Maternal smoking and hippocampal circuits

母亲吸烟与海马回路

• 批准号: 7511729
• 负责人: KATUMI SUMIKAWA
• 金额: $ 22.95万
• 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: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511729
• 关键词: Acute; Adolescent; Affect; Animals; Behavioral; Brain; Brain region; Cells; Child; Chronic; Cognitive deficits; Data; Development; Dose; Drug abuse; Excitatory Postsynaptic Potentials; Fiber; Frequencies; Goals; Hippocampus (Brain); Impaired cognition; Incidence; Interneurons; Knockout Mice; Lead; Learning; Life; Long-Term Potentiation; Measures; Mediating; Memory; Mus; Neocortex; Neonatal; Neurotransmitters; Nicotine; Nicotinic Receptors; Operative Surgical Procedures; Optics; Output; Pathway interactions; Physiologic pulse; Play; Pregnancy; Prevention; Public Health; Pyramidal Cells; Rattus; Role; Saline; Slice; Smoker; Smoking; Source; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Tobacco; Wild Type Mouse; alveus; base; cognitive function; fetal; gamma-Aminobutyric Acid; maternal cigarette smoking; monoamine; neural circuit; offspring; postnatal; postsynaptic; presynaptic; relating to nervous system; research study; synaptic function

DESCRIPTION (provided by applicant): Smoking during pregnancy is an important public health problem associated with a wide range of adverse neonatal and developmental effects. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of 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 synaptic and behavioral deficits later in life. During early postnatal development, GABAergic 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 sustained activation of a specific nAChR subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. Hippocampal CA1 pyramidal cells, which provide the major output of the hippocampus, receive two major excitatory synaptic inputs directly or indirectly from the neocortex. Nicotine modulates synaptic transmission and long-term potentiation (LTP; one form of synaptic plasticity and considered to be a cellular substrate of learning and memory) induction in opposite directions at these pathways via the activation of the a2 nAChR subtype. The expression of this subtype in GABAergic interneurons is upregulated during early postnatal development. The goals of the proposed project are to explore whether the sustained activation of the a2 nAChR subtype on GABAergic interneurons in fetal brains affects the functional development of hippocampal circuits. To achieve these goals, we will deliver a chronic nicotine dose during early development, and subsequently examine synaptic function in hippocampal slices prepared from adolescent wild-type and a2 knockout mice using electrophysiological and optical recording techniques. The specific aims are to determine whether maternal nicotine exposure affects: 1) synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner, and 2) nicotinic modulation of synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner. 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 a2 nAChRs. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of these effects. During early postnatal development, GABAergic interneurons play a critical role in neural circuit formation. The proposed experiments will test the hypothesis that maternal nicotine exposure causes inappropriate GABA release in the hippocampus, a brain region associated with memory formation, via sustained activation of a specific nicotinic acetylcholine receptor (nAChR) subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. This project will help determine not only the cellular basis of maternal smoking-induced cognitive impairments, but also may aid in the development of an effective prevention against maternal smoking-induced cognitive impairments by targeting a specific nAChR subtype.

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，与多种新生儿和发育不良影响相关。吸烟者的后代表现出注意力和认知缺陷以及学习和记忆受损，但人们对这些影响的潜在机制知之甚少。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晚年突触和行为缺陷的原因。在出生后早期发育过程中，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，母亲接触尼古丁会通过中间神经元上特定 nAChR 亚型的持续激活，导致海马体（与记忆形成相关的大脑区域）不适当的 GABA 释放，从而导致回路运行的长期干扰。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 a2 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。这种亚型在 GABA 能中间神经元中的表达在出生后早期发育过程中上调。该项目的目标是探索胎儿大脑中 GABA 能中间神经元上 a2 nAChR 亚型的持续激活是否会影响海马回路的功能发育。为了实现这些目标，我们将在早期发育过程中提供慢性尼古丁剂量，随后使用电生理学和光学记录技术检查由青少年野生型和 a2 敲除小鼠制备的海马切片中的突触功能。具体目的是确定母体尼古丁暴露是否影响：1）以 a2 nAChR 依赖性方式在两条通路上突触传递和 LTP 诱导，以及 2）a2 nAChR 中两条通路的烟碱调节突触传递和 LTP 诱导依赖方式。这些研究的结果不仅有助于确定母亲吸烟引起的认知障碍的细胞基础，而且还可能有助于通过靶向 a2 nAChR 来有效预防母亲吸烟引起的认知障碍。吸烟者的后代表现出注意力和认知缺陷以及学习和记忆受损，但人们对这些影响的潜在机制知之甚少。在出生后早期发育过程中，GABA能中间神经元在神经回路形成中发挥着关键作用。拟议的实验将验证这样的假设：母体接触尼古丁会通过中间神经元上特定烟碱乙酰胆碱受体（nAChR）亚型的持续激活，导致海马体（与记忆形成相关的大脑区域）不适当的 GABA 释放，从而导致长期的干扰电路操作。该项目不仅有助于确定母亲吸烟引起的认知障碍的细胞基础，而且还可能通过针对特定的 nAChR 亚型来帮助开发有效预防母亲吸烟引起的认知障碍的方法。