Persistent Impact of Developmental Nicotine on Cholinergic Input to DA Cells

发育期尼古丁对 DA 细胞胆碱能输入的持续影响

• 批准号: 7474709
• 负责人: Susan R. Sesack
• 金额: $ 18.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474709
• 关键词: Address; Adult; Affect; Agonist; Animal Model; Animals; Area; Attention deficit hyperactivity disorder; Axon; Behavior; Behavior assessment; Behavioral; Brain; Brain Stem; Brain region; Cells; Child; Cholinergic Agents; Classification; Communication; Conceptions; Condition; Consumption; Data; Development; Dopamine; Electron Microscopy; Ensure; Exposure to; Goals; Human; Impairment; Individual; Infant; Inhibitory Synapse; Learning Disabilities; Life; Ligands; Light; Link; Measurement; Measures; Medical; Midbrain structure; Modification; Motor Activity; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Outcome; Pathway interactions; Predisposition; Pregnancy; Pregnant Women; Problem behavior; Prosencephalon; Rattus; Recording of previous events; Regulation; Reporting; Smoke; Smoker; Smoking; Staging; Structure; System; Tegmentum Mesencephali; Testing; Tobacco; Tobacco use; Ventral Tegmental Area; addiction; approach behavior; cholinergic; cognitive function; design; dopamine system; dopaminergic neuron; fetal tobacco exposure; immunocytochemistry; improved; mature animal; motivated behavior; nerve supply; neurochemistry; neurotoxic; nicotine replacement; novel; postnatal; prenatal; receptor; research study; transmission process

DESCRIPTION (provided by applicant): More then 17% of pregnant women in the USA smoke and/or use nicotine replacement therapies. Although tobacco contains many harmful substances, nicotine not only underlies the addictiveness of tobacco consumption, it also has neurotoxic and neuroteratogenic effects on the developing brain. In animal models, exposure to nicotine during early development provokes behavioral deficits in offspring that resemble those reported in children after maternal nicotine consumption. Such behavioral impairments, most notably hyperlocomotor activity, are compellingly consistent with malfunctioning of the midbrain dopamine system and its cholinergic innervation, for which nicotine is an agonist. However, no studies to date have examined whether developmental nicotine induces structural alterations in these two cell groups that persist into adulthood. The central hypothesis guiding this proposal is that long-term behavioral impairments following nicotine exposure at particular developmental stages result from underlying morphological alterations of the brainstem dopamine and cholinergic systems. To test this hypothesis using light and electron microscopy, we will conduct the first unbiased stereological assessments of brainstem neurons in adult rats treated with nicotine prenatally or in the early postnatal period, which correspond approximately to the first and second halves of human pregnancy. We will also examine the cholinergic axons communicating between the mesopontine tegmentum (MP) and dopamine cells in the ventral tegmental area (VTA) as well as total excitatory and inhibitory synapses. In Aim 1, we will determine the persitent structural consequences of nicotine exposure during E4-E21 on the VTA and/or MP of adult animals. Aim 2 will examine the persistent structural consequences of nicoitne exposure during P1-P14 on the VTA and/or MP of adult animals. For both aims, we will measure a comprehensive set of cellular and phenotypic parameters in both the VTA and MP and will correlate anatomical measurements with behavioral assessments of locomotor activity in individual animals. The outcome of the proposed studies will allow specific predictions regarding changes in the human brain following prenatal nicotine exposure and facilitate the development of medical treatment strategies for the offspring of smokers by demonstrating the morphological impact on the brain regions that are most likely to be primarily and persistently affected. Pregnant women who smoke or who use nicotine replacement therapy during pregnancy expose their infants to neuroteratogenic effects of nicotine that can result in learning disabilities and behavioral abnormalities. This proposal uses an animal model of early nicotine exposure to examine structural damage in the brain regions that regulate cognitive function, motivated behaviors, and liability for later addiction. The data obtained in these studies will facilitate the development of medical treatment strategies for the children of smokers by revealing the brain regions that are most fundamentally affected by early nicotine exposure.

描述（由申请人提供）：超过 17% 的美国孕妇吸烟和/或使用尼古丁替代疗法。尽管烟草含有许多有害物质，但尼古丁不仅会导致吸烟成瘾，而且还会对发育中的大脑产生神经毒性和神经致畸作用。在动物模型中，早期发育过程中接触尼古丁会引起后代的行为缺陷，类似于母亲摄入尼古丁后儿童的行为缺陷。这种行为障碍，尤其是运动过度，与中脑多巴胺系统及其胆碱能神经支配的功能障碍非常一致，而尼古丁是其中的激动剂。然而，迄今为止还没有研究检验发育过程中的尼古丁是否会引起这两个细胞群的结构改变，并持续到成年期。指导该提议的中心假设是，在特定发育阶段接触尼古丁后的长期行为障碍是由脑干多巴胺和胆碱能系统的潜在形态改变引起的。为了使用光学和电子显微镜检验这一假设，我们将对产前或产后早期接受尼古丁治疗的成年大鼠的脑干神经元进行首次无偏见的体视学评估，这大约相当于人类怀孕的前半期和后半期。我们还将检查中脑桥被盖区 (MP) 和腹侧被盖区 (VTA) 多巴胺细胞之间通讯的胆碱能轴突以及总兴奋性和抑制性突触。在目标 1 中，我们将确定 E4-E21 期间接触尼古丁对成年动物 VTA 和/或 MP 的持久结构影响。目标 2 将检查 P1-P14 期间尼古丁暴露对成年动物 VTA 和/或 MP 的持续结构影响。为了实现这两个目标，我们将测量 VTA 和 MP 中的一套全面的细胞和表型参数，并将解剖测量结果与个体动物运动活动的行为评估相关联。拟议研究的结果将允许对产前接触尼古丁后人脑的变化进行具体预测，并通过证明对最有可能主要和最有可能发生尼古丁的大脑区域的形态影响，促进吸烟者后代的医疗策略的制定。持续受到影响。怀孕期间吸烟或使用尼古丁替代疗法的孕妇会使婴儿遭受尼古丁的神经致畸作用，从而导致学习障碍和行为异常。该提案使用早期接触尼古丁的动物模型来检查调节认知功能、动机行为和后期成瘾责任的大脑区域的结构损伤。这些研究中获得的数据将揭示受早期尼古丁暴露影响最根本的大脑区域，从而促进吸烟者儿童的医疗策略的制定。