PRE- AND POSTNATAL TOBACCO SMOKE EXPOSURE:EFFECTS ON NEUROCOGNITIVE DEVELOPMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 母亲吸烟与各种不良胎儿，婴儿和儿童发育结果有关。 仅在美国，每年就有大约100万婴儿在出生前暴露在香烟烟雾中！虽然母亲在怀孕期间吸烟是一个有据可查的低出生体重的危险因素，其伴随的并发症对婴儿/儿童的发展，产前吸烟暴露和出生后的神经行为/认知障碍之间的直接联系仍然不明确。在许多情况下，认知或行为功能障碍的母亲在怀孕期间吸烟的儿童已被归因于低出生体重的临床前因。然而，新出现的证据表明，暴露于香烟烟雾，或成分，如尼古丁和一氧化碳，在怀孕期间，影响中枢神经系统的结构，分子和/或功能发育的剂量远低于那些在围产期生长的变化引起。这表明，母亲吸烟引起的儿童神经行为/认知障碍问题的严重性可能被大大低估，并可能远远超出烟雾暴露的低出生体重后代。 本研究计划的全球目标是建立小鼠-人类实验相关性，以机械地研究母体吸烟诱导的神经/认知发育缺陷的神经解剖学，细胞和分子底物。因为海马体在大脑中  跨物种  在神经/认知方面，特别是在涉及学习和记忆的信息处理方面，正在调查的中心假设是，母亲在怀孕期间吸烟干扰了海马体的细胞和分子个体发生，导致后代依赖海马体的学习和记忆发生改变。本研究拟从四个方面探讨：1）在模拟人类主动吸烟的小鼠模型中，烟草烟雾暴露是否会导致小鼠海马依赖性学习和记忆的神经行为异常; 2]在发育过程中暴露于烟草烟雾引起小鼠海马中正常细胞结构和神经发生的改变，在没有对小鼠胎儿/新生儿生长的伴随影响的情况下; 3]发育期间的烟草烟雾暴露导致小鼠个体发育期间海马神经元亚型特异性基因表达的改变，所述基因是神经元发育可塑性、学习和记忆的关键介质; 4]母亲在人类怀孕期间吸烟会导致婴儿出现不良的神经生理和神经行为结果，这与已知会使婴儿在儿童时期面临学习障碍风险的大脑皮层依赖性基本感知技能的改变有关。成功完成拟议的研究将有助于了解子宫内烟草烟雾暴露对婴儿和儿童神经/认知发育的影响及其机制，  长期  将有助于诊断和干预受产前母亲烟草滥用影响的儿童的学习障碍和其他认知障碍。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Maternal cigarette smoking has been associated with a variety of adverse fetal, infant, and childhood developmental outcomes. In the United States alone, approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight, with its attendant complications for infant/childhood development, a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined. In many cases, cognitive or behavioral dysfunction in children of mothers who smoked during pregnancy has been attributed to the clinical antecedent of low birthweight. However, emerging evidence indicates that exposure to cigarette smoke, or components such as nicotine and carbon monoxide, during pregnancy, affects the structural, molecular and/or functional development of the central nervous system at doses well below those at which perinatal growth alterations are elicited. This suggests that the magnitude of the problem regarding maternal smoking-induced neurobehavioral/cognitive impairment in children may be greatly underappreciated, and may extend well beyond only smoke-exposed low birthweight offspring. The global objective of the present research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical, cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuro/cognitive development. Since the hippocampus subserves a central role  across species  in neuro/cognition, especially in the information processing involved in learning and memory, the central hypothesis under investigation is that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus, resulting in altered hippocampus-dependent learning and memory in the offspring. Four Specific Aims are proposed to determine whether: 1] Tobacco smoke exposure during development, in a murine model simulating human active cigarette smoking, results in neurobehavioral abnormalities involving hippocampus-dependent learning and memory; 2] Alterations in the establishment of normal cytoarchitecture and neurogenesis in the murine hippocampus are elicited by exposure to tobacco smoke during development, in the absence of attendant effects on murine fetal/neonatal growth; 3] Tobacco smoke exposure during development results in hippocampal neuronal subtype-specific alterations in the expression of genes during murine ontogenesis that are critical mediators of neuronal developmental plasticity, learning and memory; 4] Maternal smoking during pregnancy in humans results in adverse neurophysiological and neurobehavioral outcomes in infants, which are associated with alterations in hippocampus-dependent basic perceptual skills known to place the infant at risk for learning disabilities during childhood. Successful completion of the proposed studies will aid in understanding the effects of, and mechanisms underlying, in utero tobacco smoke exposure on neuro/cognitive development in infants and children, and  long-term  will facilitate the diagnosis of, and intervention into, learning disabilities and other cognitive impairments in children affected by prenatal maternal tobacco abuse.