Cholinergic and GABAergic Mechanisms in the Septohippocampal Pathway

隔海马通路中的胆碱能和 GABA 能机制

基本信息

批准号：
7766997
负责人：
Meenakshi Alreja
金额：
$ 30.02万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7766997
关键词：
Acetylcholine Acetylcholinesterase Inhibitors Alzheimer&apos s Disease Brain Brain region CRF receptor type 1 Clinical Research Cognition Cognitive deficits Corticotropin-Releasing Hormone Receptors Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclic Nucleotides Disease Enzymes Fiber Glutamates Guanylate Cyclase Health Human Hydrolysis Image Imagery Impaired cognition Label Learning Literature Memory Mental Depression Mental disorders Methods Muscarinic Acetylcholine Receptor Neurons Neurotransmitters Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Oxides PDE2 phosphodiesterase Pathway interactions Phosphodiesterase Inhibitors Phosphotransferases Physiological Population Recruitment Activity Research Personnel Rodent Role Schizophrenia Scopolamine Slice Stress Techniques Testing United States analog base cholinergic cholinergic neuron nerve supply normal aging phosphoric diester hydrolase prevent programs relating to nervous system septohippocampal

项目摘要

DESCRIPTION (provided by applicant): Cognitive impairment is a serious health concern in the United States; it accompanies normal aging and dementing disorders such as Alzheimer's, as well as mental illnesses, such as schizophrenia and depression. Basic and clinical studies have long recognized the importance of acetylcholine (ACh) in cognition. The cholinergic muscarinic receptor antagonist, scopolamine, impairs learning and memory in humans and rodents primarily through actions on the brain septohippocampal neurons (SHNs). Acetylcholinesterase inhibitors, although limited in efficacy, are currently the best available treatment for Alzheimer's disease. The cyclic nucleotides, cAMP and cGMP, have also been implicated in learning and memory and certain phosphodiesterase (PDE) inhibitors that prevent cyclic nucleotide hydrolysis are cognitively beneficial and can also reverse scopolamine-induced cognitive deficits. While cAMP is effectively recruited by the stress-related neurotransmitter, CRF, the gaseous neural messenger, nitric oxide (NO) is the primary activator of the cGMP cascade. The SHNs, that give rise to the mnemonically important septohippocampal pathway receive CRF innervation, are endowed with CRF1 receptors and in preliminary electrophysiological studies were activated by CRF and cAMP analogs. Additionally, cholinergic SHNs belong to the unique population of CNS neurons that express the NO synthesizing enzyme. In preliminary studies GABA-type but not cholinergic-type SHNs, were activated by NO donors and cGMP analogs. NO imaging studies and PDE inhibitors also suggested the presence of a constitutive NO/cGMP tone as well as a cAMP tone in this brain region. We hypothesize that: 1) NO released from cholinergic SHNs behaves as an intercellular messenger to activate GABAergic SHNs through activation of the cGMP-kinase cascade and that cGMP actions are terminated primarily by the cGMP-specific PDE9; 2) CRF acting via CRF1 receptors and the cAMP-kinase cascade in cholinergic SHNs indirectly activates GABAergic SHNs through increased ACh release; 3) cAMP actions are terminated primarily by PDE4 and cross-talk between the cyclic nucleotide pathways occurs through dual-substrate PDE2 and possibly through a CRF-induced increase in NO synthesis. The above hypothesis will be tested using electrophysiological, immunohistochemical and NO visualization techniques in rodent brain slices.

描述（由申请人提供）：认知障碍在美国是一个严重的健康问题；它伴随着正常的衰老和痴呆症，如阿尔茨海默氏症，以及精神疾病，如精神分裂症和抑郁症。基础和临床研究早已认识到乙酰胆碱 (ACh) 在认知中的重要性。胆碱能毒蕈碱受体拮抗剂东莨菪碱主要通过作用于大脑隔海马神经元 (SHN) 来损害人类和啮齿动物的学习和记忆。乙酰胆碱酯酶抑制剂虽然功效有限，但却是目前治疗阿尔茨海默病的最佳方法。环核苷酸、cAMP 和 cGMP 也与学习和记忆有关，某些防止环核苷酸水解的磷酸二酯酶 (PDE) 抑制剂对认知有益，还可以逆转东莨菪碱引起的认知缺陷。虽然 cAMP 是由与压力相关的神经递质 CRF（气体神经信使）有效招募的，但一氧化氮 (NO) 是 cGMP 级联的主要激活剂。 SHN 产生具有 CRF 神经支配的重要的隔海马通路，具有 CRF1 受体，并且在初步的电生理学研究中被 CRF 和 cAMP 类似物激活。此外，胆碱能 SHN 属于表达 NO 合成酶的独特 CNS 神经元群体。在初步研究中，GABA 型 SHN 被 NO 供体和 cGMP 类似物激活，但胆碱能型 SHN 不被激活。 NO 成像研究和 PDE 抑制剂也表明该大脑区域存在组成型 NO/cGMP 音调以及 cAMP 音调。我们假设：1) 从胆碱能 SHN 释放的 NO 作为细胞间信使，通过激活 cGMP 激酶级联来激活 GABA 能 SHN，并且 cGMP 作用主要由 cGMP 特异性 PDE9 终止； 2) CRF通过CRF1受体和胆碱能SHN中的cAMP激酶级联作用，通过增加ACh释放间接激活GABA能SHN； 3) cAMP 作用主要由 PDE4 终止，环核苷酸途径之间的串扰通过双底物 PDE2 以及可能通过 CRF 诱导的 NO 合成增加而发生。上述假设将使用电生理学、免疫组织化学和一氧化氮可视化技术在啮齿动物脑切片中进行测试。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neurokinins robustly activate the majority of septohippocampal cholinergic neurons.

神经激肽强烈激活大多数隔海马胆碱能神经元。

DOI：
10.1111/j.1460-9568.2007.05993.x
发表时间：
2008
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Morozova,Elena;Wu,Min;Dumalska,Iryna;Alreja,Meenakshi
通讯作者：
Alreja,Meenakshi

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

黑色素浓缩激素直接抑制 GnRH 神经元并阻止 Kisspeptin 激活，从而将能量平衡与生殖联系起来。

DOI：
10.1073/pnas.0908200106
发表时间：
2009
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Wu,Min;Dumalska,Iryna;Morozova,Elena;vandenPol,Anthony;Alreja,Meenakshi
通讯作者：
Alreja,Meenakshi

Muscarine activates the sodium-calcium exchanger via M receptors in basal forebrain neurons.

毒蕈碱通过基底前脑神经元中的 M 受体激活钠钙交换器。