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: 8042776
• 负责人: John Joshua Lawrence
• 金额: $ 27.54万
• 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/8042776
• 关键词: Acetylcholine; Active Learning; Acute; Agonist; 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; Glutamate Receptor; Glutamates; Hippocampus (Brain); Imagery; Interneurons; Knockout Mice; Label; Lead; Maps; Medial; Memory impairment; Mental disorders; Methods; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Myoepithelial cell; Nerve Degeneration; 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; 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; public health relevance; 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（由申请人提供）：乙酰胆碱（ACH）从Broca（MS-DBB）内侧隔隔离带释放到海马，深刻地改变了细胞兴奋性，网络同步和行为状态。胆碱能功能的缺陷会诱导记忆障碍，例如阿尔茨海默氏病，而神经剂或有机磷酸盐农药中毒引起的过度胆碱能活性会诱发癫痫发作并导致神经元死亡。 ACH在海马中的谷氨酸能和GABA能细胞群体上具有多种突触前和突触后靶标。最近出现的证据表明，ACH的作用可能是高度特异性的，从而改变了不同的GABA能电路的兴奋性特定于细胞类型的方式。 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选择性但协调的方式。通过散装纤维刺激，只能通过突触受体拮抗剂的鸡尾酒观察胆碱能反应，但与此同时，这种药理隔离不完全理解MS-DBB的传播如何影响兴奋性GABAERGIC和GLUTAMATAMERTGIC HAMPOCAMPALENTECTS。此外，最近发现在MS-DBB胆碱能神经元中共存的GABA和谷氨酸传输机械增加了共透传的可能性，除非能够用谷氨酸和GABAA受体完整地选择性地激活MS-DBB胆碱能纤维，否则不会观察到它们。在这一建议中，使用光活化的光活化，光活化后的光活化纤维，电生理学和计算建模的可视化，我们将测试以下中心假设，即MS-DBB胆碱能和GABA能传播的效率取决于后Sepynaptic Interneyron subseepecepecepececep。我们将第一次能够定义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AIM 1中，我们将确定MS-DBB胆碱能神经元和突触后海马间神经元亚型之间突触传播的疗效。在AIM 2中，我们将确定MS-DBB GABA能神经元和突触后海马间神经元亚型之间突触传播的功效。最后，在AIM 3中，我们将确定M1 MACHR在胆碱能诱导的网络振荡中存在的M1 MACHR的作用。 公共卫生相关性：Broca（MS-DBB）内侧隔膜 - 二核带功能障碍与大量神经退行性和精神病状态有关，例如阿尔茨海默氏病，帕金森氏病，parkinson病，精神分裂症以及神经天然气和有机农药中毒。对从MS-DBB神经元到海马靶标的突触传播的功效有更全面的了解将极大地阐明MS-DBB在海马信息处理中的作用，从而促进这些疾病的新治疗方法的发展。