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）：本申请提出了有关高亲和力胆碱转运蛋白（CHT）调节和功能的跨学科研究。 CHT进口胆碱将乙酰胆碱（ACH）合成为胆碱能神经元，从而控制胆碱能神经元的能力维持胆碱能神经传递的增加。胆碱摄取主要受突触体质膜中CHT的密度调节。 CHT内在化和向外运输的速率决定了质膜中CHT的密度。积累的证据表明，这些细胞内CHT转运机制受到不同信号通路的高度调节。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介导对认知活动的增强需求的能力，在挑战性的条件下特别动机，注意力表现。我们将研究表达CHT水平降低的小鼠，并表现出胆碱能神经元的衰减能力，可维持ACH释放的增加，在CHT介导的前额叶皮层中CHT介导的胆碱摄取后，完整的大鼠以及人类杂合的CHT的变体，以降低胆碱能力为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，以确定在对胆碱能功能征税并限制认知能力的情况下限制CHT容量的细胞和神经元机制。预计结果将证明，CHT介导的胆碱摄取的能力降低会稳健地减弱性能挑战后注意力表现的恢复，并且这种受损的性能是通过不足的前额叶胆碱能神经传递（啮齿动物）介导的，并且不足以介导正确的前颈前Cortex Cortex（humans）。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，揭示了有助于认知能力下降的神经元机制，并确定了开发预防性和症状治疗的新靶标，以确认神经精神和神经性疾病的认知症状。 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疾病和神经退行性疾病的认知障碍表现中起着重要作用，具体是精神分裂症，痴呆症和其他年龄相关的认知障碍。高亲和力胆碱转运蛋白强烈影响这种神经元系统维持活动水平升高的能力。这项研究将利用广泛的实验方法，并在小鼠，大鼠和人类中进行研究，以确定如何调节胆碱转运蛋白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该主要神经调节剂系统在认知疾病和此类疾病的新疗法开发中的作用的假设具有直接意义。