Choline transporter capacity limits motivated behavior on mice, rats, and humans

胆碱转运蛋白能力限制小鼠、大鼠和人类的动机行为

基本信息

批准号：
7984725
负责人：
MARTIN F SARTER
金额：
$ 41.19万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-09 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984725
关键词：
Acetylcholine Adopted Age-associated memory impairment Alleles Animals Area Attention Attenuated Behavioral Brodmann&apos s area Cannulas Cell membrane Choline Code Cognition Disorders Cognitive Control Animal Data Dementia Development Dialysis procedure Disease Electric Stimulation Exhibits Functional Magnetic Resonance Imaging Gene Frequency General Population Genetic Programming Genotype Hemicholinium 3 Human Impaired cognition Impairment Interdisciplinary Study Measures Medial Mediating Michigan Microdialysis Middle frontal gyrus structure Mining Molecular Motor Cortex Mus Neurobehavioral Manifestations Neurodegenerative Disorders Neuromodulator Neurons Performance Plasma Play Prefrontal Cortex Preventive Psychometrics Rattus Recovery Regulation Research Residual state Rodent Role Schizophrenia Signal Pathway Surface System Taxes Techniques Testing Time Universities Variant Wild Type Mouse attenuation basal forebrain base choline transporter cholinergic cholinergic neuron density exhaust implantation motivated behavior neurochemistry neuroimaging neuropsychiatry neuropsychological neurotransmission prevent programs public health relevance research study response trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): This application proposes interdisciplinary research on the regulation and function of the high-affinity choline transporter (CHT). The CHT imports choline for the synthesis of acetylcholine (ACh) into cholinergic neurons and thereby controls the capacity of cholinergic neurons to sustain increases in cholinergic neurotransmission. Choline uptake is primarily regulated by the density of CHTs in synaptosomal plasma membrane. The rates of CHT internalization and outward trafficking determine the density of CHTs in plasma membrane. Accumulating evidence indicates that these intracellular CHT transport mechanisms are highly regulated by diverse signaling pathways. This research will test the general hypothesis that CHT capacity limitations constrain the ability of cholinergic neurons to mediate heightened demands on cognitive activity, specifically motivated, attentional performance under challenging conditions. We will study mice expressing a reduced level of CHTs and exhibiting an attenuated capacity of cholinergic neurons to sustain increases in ACh release, intact rats following the blockade of CHT-mediated choline uptake in prefrontal cortex, and humans heterozygous for a variant of the CHT that reduces choline transport capacity by 40-50%. This research will employ molecular, neurochemical, neuropsychological and neuroimaging techniques in order to determine the cellular and neuronal mechanisms that limit CHT capacity in situations that tax cholinergic functions and thereby limit cognitive capacity. Results are expected to demonstrate that a reduced capacity for CHT-mediated choline uptake robustly attenuates the recover of attentional performance after performance challenges, and that such impaired performance is mediated via insufficient levels of prefrontal cholinergic neurotransmission (rodents) and insufficient activation of right prefrontal cortex (humans). Collectively, this research will determine the neuronal mechanisms that constrain behavioral and cognitive capacities, reveal neuronal mechanisms that contribute to cognitive decline, and define new targets for the development of preventive and symptomatic treatments for the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: The abnormal regulation of the cortical cholinergic input system plays a major role in the manifestation of the cognitive impairments of neuropsychiatric and neurodegenerative disorders, specifically schizophrenia, dementia and other age-related cognitive impairments. The high-affinity choline transporter strongly influences the capacity of this neuronal system to sustain elevated levels of activity. This research will utilize a wide range of experimental approaches and conduct research in mice, rats, and humans to determine how the choline transporter is regulated and how this transporter limits cognitive capacity. The results from this research are of direct significance for hypotheses concerning the role of this major neuromodulator system in cognitive disorders and for the development of new treatments for such disorders.

描述（由申请人提供）：本申请提出对高亲和力胆碱转运蛋白（CHT）的调节和功能进行跨学科研究。 CHT 将胆碱输入胆碱能神经元中合成乙酰胆碱 (ACh)，从而控制胆碱能神经元维持胆碱能神经传递增加的能力。胆碱摄取主要受突触体质膜中 CHT 密度的调节。 CHT 内化和向外运输的速率决定了质膜中 CHT 的密度。越来越多的证据表明这些细胞内 CHT 转运机制受到多种信号通路的高度调控。这项研究将检验以下一般假设：CHT 容量限制限制了胆碱能神经元在挑战性条件下调节对认知活动、特别动机和注意力表现的更高要求的能力。我们将研究表达 CHT 水平降低并表现出胆碱能神经元维持乙酰胆碱释放增加能力减弱的小鼠、前额皮质中 CHT 介导的胆碱摄取阻断后的完整大鼠，以及 CHT 变体杂合子的人类。胆碱运输能力降低 40-50%。这项研究将采用分子、神经化学、神经心理学和神经影像学技术，以确定在胆碱能功能负荷过重从而限制认知能力的情况下限制 CHT 能力的细胞和神经元机制。预计结果将证明，CHT 介导的胆碱吸收能力下降会严重削弱表现挑战后注意力表现的恢复，并且这种表现受损是通过前额叶胆碱能神经传递水平不足（啮齿类动物）和右前额叶皮层激活不足来介导的（人类）。总的来说，这项研究将确定限制行为和认知能力的神经元机制，揭示导致认知能力下降的神经元机制，并确定开发神经精神和神经退行性疾病认知症状的预防和对症治疗的新目标。公共卫生相关性：皮质胆碱能输入系统的异常调节在神经精神和神经退行性疾病的认知障碍的表现中起着重要作用，特别是精神分裂症、痴呆和其他与年龄相关的认知障碍。高亲和力胆碱转运蛋白强烈影响该神经元系统维持高水平活动的能力。这项研究将利用广泛的实验方法，对小鼠、大鼠和人类进行研究，以确定胆碱转运蛋白是如何调节的以及该转运蛋白如何限制认知能力。这项研究的结果对于有关这一主要神经调节系统在认知障碍中的作用的假设以及开发此类疾病的新疗法具有直接意义。