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.

怀孕期间吸烟会对孕妇的身心健康产生严重影响截至 2010 年，估计仍有 12.3% 的后代遭受智商和记忆力的长期损害。在美国，孕妇持续吸烟已被证明含有烟气。超过 8,000 种化学物质，但其中尼古丁被认为是主要的神经致畸剂。使用围产期尼古丁治疗的啮齿动物模型进行的研究表明，接触尼古丁在早期发育过程中会导致学习和记忆的长期缺陷。该领域的问题仍然是尼古丁引起的细胞和分子变化是造成这一现象的基础损害。啮齿类动物出生后的前两周，大致相当于妊娠晚期人类发育，是大脑海马体神经发生和突触发生的关键时期与记忆形成相关的区域，以识别持久的细胞、分子和电路。海马体的变化可能是尼古丁引起的认知障碍的基础，我们使用一个模型啮齿类动物产后早期尼古丁暴露针对的是海马发育的关键时期。我们测试了我们的模型，表明它会导致记忆受损，并使用了电生理学，药理学和电压敏感染料成像技术可识别尼古丁引起的变化我们发现海马网络活动、突触可塑性和海马功能发生了一些变化。海马功能的烟碱调节，全部与 α2 烟碱乙酰胆碱受体相关 (nAChR) 亚型，这可能是记忆缺陷的原因。 α2* nAChR 是大脑中表达最稀疏的 nAChR 亚型，长期以来在研究中被忽视。然而，我们已经证明这种亚型是选择性表达的。位于东方层/肺泡的 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和长时程增强（LTP；被认为是细胞底物）此外，我们的结果表明 α2* nAChR 在海马体中的重要性 - 依赖性记忆，为进一步研究认知机制奠定基础在此提出的研究中，我们将检验以下假设：发育期尼古丁暴露，通过不恰当地激活 α2* nAChR，导致 α2* nAChRs 表达中间神经元，这些变化可能与母体尼古丁诱导的我们的主要目标是确定 α2* nAChR 是否确实发挥作用。母亲尼古丁引起的记忆障碍的因果作用，以及不良影响是否可以通过通过表达 α2* nAChR 的中间神经元的药理学和光遗传学操作来拯救。海马中 α2* nAChR 的表达非常有限，决定了它们在尼古丁诱导的中的作用认知缺陷可以为母亲吸烟的儿童提供独特而强大的治疗目标怀孕。