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

• 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
• 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' 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

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Broca内侧隔对角带（MS-DBB）释放到海马深刻改变细胞兴奋性、网络同步和行为状态。胆碱能功能的缺陷会导致记忆障碍，如阿尔茨海默病，而神经毒剂或有机磷农药中毒引起的胆碱能活性过度会诱发癫痫发作并导致神经元死亡。乙酰胆碱在海马的谷氨酸能和gaba能细胞群上具有不同的突触前和突触后靶点。最近的证据表明，乙酰胆碱的作用可能是高度特异性的，以细胞类型特异性的方式改变不同gaba能回路的兴奋性。虽然中间神经元和主细胞的激活是这些振荡的基础，但由于系统研究确定的中间神经元群的技术困难，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，胆碱能突触传递到特定靶细胞的信息仍然知之甚少。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。通过大纤维刺激，胆碱能反应只能通过突触受体拮抗剂的混合物来观察，但与此同时，这种药理学隔离阻碍了对MS-DBB传递如何影响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MS-DBB胆碱能神经元中同时存在GABA和谷氨酸传递机制，提出了共同传递的可能性，除非MS-DBB胆碱能纤维能够在谷氨酸和GABAA受体完整的情况下被选择性激活，否则无法观察到这种可能性。在本研究中，我们将结合MS-DBB传入事件的光激活、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，验证MS-DBB胆碱能和gaba能传递的有效性取决于突触后中间神经元亚型的中心假设。我们将首次能够定义MS-DBB传入事件的空间定位与细胞类型特异性调节的生理后果之间的关系。在Aim 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有效性。在Aim 2中，我们将确定MS-DBB gaba能神经元与突触后海马间神经元亚型之间突触传递的有效性。最后，在Aim 3中，我们将确定PV电池上存在的M1 machr在胆碱能诱导的网络振荡中的作用。