Nicotinic Control of Non-Nicotinic Synapses in the Hippocampus

海马体非烟碱突触的烟碱控制

• 批准号: 7730506
• 负责人: Darwin K BERG
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730506
• 关键词: AMPA Receptors; Acetylcholine; Acute; Address; Adult; Affect; Alzheimer' s Disease; Appearance; Arousal; Behavior; Biological; Biological Neural Networks; Brain; Cations; Cells; Chloride Ion; Chlorides; Cognition; Complement; Dendrites; Dendritic Spines; Deposition; Development; Embryonic Development; Environment; Gated Ion Channel; Glutamates; Hippocampus (Brain); Housing; Image; Ion Channel; Knockout Mice; Knowledge; Life; Ligands; Long-Term Effects; Mammals; Molecular; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Outcome; Output; Parkinson Disease; Pathway interactions; Phase; Play; Process; Recruitment Activity; Regulation; Risk; Role; Shapes; Signal Pathway; Signal Transduction; Slice; Surface; Synapses; System; Testing; Therapeutic Intervention; Tobacco; Tobacco use; Vertebral column; Work; cell type; cholinergic; critical period; dentate gyrus; design; experience; gamma-Aminobutyric Acid; genetic manipulation; hippocampal pyramidal neuron; in vivo; loss of function; nerve supply; nervous system development; neurogenesis; newborn neuron; novel; postnatal; postsynaptic; presynaptic; public health relevance; receptor; research study; synaptic function; synaptogenesis

DESCRIPTION (provided by applicant): Nicotinic cholinergic signaling uses the transmitter acetylcholine to activate ligand-gated ion channels that are cation-selective in mammals. This form of signaling is widespread in the nervous system, reaches peak levels during early postnatal life, and continues throughout adulthood. It contributes to a variety of behaviors including arousal and cognition, participates in a number of neurodegenerative disorders including Alzheimer's and Parkinson's diseases, and is responsible for nicotine addiction. Despite intensive effort, little is understood about the role of nicotinic signaling during development when it drives spontaneous waves of excitation across the nervous system, and little is understood about the nicotinic mechanisms that subsequently exert global effects across networks in the adult brain. This proposal tests two novel hypotheses fundamental to these issues. The first is that nicotinic signaling during development promotes the formation of glutamatergic synapses both on early postnatal and adult born neurons (Aims I & II). Since glutamatergic pathways provide the principal form of excitation in brain, this effect of nicotinic input is likely to have lasting consequences for nervous system function. The second hypothesis is that nicotinic activity in the adult brain can acutely and reversibly alter GABAergic signaling such that it stops being inhibitory and transiently becomes excitatory (Aim III). This could exert far-reaching effects across networks radically altering output. Preliminary studies performed on the hippocampus strongly support these ideas. The two major nicotinic acetylcholine receptors, homopentameric ?7-nAChRs and heteropentameric ?2-containing nAChRs, appear to complement each other in promoting glutamate synapse formation. One appears to act in cell-autonomous fashion to drive postsynaptic spine formation while the other may act indirectly to recruit components required for synaptic function. Preliminary results also support the second hypothesis: low levels of nicotine experienced by tobacco users may be sufficient to transiently invert the chloride gradient in adult neurons, thereby rendering GABA temporarily depolarizing. This could dramatically change the excitability of networks housing those neurons. The hypotheses will be tested by pharmacological and genetic manipulation, including loss-of-function and rescue experiments, performed on hippocampal slices and in vivo. The underlying molecular mechanisms will be analyzed and their consequences evaluated for system function. Imaging and electrophysiological approaches will be combined in this analysis. The experiments proposed here test pivotal ideas about the purpose of nicotinic cholinergic signaling in the nervous system. The results are likely to change how we think about fundamental processes guiding development and regulation of function in neural networks. The vulnerability of these processes to exploitation by tobacco-derived nicotine gives this work compelling health-related significance. PUBLIC HEALTH RELEVANCE: This project will test new ideas about the roles of endogenous nicotinic cholinergic signaling in shaping the developing nervous system and controlling function subsequently in the adult. Because these are the same pathways hijacked by nicotine from tobacco consumption, the studies will also provide important information about the systems at risk and consequences likely to ensue. In addition to addressing fundamental aspects of nervous system function, the studies may identify targets for therapeutic intervention both to reverse or to correct biological deficiencies and to mitigate the impact of habitual tobacco use.

描述（由申请人提供）：烟碱胆碱能信号传导使用递质乙酰胆碱激活哺乳动物中具有阳离子选择性的配体门控离子通道。这种形式的信号在神经系统中广泛存在，在出生后的早期达到峰值水平，并持续整个成年期。它有助于各种行为，包括唤醒和认知，参与许多神经退行性疾病，包括阿尔茨海默病和帕金森病，并负责尼古丁成瘾。尽管进行了大量的努力，但人们对烟碱信号在发育过程中的作用知之甚少，当它驱动神经系统的自发兴奋波时，对随后在成人大脑网络中发挥全局作用的烟碱机制也知之甚少。这个提议测试了两个对这些问题至关重要的新假设。第一个是发育过程中的烟碱信号促进了出生后早期和成年出生的神经元上的突触的形成（目的I和II）。由于多巴胺能通路提供了大脑中主要的兴奋形式，烟碱输入的这种效应可能对神经系统功能产生持久的影响。第二个假设是，成人大脑中的烟碱活性可以急性和可逆地改变GABA能信号传导，使其停止抑制并短暂变为兴奋性（目的III）。这可能会对整个网络产生深远的影响，从根本上改变产出。对海马体进行的初步研究有力地支持了这些观点。两个主要的烟碱乙酰胆碱受体，同型五聚体？7-nAChRs和异五聚体？2-含有nAChR的蛋白质，似乎在促进谷氨酸突触形成中相互补充。一个似乎以细胞自主的方式驱动突触后棘的形成，而另一个可能间接地招募突触功能所需的组件。初步结果也支持第二个假设：烟草使用者所经历的低水平尼古丁可能足以瞬时逆转成人神经元中的氯离子梯度，从而使GABA暂时去极化。这可能会极大地改变容纳这些神经元的网络的兴奋性。这些假设将通过药理学和遗传操作进行测试，包括在海马切片和体内进行的功能丧失和拯救实验。将分析潜在的分子机制，并评估其对系统功能的影响。成像和电生理方法将结合在这项分析中。这里提出的实验测试关于烟碱胆碱能信号在神经系统中的目的的关键思想。这些结果可能会改变我们对指导神经网络功能发育和调节的基本过程的看法。这些过程容易受到烟草衍生尼古丁的利用，这使得这项工作具有令人信服的健康相关意义。 公共卫生相关性：本项目将测试内源性烟碱胆碱能信号在塑造发育中的神经系统和控制功能中的作用的新想法。由于这些是烟草消费中尼古丁劫持的相同途径，这些研究还将提供有关风险系统和可能随之而来的后果的重要信息。除了解决神经系统功能的基本方面外，这些研究还可以确定治疗干预的目标，以扭转或纠正生物缺陷并减轻习惯性烟草使用的影响。