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

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CHTs密度的调节。CHT的内化和外输速率决定了细胞膜上CHT的密度。越来越多的证据表明，这些细胞内CHT的运输机制是高度调节的不同的信号通路。这项研究将测试的一般假设，CHT容量限制胆碱能神经元的能力，以调解认知活动，特别是动机，在具有挑战性的条件下的注意力表现的要求提高。我们将研究小鼠表达降低水平的CHT和表现出衰减的胆碱能神经元的能力，以维持增加乙酰胆碱释放，完整的大鼠后，阻断CHT介导的胆碱摄取在前额叶皮层，和人类杂合子的CHT的变异，减少胆碱转运能力的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，以确定在税收胆碱能功能的情况下限制CHT能力的细胞和神经元机制，从而限制认知能力。预期结果将证明，CHT介导的胆碱摄取能力的降低强烈减弱了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前额胆碱能神经传递水平不足（啮齿动物）和右前额皮质激活不足（人类）介导的。总的来说，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变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，大鼠和人类中进行研究，以确定胆碱转运蛋白是如何调节的，以及这种转运蛋白如何限制认知能力。从这项研究的结果是直接意义的假设有关的作用，这一主要的神经调质系统在认知障碍和发展新的治疗方法，这种疾病。

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.