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: 8134323
• 负责人: John Joshua Lawrence
• 金额: $ 30.59万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134323
• 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. PUBLIC HEALTH RELEVANCE: Dysfunction of the medial septum-diagonal band of Broca (MS-DBB) is implicated in a large number of neurodegenerative and psychiatric disease states, such as Alzheimer's disease, Parkinson's disease, schizophrenia, and nerve gas and organic pesticide poisoning. A more complete understanding of the efficacy of synaptic transmission from MS-DBB neurons to hippocampal targets will greatly elucidate the role of the MS-DBB in hippocampal information processing, facilitating the development of new therapeutic approaches for these diseases.

描述(申请人提供)：乙酰胆碱(ACh)从Broca的内侧隔-斜角带(MS-DBB)释放到海马区，深刻改变细胞的兴奋性、网络同步性和行为状态。胆碱能功能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过度胆碱能活动可导致癫痫发作和神经元死亡。ACh对海马区的谷氨酸能和GABA能细胞群有不同的突触前和突触后靶点。最近出现的证据表明，ACh的作用可以是高度特异性的，以细胞类型特异性的方式改变不同GABA能回路的兴奋性。尽管中间神经元和主细胞的激活是这些振荡的基础，但由于系统研究确定的中间神经元群体的技术困难，缺乏关于海马靶细胞接收的胆碱能传入的密度和空间定位的信息，以及无法以选择性而又协调的方式激活广泛分布的MS-DBB神经元群体，对胆碱能突触向特定靶细胞的传递仍知之甚少。通过大纤维刺激，胆碱能反应只能通过突触受体拮抗剂的鸡尾酒才能观察到，但同时，这种药物隔离也阻碍了对MS-DBB传递如何影响兴奋性GABA能和谷氨酸能海马网的全面了解。此外，最近发现在MS-DBB胆碱能神经元中共存的GABA和谷氨酸传递机制增加了共传递的可能性，除非MS-DBB胆碱能纤维在谷氨酸和GABAA受体完整的情况下被选择性地激活，否则不可能观察到这种情况。在这个方案中，我们将结合MS-DBB传入的光激活、光激活纤维的后免疫细胞化学显示、电生理学和计算模型，检验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。我们将首次能够确定MS-DBB传入的空间定位与细胞类型特异性调制的生理后果之间的关系。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的突触传递的有效性。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的突触传递的有效性。最后，在目标3中，我们将确定存在于PV细胞上的M1 mAChRs在胆碱诱导的网络振荡中的作用。 公共卫生相关性：Broca内侧隔-斜角带(MS-DBB)功能障碍与大量神经退行性疾病和精神疾病有关，如阿尔茨海默病、帕金森病、精神分裂症、神经毒气和有机农药中毒。更全面地了解MS-DBB神经元向海马靶的突触传递的有效性，将极大地阐明MS-DBB在海马信息处理中的作用，有助于开发治疗这些疾病的新方法。