Functional significance of dopamine plasticity induced by neonatal nicotine exposure affecting adult drug preference

新生儿尼古丁暴露诱导的多巴胺可塑性影响成人药物偏好的功能意义

• 批准号: 9888173
• 负责人: Davide Dulcis
• 金额: $ 22.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888173
• 关键词: Address; Adolescent; Adult; Affect; Age; Alcohols; Anatomy; Appearance; Behavior; Brain; Chronic; Data; Development; Dopamine; Drug abuse; Electronic cigarette; Embryo; Exposure to; Fiber; Goals; Health; Health Campaign; Human; Knowledge; Lactation; Life; Measures; Mediating; Methamphetamine; Modernization; Molecular; Mus; Neonatal; Neuronal Plasticity; Neurons; Neurotransmitters; Nicotine; Nucleus Accumbens; Output; Periodicity; Pharmaceutical Preparations; Phenotype; Photometry; Predisposition; Pregnancy; Pregnant Women; Process; Psychological reinforcement; Public Health; Rattus; Research; Rewards; Role; Scanning; Smoker; Smoking; Substance of Abuse; Synapses; System; Technology; Testing; Therapeutic Intervention; Tobacco; Tobacco use; Transgenic Mice; United States; Ventral Tegmental Area; Work; addiction; dopaminergic neuron; experience; experimental study; functional plasticity; in vivo; insight; maternal nicotine exposure; mature animal; neonatal exposure; neural circuit; neural network; neuronal circuitry; nicotine exposure; nicotine patch; nicotine use; novel; offspring; optogenetics; preference; psychostimulant; recruit; response; reward processing; tobacco products

Project Summary Abstract Neonatal exposure to nicotine and other psychostimulants has a significant impact on the function of reward- seeking centers affecting nicotine consumption and the susceptibility to drug abuse in the adult. Alteration in circuit activation during development triggers the appearance of dopaminergic phenotype in neurons that normally produce different neurotransmitters. The immediate goal of our research is to understand the functional significance of this novel form of nicotine- induced form of neuroplasticity at the level of identified neurons in the adult brain. The hypothesis is that neonatal activation of a neural circuit induced by nicotine exposure leads to transmitter plasticity in neurons in the activated circuit, which leads to corresponding changes in nicotine consumption and other reward seeking- behaviors in the adult. Our goal is to identify the neurons involved in this novel form of plasticity and determine whether newly expressing dopaminergic (TH+) terminals release dopamine in the reward center to activate target neurons of the nucleus accumbens. The long-term goal of this research is to understand how neural network activation can be used to induce neurotransmitter plasticity to enable therapeutic interventions in the addiction-susceptible brain. These studies will provide new insights into the anatomical and functional plasticity of the developing reward center affecting adult drug preference. Transgenic mouse lines and modern technologies, such as Fast-Scan Cyclic Voltammetry and optogenetics, implemented to measure evoked dopamine release and record neuronal activity (via fiber photometry) in selected classes of neurons enable analysis of the functional significance of neurotransmitter plasticity caused by developmental exposure to psychostimulants as well as its role in reprogramming cellular phenotypes and drug preference in vivo. Significantly, this work will identify the cellular and molecular identity and connectivity of reward-mediating neurons that are nicotine-primed during development to be recruited for dopamine expression and release following secondary nicotine exposure in the adult.

项目摘要 新生儿暴露于尼古丁和其他精神兴奋剂对奖赏功能有显著影响- 寻找影响成人尼古丁消耗和药物滥用易感性的中心。的改变 发育过程中的回路激活触发了神经元中多巴胺能表型的出现， 通常产生不同的神经递质。 我们研究的直接目标是了解这种新型尼古丁的功能意义- 在成人大脑中识别出的神经元水平上的神经可塑性的诱导形式。前提是 尼古丁暴露诱导的新生儿神经回路激活导致神经元中的递质可塑性， 激活的回路，导致尼古丁消耗和其他奖励寻求的相应变化- 成年人的行为。我们的目标是识别参与这种新形式可塑性的神经元，并确定 新表达的多巴胺能（TH+）末梢是否在奖赏中心释放多巴胺， 靶神经元的神经元。这项研究的长期目标是了解神经系统如何 网络激活可用于诱导神经递质可塑性， 易上瘾的大脑 这些研究将为发育中奖赏的解剖学和功能可塑性提供新的见解 影响成人药物偏好的中心转基因小鼠品系和现代技术，如快速扫描 循环伏安法和光遗传学，用于测量诱发的多巴胺释放并记录神经元 在选定类别的神经元中的活动（通过纤维光度法）使得能够分析神经元的功能意义。 神经递质可塑性所造成的发展暴露于精神兴奋剂，以及它的作用， 在体内重编程细胞表型和药物偏好。 重要的是，这项工作将确定奖励介导的细胞和分子的身份和连接性， 在发育过程中被尼古丁激发的神经元被募集用于多巴胺的表达和释放 在成年人二次尼古丁暴露后。