Dopamine and NMDA: role in novelty detection

多巴胺和 NMDA:在新颖性检测中的作用

基本信息

  • 批准号:
    7858385
  • 负责人:
  • 金额:
    $ 25.68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-01 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

Both NMDA hypofunction and dopamine hyperfunction have been implicated in Schizophrenia. Moreover, the hippocampal region appears to be involved in the disease, perhaps because of aberrant novelty detection processes in the CA1 region. These novelty detection processes may depend on predictions arriving at CA1 from CAS via the Schaffer collaterals (SC) and sensory reality arriving directly from cortex via the perforant path (PP). It is therefore important to understand dopamine and NMDAR function in CA1, to elucidate the ways in which they contribute to pathway interactions, and to test the hypothesis that these pathway interactions indeed underlie a novelty detection process. Aim 1 seeks to understand the role of dopamine/NMDAR interactions at the SC and PP. Preliminary evidence indicates that D1 modulation can affect the NMDA conductance through a postsynaptic process, that the NMDA subunits are different in the two pathways and that D1 modulation may depend on NMDA subunit composition. This line of investigation will be continued and extended to D2 modulation. The ability to excite individual synapses using two-photon uncaging of glutamate will allow the first study of dopaminergic modulation at single dendritic spines. It will thus be possible to test whether this modulation is heterogeneous at the single spine level. Aim 2 utilizes both in vivo and in vitro approaches to test the hypothesis that pathway interactions perform a novelty detection process. Whole cell recording will be used to understand the biophysics of pathway interaction and the role of NMDAR and dopaminergic modulation in this process. Preliminary work suggests that pathway interactions can lead to supra-linear dendritic responses and that these are dependent on the NMDAR function. However, other work indicates that naturally occurring processes mediated by GABA conductances and lh can prevent (brake) the supralinearity. Experiments will be conducted to determine whether there are pathway timing conditions or neuromodulatory conditions in which the effectiveness of the brake is minimized. A supralinear response generated by an NMDA spike would be a candidate biophysical response to mediate novelty detection (a match signal). The role of dopamine in modulating these pathways (as studied in Aim 1) will also be examined. A critical need in understanding the pathway interactions studied in vitro is to obtain data about the CA1 computations that occur in vivo. In collaboration with the Center member, Howard Eichenbaum, recordings will be made from the CA1 region during the presentation of novel sequences. Multiple tetrodes will be used to test whether CA1 is a site of novelty detection, as proposed on theoretical grounds. Together these lines of investigation will help to integrate events spanning across multiple levels and elucidate how molecular defects in the NMDA and dopamine system could contribute to symptoms of schizophrenia.
NMDA功能低下和多巴胺功能亢进都与精神分裂症有关。此外,

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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JOSEPH T. COYLE其他文献

Combined Use of Tricyclic Antidepressants and Neuroleptics in the Management of Terminally 111 Children: A Report on Three Cases
  • DOI:
    10.1016/s0002-7138(09)60569-0
  • 发表时间:
    1985-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    MOHAMMAD MAISAMI;BARBARA H. SOHMER;JOSEPH T. COYLE
  • 通讯作者:
    JOSEPH T. COYLE
Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea
用红藻氨酸损伤纹状体神经元可提供亨廷顿舞蹈病的模型
  • DOI:
    10.1038/263244a0
  • 发表时间:
    1976-09-01
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    JOSEPH T. COYLE;ROBERT SCHWARCZ
  • 通讯作者:
    ROBERT SCHWARCZ

JOSEPH T. COYLE的其他文献

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{{ truncateString('JOSEPH T. COYLE', 18)}}的其他基金

Drug Abuse, Schizophrenia, NMDA Receptor
药物滥用、精神分裂症、NMDA 受体
  • 批准号:
    8491057
  • 财政年份:
    2013
  • 资助金额:
    $ 25.68万
  • 项目类别:
Drug Abuse, Schizophrenia, NMDA Receptor
药物滥用、精神分裂症、NMDA 受体
  • 批准号:
    8658065
  • 财政年份:
    2013
  • 资助金额:
    $ 25.68万
  • 项目类别:
Computational Core
计算核心
  • 批准号:
    8074013
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
BIOSTATISTICAL RESEARCH CORE
生物统计研究核心
  • 批准号:
    8074012
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
NMDA hypofunction and episodic memory: An animal model
NMDA 功能减退和情景记忆:动物模型
  • 批准号:
    8074007
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
Clinical Trials with Glutamatergic Agents
谷氨酸能药物的临床试验
  • 批准号:
    8074010
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
Biomarkers of NMDA dysfunction and D-serine effects
NMDA 功能障碍和 D-丝氨酸效应的生物标志物
  • 批准号:
    8074011
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
Functional MR of the Effects of D-Serine
D-丝氨酸作用的功能 MR
  • 批准号:
    8074009
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
Mouse Models of NMDAR Hypofunction
NMDAR 功能减退小鼠模型
  • 批准号:
    8074008
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:
Dopamine and NMDA: role in novelty detection
多巴胺和 NMDA:在新颖性检测中的作用
  • 批准号:
    8074006
  • 财政年份:
    2010
  • 资助金额:
    $ 25.68万
  • 项目类别:

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