PRESYNAPTIC PLASTICITY OF VESICULAR DOPAMINE RELEASE

囊泡多巴胺释放的突触前可塑性

基本信息

批准号：
7596707
负责人：
David Sulzer
金额：
$ 14.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7596707
关键词：
Acridine Orange Acute Adderall Adrenal Glands Alkalinization Amphetamines Appendix Area Autoreceptors Back Basal Ganglia Behavior Caliber Catecholamines Cell membrane Cells Chromaffin Cells Chromaffin granule Chromosome Pairing Chronic Cocaine Collaborations Corpus striatum structure Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoplasmic Granules Data Dense Core Vesicle Detection Dopamine Drug effect disorder Dyes Electric Capacitance Endocytosis Event Exocytosis Exposure to Flicker Fusion GDNF gene GDNF receptors Genetic Green Fluorescent Proteins Hippocampus (Brain)Incentives Incidence Individual Kinetics Knowledge Label Learning Letters Maintenance Measurement Measures Mediating Membrane Methods Methylphenidate Midbrain structure Molecular Conformation Mus Neurites Neurons Neurotransmitters Noise Numbers Optics Pathway interactions Phorbol 12,13-Dibutyrate Phorbol Esters Pituitary Gland Plastics Polymerase Chain Reaction Population Presynaptic Receptors Principal Investigator Probability Protein Isoforms Protein Kinase C Protein Overexpression Publishing Recording of previous events Regulation Reporting Resolution Ritalin Role Running Second Messenger Systems Secretory Vesicles Self Administration Signal Pathway Signal Transduction Site Solutions Staurosporine Stimulus Synapses Synaptic Vesicles Techniques Thinking Time Transgenic Mice Varicosity Vesicle Work axon growth base citrate carrier density dopamine transporter dopaminergic neuron effusion feeding foot kinase inhibitor mast cell millisecond mutant neurite growth presynaptic programs promoter protein kinase C-delta psychostimulant quantum receptor response second messenger selective attention size social synaptogenesis transmission process uptake

项目摘要

Presynaptic plasticity of dopamine release in the cortex and basal ganglia is involved in learning cues that elicit cocaine self-administration and underlie selective attention by filtering non-salient stimuli. The objective of this proposal is to characterize mechanisms that mediate presynaptic plasticity at the level of the dopaminergic synaptic vesicle exocytosis. We recently reported that the fusion pores of small DAergic synaptic vesicles can flicker once or multiple times as fast as 10 kHz, thus regulating the amount of transmitter released from a vesicle. This provides the basis for Aim 1, which asks how flickering of fusion pores is regulated. In chromaffin cells, we discovered that the level of vesicle acidification is not invariant but enhanced by cellular activity, which can increase quantal size. In this proposal, we show evidence for enhanced vesicular acidification that may underlie drug actions (e.g., Ritalin), and a means for behavior to feed back to alter long-term transmission. This provides the basis for Aim 2 explores whether psychostimulants regulate quantal size via rebound of vesicular acidification. Finally, we identified how a variety of presynaptic receptors alter DA transmission at the quantal level (e.g., GDNF, D2, nicotinic, and mGluR activation) and why these factors are important for DA as social synapses. Most of the work has been on acute effects of neurotransmitters. New evidence indicates long-lasting effects of neurotransmitters on DA transmission, particularly on the density/formation of axonal presynaptic varicosities. Accordingly, Aim 3 will examine how neurotransmitters regulate DAergic presynaptic varicosity formation.

皮质和基底神经节中多巴胺释放的突触前可塑性参与学习线索通过过滤非偏好的刺激来引起可卡因自我给药和选择性关注。目标该提议的特征是在介导突触前可塑性水平的机制多巴胺能突触囊泡胞吐作用。我们最近报道说，小脂肪囊泡的融合孔一次或多个可以闪烁一次时间速度为10 kHz，因此调节了从囊泡释放的发射机量。这提供了 AIM 1的基础，询问如何调节融合孔的闪烁。在铬蛋白细胞中，我们发现囊泡酸化水平不是不变的，而是通过细胞活性，可以增加数量大小。在此提案中，我们展示了增强囊泡的证据可能是毒品作用的酸化（例如，利他林），是行为反馈以改变的手段长期传播。这为目标2提供了基础通过囊泡酸化反弹的量化大小。最后，我们确定了各种突触前受体如何在数量水平上改变DA的传播（例如，gdnf，d2，烟碱和mglur激活）以及为什么这些因素对DA作为社会很重要突触。大多数工作都是对神经递质的急性作用。新证据表明持久神经递质对DA传播的影响，特别是对轴突的密度/形成突触前静脉曲张。因此，AIM 3将检查神经递质如何调节DAERGIC 突触前的静脉曲张形成。