Roles and mechanisms of neurotensin in learning and memory

神经降压素在学习记忆中的作用和机制

• 批准号: 8706231
• 负责人: Saobo Lei
• 金额: $ 34.5万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706231
• 关键词: APP-PS1; Action Potentials; Affinity; Agonist; Alanine; Alzheimer' s Disease; American; Amino Acids; Bathing; Blood - brain barrier anatomy; Cell model; Cells; Cholinesterase Inhibitors; Cognitive; Data; Dementia; Deterioration; Disease; Dose; Elderly; Frequencies; G-Protein-Coupled Receptors; Individual; Knockout Mice; Learning; Long-Term Potentiation; Mediating; Memantine; Membrane; Memory; Microinjections; Molecular; Mus; Mutate; NMDA receptor antagonist; Neurons; Neurotensin; Neurotensin Receptors; Pathway interactions; Patients; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Phospholipase C; Phosphorylation; Phosphorylation Inhibition; Phosphorylation Site; Physiological; Potassium Channel; Protein Isoforms; Protein Kinase C; Role; Series; Serine; Serine Phosphorylation Site; Signal Transduction; Slice; Structure; Subcutaneous Injections; Synapses; Synaptic Transmission; Testing; Therapeutic; Transmembrane Domain; Whole-Cell Recordings; citrate carrier; clinically significant; density; entorhinal cortex; improved; in vivo; mouse model; mutant; neuronal excitability; novel strategies; postsynaptic; public health relevance; receptor; research study; response; small molecule

DESCRIPTION (provided by applicant): Neurotensin (NT) is a tridecapeptide widely distributed in the CNS including the entorhinal cortex (EC) which is crucial for learning and memory and undergoes the earliest pathological alterations in Alzheimer's Disease (AD). Whereas high density of NT receptors has been detected in the EC, the roles of NT in learning and memory and in AD have not been determined. AD is characterized by progressive deterioration of cognitive performance and afflicts ~5.3 million Americans. The current drugs available for the treatment of AD including the cholinesterase inhibitors and the partial NMDA receptor antagonist memantine only benefit a subset of patients for a limited period. Therefore, identifying and characterizing additional mechanisms through which cognitive deficiency can be improved still represent an important approach for AD therapy. We propose to study the roles and the underlying mechanisms of NT in facilitation of spatial memory in the EC and then test the possibility of using NT receptor agonists for AD therapy in AD mouse model. We have substantial preliminary data demonstrating that NT induced Long-Term Excitation (LTE) of neuronal excitability in the EC. We also demonstrated that microinjection of NT into the EC facilitated spatial learning and memory in Barnes Maze Test. The objective of this project is to determine the involved cellular and molecular mechanisms by testing the hypothesis that NT induces LTE of neuronal excitability and facilitates spatial learning and memory via NTS1/PLC/PKC-dependent inhibition of TREK-2 channels. Aim 1 will identify mechanisms underlying NT-induced LTE of neuronal excitability in the EC. We will identify the roles of PKC isoforms, PKC phosphorylation sites in TREK-2 channels and PKC- dependent phosphorylation of TREK-2 channels in vivo in NT-mediated LTE in the EC. Aim 2 will determine the mechanisms whereby NT facilitates spatial learning and memory by testing the hypothesis that NT augments spatial learning and memory via activation of PLC and PKC pathway resulting in inhibition of TREK-2 channels in the EC by using both pharmacological approach and knockout mice. Aim 3 will identify effects of NT and PD149163, a small molecule NTS1 agonist that can penetrate the blood-brain barrier on spatial learning and memory in APP/PS1 mice, an AD mouse model. We expect to determine the cellular and molecular mechanisms whereby NT facilitates spatial learning and memory and identify a novel approach of using NTS1 agonists for AD therapy in AD mouse model.

描述（由申请人提供）：神经辛（NT）是一种在包括学习和记忆至关重要的中枢神经系统中广泛分布在中枢神经系统中的三肽，并且经历了阿尔茨海默氏病（AD）中最早的病理改变。尽管在EC中已经检测到了NT受体的高密度，但尚未确定NT在学习和记忆和AD中的作用。 AD的特征是认知表现的逐渐恶化，折磨约530万美国人。当前可用于治疗AD的药物在内，包括胆碱酯酶抑制剂和部分NMDA受体拮抗剂美容剂仅在有限的时间内使一部分患者受益。因此，识别和表征可以改善认知缺乏的其他机制仍然代表了广告疗法的重要方法。我们建议研究NT在EC中促进空间记忆方面的作用和潜在机制，然后测试在AD小鼠模型中使用NT受体激动剂进行AD疗法的可能性。我们有大量的初步数据，表明NT诱导EC中神经元兴奋性的长期激发（LTE）。我们还证明了在Barnes迷宫测试中，NT对EC促进的空间学习和记忆的微小注射。该项目的目的是通过测试NT诱导神经元兴奋性LTE的假设来确定所涉及的细胞和分子机制，并通过NTS1/PLC/PKC依赖性抑制TREK-2通道来促进空间学习和记忆。 AIM 1将确定EC中NT诱导的神经元兴奋性LTE的基础机制。我们将确定trek-2通道中PKC同工型，PKC磷酸化位点的作用以及在EC中NT介导的LTE中Trek-2通道的PKC依赖性磷酸化。 AIM 2将通过测试NT通过PLC和PKC途径的激活来增强空间学习和记忆的假设来确定NT促进空间学习和记忆的机制，从而通过使用药理方法和敲除小鼠来抑制EC中的TREK-2通道，从而增强空间学习和记忆。 AIM 3将识别NT和PD149163的影响，这是一种小分子NTS1激动剂，可以穿透App/PS1小鼠的空间学习和记忆的血脑屏障，这是AD小鼠模型。我们期望确定NT促进空间学习和记忆的细胞和分子机制，并确定在AD小鼠模型中使用NTS1激动剂进行AD治疗的新方法。