PRESYNAPTIC PLASTICITY OF VESICULAR DOPAMINE RELEASE

皮层和基底节多巴胺释放的突触前可塑性参与学习线索 通过过滤不明显的刺激，引发可卡因自我管理和选择性注意。目标是 这一建议的目的是描述在突触前可塑性水平上的调节机制。 多巴胺能突触囊泡胞吐。 我们最近报道，小的DAR能突触囊泡的融合毛孔可以闪烁一次或多次 高达10千赫的速度，从而调节从囊泡中释放的传递量。这提供了 目标1的基础，该目标询问如何调节融合毛孔的闪烁。 在嗜铬细胞中，我们发现囊泡的酸化程度并不是一成不变的，而是被 细胞活动，这可以增加量子大小。在这个提案中，我们展示了增强水泡的证据。 酸化可能是药物作用的基础(例如，利他林)，以及行为反馈改变的手段 长期传播。这为目标2探索精神刺激剂是否能调节 泡囊酸化反弹的量子大小。 最后，我们确定了各种突触前受体如何在量子水平上改变DA传递 (例如，GDNF、D2、尼古丁和mGluR激活)以及为什么这些因素作为社会因素对DA很重要 突触。大部分工作都是关于神经递质的急性影响。新证据表明长期存在 神经递质对多巴胺传递的影响，特别是对轴突密度/形成的影响 突触前静脉曲张。因此，目标3将研究神经递质如何调节多巴胺能 突触前静脉曲张形成。

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.