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
• 负责人: KATUMI SUMIKAWA
• 金额: $ 34.32万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783218
• 关键词: 3-aminobutyric acid; Adolescence; Adverse effects; Affect; Animals; Biological; Brain; Brain region; Child; Chronic; Cognitive deficits; Development; Dose; Dyes; Excitatory Synapse; Genetic Transcription; Goals; Hippocampus (Brain); Image; Impaired cognition; In Situ Hybridization; Incidence; Interneurons; Knockout Mice; Learning; Long-Term Potentiation; Mediating; Memory; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neocortex; Nicotine; Nicotinic Receptors; Operative Surgical Procedures; Optics; Output; Pathway interactions; Pattern; Play; Polymerase Chain Reaction; Postsynaptic Membrane; Pregnancy; Prevention; Public Health; Pyramidal Cells; Radioactive; Rattus; Research; Reverse Transcription; Risk; Role; Slice; Smoker; Smoking; Source; Staging; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Time; Tobacco; Tobacco smoking; base; cognitive function; drug seeking behavior; gamma-Aminobutyric Acid; information processing; maternal cigarette smoking; neural circuit; offspring; postnatal; prevent; public health relevance; research study; response; selective expression; synaptic function; therapy development; voltage

DESCRIPTION (provided by applicant): Smoking during pregnancy is an important public health problem associated with a wide range of adverse developmental effects. The offspring of smokers have an elevated risk of tobacco smoking, cognitive deficits, and impaired learning and memory during adolescence, but little is known about the mechanisms underlying 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 adverse effects during adolescence. During early postnatal development, 3-aminobutyric acid (GABA)ergic 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 nAChRs, resulting in a long-lasting disturbance of circuit operation extending into adolescence. Hippocampal CA1 pyramidal cells, which provide the major output of the hippocampus, receive two major excitatory synaptic inputs either directly or indirectly from the neocortex. Nicotine modulates synaptic transmission and long-term potentiation (LTP; one form of synaptic plasticity considered to be a cellular substrate of learning and memory) induction in opposite directions at these pathways via activation of the 12 nAChR subtype. This subtype, the most sparsely expressed nAChR subtype in the brain, shows a distinct localization in a subset of GABAergic interneurons in the hippocampus and its activation also modulates LTP induction in these interneurons. These observations suggest that this subtype is an important component in hippocampal circuitry involved in cognitive function. Because this nAChR subtype is continuously activated in the presence of nicotine, maternal nicotine-induced adverse effects may be due to altered functioning of 12* nAChR-expressing interneurons. The goal of this project is to determine whether maternal nicotine exposure influences the functioning of 12* nAChR-expressing interneurons, affecting normal circuit operation and, therefore, information processing in the hippocampus. To achieve this goal, we will deliver a chronic nicotine dose during early postnatal development, and subsequently examine synaptic functioning in hippocampal slices prepared from the rats at various developmental stages, using electrophysiological and optical recording techniques, as well as morphological and molecular biological techniques. The specific aims are to determine whether maternal nicotine exposure affects: 1) the expression of 12* nAChRs and the number of 12* nAChR- expressing interneurons, 2) the operation of circuits, 3) the operation of inhibitory circuits, 4) the nicotinic modulation of N-methyl-D-aspartate receptor responses in pyramidal cells, and 5) the induction of LTP in 12* nAChR-expressing interneurons and at the two major excitatory synapses. 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 the 12 nAChR subtype. PUBLIC HEALTH RELEVANCE: Maternal smoking during pregnancy elevates the risk of attentional and cognitive deficits during adolescence. The proposed experiments will test the hypothesis that maternal nicotine exposure causes inappropriate stimulation of nicotinic acetylcholine receptors in the hippocampus, a brain region associated with memory formation, which results in a long-lasting disturbance of neural circuit operation, and therefore affecting the mechanisms underlying learning and memory during adolescence. Results from the proposed experiments will help determine the cellular basis of maternal smoking-induced cognitive deficits in children.

描述（由申请人提供）：怀孕期间的吸烟是与广泛不利发展效果相关的重要公共卫生问题。吸烟者的后代具有烟草吸烟，认知缺陷以及青春期学习和记忆力受损的风险，但对这些影响的基础机制知之甚少。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，NACHR的不当刺激很可能导致青春期不良反应的发展。在产后早期发育期间，3-氨基丁酸（GABA）ERGIC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，母体尼古丁的暴露会导致海马中的不适当的GABA释放，海马是与记忆形成相关的大脑区域，通过NACHRS，导致电路操作延伸到青春期的持久干扰。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；一种被认为是学习和记忆记忆的细胞底物的一种形式的突触可塑性）通过12 NACHR亚型的激活在相反的方向上诱导了相反的方向。这种亚型是大脑中最稀少的NACHR亚型，在海马中的GABA能中间神经元中显示了明显的定位，其激活也调节了这些神经元中的LTP诱导。这些观察结果表明，该亚型是参与认知功能的海马电路中的重要组成部分。因为在存在尼古丁的情况下，这种NACHR亚型被连续激活，所以母体尼古丁诱导的不良反应可能是由于12* NACHR表达NACHR的中间神经元的功能改变所致。该项目的目的是确定母体尼古丁的暴露是否影响12*表达NACHR的中间神经元的功能，从而影响正常的电路操作，从而影响海马中的信息处理。为了实现这一目标，我们将在产后早期发育期间提供慢性尼古丁剂量，然后使用电生理和光学记录技术以及形态学和分子生物学技术在各种发育阶段中检查从大鼠在各种发育阶段中制备的海马切片中的突触功能。具体目的是确定孕产妇尼古丁的暴露是否影响：1）12* nACHR的表达和12* nACHR表达中间神经元的12* NACHR的数量，2）电路的操作，3）抑制性电路的运行，4）4）N-甲基 - d-木酸盐响应的尼古丁调节，以及5）在5）中的5），以及5）在5）中属于5）。中间神经元和两个主要的兴奋性突触。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，还可以通过靶向12个NACHR亚型来帮助开发针对孕产妇吸烟引起的认知障碍的有效预防。 公共卫生相关性：怀孕期间的孕产妇吸烟增加了青春期注意力和认知缺陷的风险。提出的实验将检验以下假设：母体尼古丁暴露会导致海马中烟碱乙酰胆碱受体的不适当刺激，这是一种与记忆形成相关的大脑区域，这会导致神经回路的持续干扰，从而影响了在自然化过程中的基础机制。提出的实验的结果将有助于确定孕产妇吸烟引起的儿童认知缺陷的细胞基础。