Differential modes of cholinergic transmission onto cellular hippocampal targets

胆碱能传输到细胞海马靶标的不同模式

基本信息

批准号：
8662325
负责人：
John Joshua Lawrence
金额：
$ 26.71万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662325
关键词：
Acetylcholine Active Learning Acute Alzheimer&apos s Disease Bathing Behavioral Cells Cessation of life Cholecystokinin Cholinergic Fibers Cholinergic Receptors Computer Simulation Data Dependovirus Development Diagonal Band of Broca Diffusion Disease Electrophysiology (science)Epilepsy Event Fiber Frequencies Functional disorder GABA Receptor Glutamate Receptor Glutamates Health Hippocampus (Brain)Imagery Interneurons Knockout Mice Label Lead Light Maps Medial Memory impairment Mental disorders Methods Modeling Mus Muscarinic Acetylcholine Receptor Myoepithelial cell Neurodegenerative Disorders Neurons Organophosphates Parkinson Disease Parvalbumins Pathway interactions Physiological Population Probability Pyramidal Cells Role Schizophrenia Seizures Site Slice Spatial Distribution Specificity Synapses Synaptic Receptors Synaptic Transmission Techniques Testing Time Training acetylcholine receptor agonist biocytin cell type cholinergic cholinergic neuron density gamma-Aminobutyric Acid information processing innovation mathematical model nerve agent nerve gas novel novel therapeutic intervention overexpression patch clamp pesticide poisoning photoactivation postsynaptic presynaptic receptor research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): Acetylcholine (ACh) release from the medial septum-diagonal band of Broca (MS-DBB) to the hippocampus profoundly alters cellular excitability, network synchronization, and behavioral state. Deficits in cholinergic function induce memory impairments, such as in Alzheimer's disease, while excessive cholinergic activity resulting from nerve agent or organophosphate pesticide poisoning can induce seizures and lead to neuronal death. ACh has diverse pre- and postsynaptic targets onto both glutamatergic and GABAergic cell populations in the hippocampus. Recent evidence has emerged indicating that the actions of ACh can be highly specific, altering the excitability of distinct GABAergic circuits a cell type-specific manner. Although activation of interneurons and principal cells underlie these oscillations, cholinergic synaptic transmission onto specific target cells remains poorly understood due to technical difficulties in systematically studying defined interneuron populations, the lack of information on the density and spatial localization of cholinergic afferents received by hippocampal target cells, and the inability to activate diffusely distributed populations of MS-DBB neurons in a selective yet coordinated manner. Through bulk fiber stimulation, cholinergic responses can be observed only through a cocktail of synaptic receptor antagonists, yet at the same time, this pharmacological isolation prohibits a complete understanding of how MS-DBB transmission impacts the excitability GABAergic and glutamatergic hippocampal networks. Moreover, the recent discovery of GABA and glutamate transmission machinery co-existing in MS-DBB cholinergic neurons raises the possibility of co-transmission, which would not be observed unless MS-DBB cholinergic fibers can be selectively activated with glutamate and GABAA receptors intact. In this proposal, using a combination of photoactivation of MS-DBB afferents, post-hoc immunocytochemical visualization of photoactivated fibers, electrophysiology, and computational modeling, we will test the central hypothesis that the efficacy of MS-DBB cholinergic and GABAergic transmission depends on the postsynaptic interneuron subtype. For the first time, we will be able to define the relationship between the spatial localization of MS-DBB afferents and the physiological consequence of cell type specific modulation. In Aim 1, we will determine the efficacy of synaptic transmission between MS-DBB cholinergic neurons and postsynaptic hippocampal interneuron subtypes. In Aim 2, we will determine the efficacy of synaptic transmission between MS-DBB GABAergic neurons and postsynaptic hippocampal interneuron subtypes. Finally, in Aim 3, we will determine the role of M1 mAChRs present on PV cells in cholinergically-induced network oscillations.

描述（由申请人提供）：乙酰胆碱（ACh）从布罗卡内侧隔对角带（MS-DBB）释放到海马体，深刻改变细胞兴奋性、网络同步和行为状态。胆碱能功能缺陷会导致记忆障碍，例如阿尔茨海默病，而神经毒剂或有机磷农药中毒导致的胆碱能活动过度会诱发癫痫发作并导致神经元死亡。 ACh 对海马谷氨酸能和 GABA 能细胞群有多种突触前和突触后靶标。最近的证据表明，ACh 的作用具有高度特异性，能够以细胞类型特异性的方式改变不同 GABA 能回路的兴奋性。尽管中间神经元和主细胞的激活是这些振荡的基础，但由于系统研究定义的中间神经元群体的技术困难、缺乏海马靶细胞接收的胆碱能传入的密度和空间定位的信息，胆碱能突触向特定靶细胞的传递仍然知之甚少。，以及无法以选择性但协调的方式激活分散分布的 MS-DBB 神经元群体。通过大量纤维刺激，只能通过突触受体拮抗剂的混合物才能观察到胆碱能反应，但与此同时，这种药理学隔离阻碍了对 MS-DBB 传输如何影响 GABA 能和谷氨酸能海马网络兴奋性的完整理解。此外，最近发现 GABA 和谷氨酸传输机制共存于 MS-DBB 胆碱能神经元中，提出了共传输的可能性，除非 MS-DBB 胆碱能纤维能够被完整的谷氨酸和 GABAA 受体选择性激活，否则不会观察到这种情况。在本提案中，结合使用 MS-DBB 传入神经的光激活、光激活纤维的事后免疫细胞化学可视化、电生理学和计算模型，我们将测试中心假设，即 MS-DBB 胆碱能和 GABA 能传输的功效取决于突触后中间神经元亚型。我们将首次能够定义 MS-DBB 传入神经的空间定位与细胞类型特异性调节的生理结果之间的关系。在目标 1 中，我们将确定 MS-DBB 胆碱能神经元和突触后海马中间神经元亚型之间突触传递的功效。在目标 2 中，我们将确定 MS-DBB GABA 能神经元和突触后海马中间神经元亚型之间突触传递的功效。最后，在目标 3 中，我们将确定光伏电池上存在的 M1 mAChR 在胆碱能诱导的网络振荡中的作用。