Maternal smoking and hippocampal circuits
母亲吸烟与海马回路
基本信息
- 批准号:7511729
- 负责人:
- 金额:$ 22.95万
- 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
- 来源:
- 关键词:AcuteAdolescentAffectAnimalsBehavioralBrainBrain regionCellsChildChronicCognitive deficitsDataDevelopmentDoseDrug abuseExcitatory Postsynaptic PotentialsFiberFrequenciesGoalsHippocampus (Brain)Impaired cognitionIncidenceInterneuronsKnockout MiceLeadLearningLifeLong-Term PotentiationMeasuresMediatingMemoryMusNeocortexNeonatalNeurotransmittersNicotineNicotinic ReceptorsOperative Surgical ProceduresOpticsOutputPathway interactionsPhysiologic pulsePlayPregnancyPreventionPublic HealthPyramidal CellsRattusRoleSalineSliceSmokerSmokingSourceSynapsesSynaptic TransmissionSynaptic plasticityTechniquesTestingTobaccoWild Type Mousealveusbasecognitive functionfetalgamma-Aminobutyric Acidmaternal cigarette smokingmonoamineneural circuitoffspringpostnatalpostsynapticpresynapticrelating to nervous systemresearch studysynaptic function
项目摘要
DESCRIPTION (provided by applicant): Smoking during pregnancy is an important public health problem associated with a wide range of adverse neonatal and developmental effects. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of these effects. Animal studies support the view that nicotine, the principle neuroactive component of tobacco, is responsible for these effects. The effects of nicotine are mediated by its interaction with nicotinic acetylcholine receptors (nAChRs). Thus, inappropriate stimulation of nAChRs is most likely responsible for the development of synaptic and behavioral deficits later in life. During early postnatal development, GABAergic interneurons play a critical role in neural circuit formation. Our central hypothesis is that maternal nicotine exposure causes inappropriate GABA release in the hippocampus, a brain region associated with memory formation, via sustained activation of a specific nAChR subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. Hippocampal CA1 pyramidal cells, which provide the major output of the hippocampus, receive two major excitatory synaptic inputs directly or indirectly from the neocortex. Nicotine modulates synaptic transmission and long-term potentiation (LTP; one form of synaptic plasticity and considered to be a cellular substrate of learning and memory) induction in opposite directions at these pathways via the activation of the a2 nAChR subtype. The expression of this subtype in GABAergic interneurons is upregulated during early postnatal development. The goals of the proposed project are to explore whether the sustained activation of the a2 nAChR subtype on GABAergic interneurons in fetal brains affects the functional development of hippocampal circuits. To achieve these goals, we will deliver a chronic nicotine dose during early development, and subsequently examine synaptic function in hippocampal slices prepared from adolescent wild-type and a2 knockout mice using electrophysiological and optical recording techniques. The specific aims are to determine whether maternal nicotine exposure affects: 1) synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner, and 2) nicotinic modulation of synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner. Results from these studies will help determine not only the cellular basis of maternal smoking- induced cognitive impairments, but may also aid in the development of an effective prevention against maternal smoking-induced cognitive impairments by targeting a2 nAChRs. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of these effects. During early postnatal development, GABAergic interneurons play a critical role in neural circuit formation. The proposed experiments will test the hypothesis that maternal nicotine exposure causes inappropriate GABA release in the hippocampus, a brain region associated with memory formation, via sustained activation of a specific nicotinic acetylcholine receptor (nAChR) subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. This project will help determine not only the cellular basis of maternal smoking-induced cognitive impairments, but also may aid in the development of an effective prevention against maternal smoking-induced cognitive impairments by targeting a specific nAChR subtype.
