Dissecting Mechanisms of Striatal Acetylcholine Transmission in the Vertebrate Brain

解析脊椎动物大脑中纹状体乙酰胆碱传输的机制

• 批准号: 10685277
• 负责人: Kathleen Allison Beeson
• 金额: $ 7.2万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685277
• 关键词: Ablation; Acetylcholine; Affect; Area; Axon; Basal Ganglia; Behavior; Brain; Brain imaging; Calcium; Calcium Channel; Central Nervous System; Cholinergic Receptors; Complex; Corpus striatum structure; Data; Disease; Distant; Dopamine; Electrophysiology (science); Elements; Enzymes; Exocytosis; Functional Imaging; Genes; Genetic; Goals; Health; Interneurons; Learning; Locomotion; Measurement; Measures; Messenger RNA; Modeling; Molecular; Morphology; Motivation; Mus; Nerve; Nervous System Physiology; Neuromodulator; Neuromuscular Junction; Neurons; Nicotinic Receptors; Phase; Phospholipids; Proteins; Rewards; Signal Transduction; Site; Slice; Structure; Synapses; System; Testing; Tissue imaging; Tissues; Transcript; Transgenic Organisms; Varicosity; Vesicle; Work; brain volume; cholinergic; conditional knockout; esterase; fluorescence imaging; insight; mouse genetics; nano; neuroregulation; presynaptic; receptor; scaffold; secretory protein; sensor; social cognition; spatial relationship; superresolution microscopy; synaptotagmin I; tool; transmission process; vesicular release

PROJECT SUMMARY Acetylcholine critically controls complex neurological functions through its modulation of brain circuits. In contrast to the well-studied mechanisms of acetylcholine signaling at the neuromuscular junction, its transmission modes and mechanisms in the vertebrate central nervous system are not well understood. In the striatum, acetylcholine exerts rapid and powerful control over local dopaminergic activity. Together, these neuromodulators regulate a variety of important behaviors, including motivation and reward-related learning. Because acetylcholine is rapidly degraded after it is released in striatal tissues, the fidelity of acetylcholine to dopamine signaling must involve either tight spatial relationships between release sites and receptors, and/or fast transmission. However, neuromodulator signaling is classically modeled as occurring through volume transmission, involving dispersed, non-specific release as opposed to synaptic, point-to-point signaling – a concept that remains to be proven. Furthermore, the molecular mechanisms underlying striatal acetylcholine signaling remain elusive. I hypothesize that sparse cholinergic terminals require molecular elements for highly synchronous acetylcholine release. In this scenario, rapid and precise vesicle release could produce a synchronous wave of high-concentration acetylcholine, which might allow even distant receptors to sense this signal with potency. To test this hypothesis, I propose to examine the morphological and molecular substrate of striatal acetylcholine transmission in two aims. First, I will dissect the structure of acetylcholine to dopamine signaling in the striatum, including the presence of secretory machinery in acetylcholine nerve terminals and their apposition to acetylcholine receptors on dopamine axons, using superresolution microscopy. In a second aim, I will functionally test whether acetylcholine release onto dopamine axons requires secretory proteins that are predestined to generate fast and precise release, enabling phasic acetylcholine transmission. Additionally, I will determine how this transmission mode impacts subsequent dopamine signaling. To do this, I will use genetic tools paired with simultaneous imaging of fluorescent acetylcholine sensors and amperometric dopamine measurements in striatal slices. Together, these findings will inform our fundamental understanding of cholinergic to dopaminergic signaling in the striatum, including the identification of important genes that regulate acetylcholine transmission. This molecular-level understanding will ultimately be important to better understand brain function and disease.

项目总结