Maternal nicotine exposure and memory impairments in offspring

母亲尼古丁暴露与后代记忆障碍

基本信息

批准号：
10207576
负责人：
KATUMI SUMIKAWA
金额：
$ 34.76万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207576
关键词：
Adolescence Adverse effects Agonist Brain Brain region Cells Chemicals Child Cognitive deficits Development Dose Down-Regulation Elderly Electrophysiology (science)Epigenetic Process Face Foundations Goals Hippocampus (Brain)Human Development Human Milk Hypersensitivity Imaging Techniques Impaired cognition Impairment Interneuron function Interneurons Learning Life Long-Term Potentiation Mediating Mediator of activation protein Memory Memory impairment Mental Health Methods Modeling Molecular Mothers Mus Mutant Strains Mice Nature Neurons Nicotine Nicotinic Receptors Optics Perinatal Pharmacology Play Pregnancy Pregnant Women Rattus Receptor Activation Research Risk Rodent Rodent Model Role Smoke Smoking Synaptic plasticity Testing Therapeutic Third Pregnancy Trimester Time Transgenic Organisms United States Wild Type Mouse alveus cigarette smoke cigarette smoking critical period epigenetic silencing experimental study maternal cigarette smoking maternal nicotine exposure neural circuit neurogenesis neuroteratogen nicotine exposure nicotine treatment offspring optogenetics physical conditioning postnatal postnatal development prevent receptor downregulation receptor function selective expression smoking during pregnancy synaptogenesis therapeutic target therapy adverse effect therapy development voltage sensitive dye

项目摘要

Cigarette smoking during pregnancy can have severe impacts on the mental and physical health of offspring, including long-lasting impairments in IQ and memory. Still, as of 2010 an estimated 12.3% of expectant mothers in the United States continued smoking. Cigarette smoke has been shown to contain more than 8,000 chemicals, but among these nicotine is thought to be the leading neuroteratogen. Several studies using rodent models of perinatal nicotine treatment have demonstrated that exposure to nicotine during early development causes long-lasting deficits in learning and memory. However, the outstanding question in the field remains which cellular and molecular changes induced by nicotine underlie this cognitive impairment. The first two weeks of postnatal development of rodents, which is roughly equivalent to the third trimester of human development, is a critical time for neurogenesis and synaptogenesis in the hippocampus, a brain region associated with memory formation. In order to identify long-lasting cellular, molecular and circuitry changes in the hippocampus that may underlie nicotine-induced cognitive impairments, we use a model of early postnatal nicotine exposure in rodents that targeted this critical period of hippocampal development. We have tested our model to show that it results in impaired memory, and used electrophysiological, pharmacological and voltage sensitive dye imaging techniques to identify nicotine-induced changes in hippocampal function. We found several changes in hippocampal network activity, synaptic plasticity and nicotinic modulation of hippocampal function, all associated with the α2 nicotinic acetylcholine receptor (nAChR) subtype, that could be the cause of memory deficits. The α2* nAChR, the most sparsely expressed nAChR subtype in the brain, has long been ignored in the study of nicotine's central action. However, we have shown that this subtype, which is selectively expressed in GABAergic interneurons in the stratum oriens/alveus, is an important component in the hippocampal circuitry gating information flow and long-term potentiation (LTP; considered to be a cellular substrate of learning and memory). Furthermore, our results suggest the importance of α2* nAChRs in hippocampus- dependent memory, and lay the foundation for further studies of the mechanisms underlying cognitive impairment after maternal smoking. In the research proposed here, we will test the hypotheis that developmental nicotine exposure, by inappropriately activating α2* nAChRs, causes functional alterations of α2* nAChRs-expressing interneurons, and that these changes could be tied to maternal-nicotine-induced hippocampal memory impairments. Our major goals are to determine whether the α2* nAChR indeed plays a causal role in maternal-nicotine-induced memory impairments, and whether the adverse effects can be rescued by pharmacological and optogenetic manipulations of α2* nAChR-expressing interneurons. Given the very limited expression of α2* nAChRs in the hippocampus, determinating their role in nicotine-induced cognitive deficits could yield a unique and powerful therapeutic target for children whose mothers smoked in pregnancy.

怀孕期间吸烟可能会对身心健康产生严重影响后代，包括智商和记忆中的长期损害。不过，截至2010年估计有12.3％美国的准妈妈继续吸烟。香烟烟已被证明包含超过8,000种化学物质，但在这些尼古丁中，被认为是主要的神经瘤原。一些使用围产期尼古丁治疗的啮齿动物模型的研究表明，暴露于尼古丁在早期发展期间，在学习和记忆中引起了持久的定义。但是，杰出的野外的问题仍然存在于尼古丁引起的细胞和分子变化的基础认知障碍。啮齿动物产后发育的前两周，大约等同于第三个三个月人类发育是海马，大脑神经发生和突触发生的关键时期与内存形成相关的区域。为了识别持久的细胞，分子和电路海马的变化可能是尼古丁引起的认知障碍的基础的，我们使用的模型针对海马发育的关键时期的啮齿动物的早期产后尼古丁暴露。我们已经测试了我们的模型，以表明它会导致记忆受损，并使用电生理学，药理和电压敏感的染料成像技术，以鉴定尼古丁诱导的变化海马功能。我们发现海马网络活动，突触可塑性和海马功能的烟碱调节，所有与α2烟碱乙酰胆碱受体有关（NACHR）亚型，这可能是记忆缺陷的原因。 α2* nACHR是大脑中最稀疏表达的NACHR亚型，早已被忽略研究尼古丁的中心作用。但是，我们已经证明了这种亚型，该亚型被选择性地表达在术阶层/牙槽中的GABA能中间神经元中，是海马的重要组成部分电路门控信息流量和长期潜在（LTP；被认为是细胞底物学习和记忆）。此外，我们的结果表明α2* NACHR在海马 - 依赖记忆，并为认知基础机制的进一步研究奠定基础吸烟后的损害。在这里提出的研究中，我们将测试假设通过不当激活α2* NACHRS的发育性尼古丁暴露会导致功能改变 α2*表达NACHRS的中间神经元，并且这些变化可以与母体 - 纽索丁诱导海马记忆障碍。我们的主要目标是确定α2* NACHR是否确实在玩在母体 - 纽索丁引起的记忆障碍中的因果作用，以及不良影响是否可以是由表达NACHR的中间神经元的药物和光遗传操作营救。给出海马中α2* NACHR的表达非常有限，确定了它们在尼古丁诱导的认知缺陷可以为母亲吸烟的儿童带来独特而有力的治疗靶标怀孕。