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
• 负责人: KATUMI SUMIKAWA
• 金额: $ 34.08万
• 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/7935194
• 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; 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; operation; 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）：怀孕期间吸烟是一个重要的公共卫生问题，与多种不良发育影响相关。吸烟者的后代在青春期吸烟、认知缺陷以及学习和记忆受损的风险较高，但人们对这些影响的机制知之甚少。动物研究支持这样的观点，即烟草的主要神经活性成分尼古丁是造成这些影响的原因。尼古丁的作用是通过其与烟碱乙酰胆碱受体（nAChR）的相互作用介导的。因此，nAChR 的不当刺激很可能是导致青春期不良反应发生的原因。在出生后早期发育过程中，3-氨基丁酸 (GABA) 能中间神经元在神经回路形成中发挥着关键作用。我们的中心假设是，母亲接触尼古丁会导致海马体（与记忆形成相关的大脑区域）通过 nAChR 释放不适当的 GABA，从而导致神经回路运作的长期干扰，一直延伸到青春期。海马 CA1 锥体细胞提供海马的主要输出，直接或间接从新皮质接收两种主要的兴奋性突触输入。尼古丁通过激活 12 nAChR 亚型，以相反的方向调节突触传递和长时程增强（LTP；突触可塑性的一种形式，被认为是学习和记忆的细胞基质）诱导。该亚型是大脑中表达最稀疏的 nAChR 亚型，在海马 GABA 能中间神经元子集中显示出明显的定位，并且其激活也调节这些中间神经元中的 LTP 诱导。这些观察结果表明，这种亚型是参与认知功能的海马回路的重要组成部分。由于这种 nAChR 亚型在尼古丁存在的情况下持续激活，母体尼古丁引起的不良反应可能是由于 12* nAChR 表达中间神经元的功能改变所致。该项目的目标是确定母亲接触尼古丁是否会影响表达 12* nAChR 的中间神经元的功能，从而影响正常的回路操作，从而影响海马体的信息处理。为了实现这一目标，我们将在出生后早期发育期间提供慢性尼古丁剂量，随后使用电生理学和光学记录技术以及形态学和分子生物学技术检查从不同发育阶段的大鼠制备的海马切片的突触功能。具体目的是确定母体尼古丁暴露是否影响：1) 12* nAChR 的表达和表达 12* nAChR 的中间神经元的数量，2) 回路的运行，3) 抑制回路的运行，4) 烟碱调节锥体细胞中的 N-甲基-D-天冬氨酸受体反应，以及 5) 在 12* nAChR 表达的中间神经元中诱导 LTP两个主要的兴奋性突触。这些研究的结果不仅有助于确定孕产妇吸烟引起的认知障碍的细胞基础，而且还可能有助于通过针对 12 nAChR 亚型来有效预防孕产妇吸烟引起的认知障碍。 公共卫生相关性：母亲在怀孕期间吸烟会增加青春期注意力和认知缺陷的风险。拟议的实验将检验这样的假设：母亲接触尼古丁会导致海马体（与记忆形成相关的大脑区域）中的烟碱乙酰胆碱受体受到不当刺激，从而导致神经回路运行的长期干扰，从而影响学习的机制以及青春期的记忆力。拟议实验的结果将有助于确定母亲吸烟引起的儿童认知缺陷的细胞基础。