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

描述（由申请人提供）：本申请拟对高亲和胆碱转运体（CHT）的调控和功能进行跨学科研究。CHT输入胆碱合成乙酰胆碱（ACh）进入胆碱能神经元，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中cht的密度调节。内化和外移的速度决定了质膜内CHTs的密度。越来越多的证据表明，这些细胞内的CHT转运机制受到多种信号通路的高度调节。本研究将检验一般假设，即CHT容量限制限制了胆碱能神经元调节认知活动，特别是在挑战性条件下的动机和注意力表现的能力。我们将研究表达CHTs水平降低且胆碱能神经元维持乙酰胆碱释放增加的能力减弱的小鼠，前额皮质中CHTs介导的胆碱摄取阻断后的完整大鼠，以及将胆碱运输能力降低40-50%的CHT变体杂合的人类。这项研究将采用分子、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损的情况下限制CHT容量的细胞和神经元机制，从而限制认知能力。研究结果表明，在表现挑战后，由cht介导的胆碱摄取能力降低会显著削弱注意力表现的恢复，而这种表现受损是由额叶前部胆碱能神经传递水平不足（啮齿动物）和右侧前额叶皮层激活不足（人类）介导的。总的来说，这项研究将确定约束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，并为神经精神和神经退行性疾病的认知症状的预防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.