描述(由申请人提供):怀孕期间的吸烟是与多种不良新生儿和发育效果相关的重要公共卫生问题。吸烟者的后代表现出注意力和认知缺陷以及学习和记忆力受损,但对这些影响的潜在机制知之甚少。动物研究支持这样一种观点,即烟草的主要神经活性成分尼古丁是造成这些作用的原因。尼古丁与烟碱乙酰胆碱受体(NACHRS)的相互作用介导。因此,对NACHR的不当刺激很可能导致生命之后的突触和行为缺陷的发展。在产后早期发育期间,GABA能中间神经元在神经回路形成中起关键作用。我们的中心假设是,通过持续激活特定的NACHR亚型在中间神经元上的特定NACHR亚型,导致海马中的母体尼古丁的暴露会导致与记忆形成相关的大脑区域的不适当GABA释放,从而导致持久的电路操作干扰。提供海马的主要输出的海马CA1锥体细胞直接或间接从新皮层接收两个主要的兴奋性突触输入。尼古丁调节突触传播和长期增强(LTP;一种突触可塑性的一种形式,被认为是学习和记忆的细胞底物)通过A2 NACHR亚型的激活在这些途径上的相反方向诱导。在产后早期发育期间,该亚型在GABA能中间神经元中的表达被上调。拟议项目的目标是探索A2 NACHR亚型在胎儿大脑中的GABA能中间神经元的持续激活是否会影响海马电路的功能发展。为了实现这些目标,我们将在早期发育过程中提供慢性尼古丁剂量,然后使用电生理和光学记录技术在青少年野生型和A2敲除小鼠中制备的海马切片中的突触功能。具体目的是确定母体尼古丁的暴露是否影响:1)以A2 NACHR依赖性方式在这两种途径处的突触传播和LTP诱导,以及2)在A2 NACHR依赖性方式中,两种途径在两种途径上对突触传递和LTP诱导的烟碱调节。这些研究的结果将不仅有助于确定孕产妇吸烟引起的认知障碍的细胞基础,而且还可以帮助通过靶向A2 NACHRS来开发有效预防孕产妇吸烟引起的认知障碍。吸烟者的后代表现出注意力和认知缺陷以及学习和记忆力受损,但对这些影响的潜在机制知之甚少。在产后早期发育期间,GABA能中间神经元在神经回路形成中起关键作用。提出的实验将检验以下假设:通过持续激活特定的烟碱乙酰胆碱受体(NACHR)亚型,在海马中导致海马中的尼古丁暴露会导致与记忆形成相关的大脑区域的不适当GABA释放,从而导致电路运算的长期升级。该项目将不仅有助于确定孕产妇吸烟引起的认知障碍的细胞基础,而且还可以通过针对特定的NACHR亚型来开发有效预防孕产妇吸烟引起的认知障碍。
项目成果
期刊论文数量(0)
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KATUMI SUMIKAWA其他文献
KATUMI SUMIKAWA的其他文献
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{{ truncateString('KATUMI SUMIKAWA', 18)}}的其他基金
Maternal nicotine exposure and memory impairments in offspring
母亲尼古丁暴露与后代记忆障碍
- 批准号:
10207576 - 财政年份:2017
- 资助金额:
$ 22.95万 - 项目类别:
Maternal nicotine exposure and development of hippocampal circuits
母亲尼古丁暴露与海马回路的发育
- 批准号:
8507188 - 财政年份:2009
- 资助金额:
$ 22.95万 - 项目类别:
Maternal nicotine exposure and development of hippocampal circuits
母亲尼古丁暴露与海马回路的发育
- 批准号:
8310242 - 财政年份:2009
- 资助金额:
$ 22.95万 - 项目类别:
Maternal nicotine exposure and development of hippocampal circuits
母亲尼古丁暴露与海马回路的发育
- 批准号:
7783218 - 财政年份:2009
- 资助金额:
$ 22.95万 - 项目类别:
Maternal nicotine exposure and development of hippocampal circuits
母亲尼古丁暴露与海马回路的发育
- 批准号:
7935194 - 财政年份:2009
- 资助金额:
$ 22.95万 - 项目类别:
Maternal nicotine exposure and development of hippocampal circuits
母亲尼古丁暴露与海马回路的发育
- 批准号:
8123159 - 财政年份:2009
- 资助金额:
$ 22.95万 - 项目类别:
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