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

• 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
• 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' 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

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)：本申请建议对高亲和力胆碱转运体(CHT)的调节和功能进行跨学科研究。CHT输入胆碱，用于合成乙酰胆碱(ACh)到胆碱能神经元，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上CHTs密度的调节。CHT内化和向外转运的速率决定了CHTs在质膜上的密度。越来越多的证据表明，这些细胞内CHT转运机制受到不同信号通路的高度调控。这项研究将检验这一普遍假设，即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、特定动机、注意力表现的高需求的能力。我们将研究表达CHTs水平降低、胆碱能神经元维持ACh释放增加的能力减弱的小鼠、阻断CHT介导的前额叶皮质胆碱摄取后的完整大鼠，以及CHT变异体的杂合体，该变异体使胆碱转运能力减少40%-50%。这项研究将使用分子、神经化学、神经心理学和神经成像技术，以确定在胆碱能功能受累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介导的胆碱摄取能力的下降强烈地减弱了在操作挑战后注意力表现的恢复，这种损害的表现是通过额叶前部胆碱能神经传递(啮齿动物)和右侧前额叶皮质(人类)激活不足来调节的。总而言之，这项研究将确定限制行为和认知能力的神经机制，揭示导致认知能力下降的神经机制，并为神经精神和神经退行性疾病的认知症状的预防性和对症治疗的发展确定新的目标。 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主要作用，特别是精神分裂症、痴呆和其他与年龄相关的认知障碍。高亲和力的胆碱转运体强烈影响这一神经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，并在小鼠、大鼠和人类身上进行研究，以确定胆碱转运体是如何调节的，以及这种转运体如何限制认知能力。这项研究的结果对关于这一主要神经调节系统在认知障碍中的作用的假说和此类障碍的新治疗方法的开发具有直接意义。