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

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。

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.