation assays. (4) To characterize the nature and consequences of adolescent drug exposure in both behavioral and molecular terms, we will replicate selected experiments outlined in Aims 1-3 (a) on adolescent mice to compare these results to those obtained on adults, and (b) on adult mice preexposed to nicotine or cocaine to identify the consequences of adolescent drug exposure for drug responses in adulthood to the same or different drugs. Preliminary results from pilot studies support the proposed approach. In addition to testing certain fundamental hypotheses for understanding addiction, these molecular insights are potentially useful for two reasons: (1) They may provide new molecular targets for the treatment of addiction; (2) They are likely to provide new hypotheses about drug behavior in human populations that can be further explored in epidemiological data. Drug abuse represents one of the most important public health issues in the nation. Drug abuse begins in adolescence, with the use of one of the legal drugs, alcohol or tobacco (nicotine); those who use one of these drugs are at much greater risk of progressing to the use of illicit drugs, such as marijuana or cocaine. Those who start smoking in adolescence are much more likely to continue smoking as adults and to experience the adverse health consequences of smoking than individuals who start smoking later in life. The proposed research aims to elucidate the biological mechanisms that underlie the progression in drug use from nicotine to cocaine by using a mouse model. The findings of the research may make it possible to develop new drugs to prevent and treat substance abuse. [unreadable] [unreadable] [unreadable]
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1 |
2012 — 2016 |
Ju, Jingyue [⬀] Kandel, Eric R (co-PI) Moroz, Leonid L (co-PI) [⬀] Sander, Chris (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. |
Genomic Approaches to Deciphering Memory Circuits @ Columbia Univ New York Morningside
DESCRIPTION (provided by applicant): The objective of the proposed research is to conduct a thorough single-cell and cell-compartment gene expression study through the application of high throughput genomic technologies to identify the genomic bases of neuronal identity, polarity and plasticity. Utilizing the well-studied gill withdrawal reflex memory circuit from the model organism Aplysia californica, our goal is to define systematically the molecular repertoire (genomic blueprint) of the neurites and individual synapses of the key neurons that make up this cellular ensemble. We will define the compartmental transcriptomes (the sets of mRNAs, miRNAs and other ncRNAs) within the components of the functional circuit (cells and synapses), which are reconstituted in vitro by co- culture of 2-4 of its best characterized cells (L7 motor neuron, sensory neuron, stimulatory and inhibitory interneurons). This fully operational neural circuit reconstructed in cell culture bears many important properties of the intact circuit, and has been used with great success to ascertain the molecular underpinnings of memory formation in Aplysia, numerous aspects of which are conserved within the animal kingdom, including in the human brain. The systems biology approach will be applied to reveal gene regulatory networks and their potential role in the establishment and maintenance of long-term memory using learned fear as an experimental paradigm, focusing on synaptic mechanisms of long-term facilitation (LTF) and depression (LTD). We will use this genomic and systems biology approach to explore the following three fundamental brain mechanisms: (1) the molecular basis of neuronal identity, by revealing those transcripts that are unique to or shared among these neurons or specialized synapses; (2) the molecular signals controlling cellular polarity and the formation of the precise pattern of interconnections which underlie behavior, in part directed by the distribution of mRNAs in the central and peripheral compartments of these cells; and (3) the molecular basis of synapse-specific neuronal plasticity and neuronal growth, with special attention paid to the mRNA repertoire within the individual synapses at the junctions between pairs of pre- and post-synaptic neurons. The combined approach will take advantage of an already established team of experts in genomics, bioengineering, neuroscience, and bioinformatics. Though these paradigms will be established in the large well-characterized neurons of Aplysia, the mechanisms revealed and the technologies developed will have a broad impact in the biology of any polarized cell type with asymmetric distribution of RNAs and proteins.
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0.939 |