PROJECT 1 - Synaptic selection by Monoamines

腹侧中脑(VM)多巴胺(DA)突触活动的重要性从它们在运动中的作用可见一斑。 学习和行为障碍，包括药物依赖。这些突触有助于正常的 运动序列的执行、学习和习惯养成通过调节长短两种方式 基底节、纹状体轴突终末和体树突区两个水平的可塑性 这些动作共同决定了哪些中间棘神经元(MSN)突触将活动转移到 黑质网状核(SNR)黑丘脑神经元整合基底节环路并驱动 大脑皮层控制行为， 突触囊泡从轴突终末胞吐释放的DA作用于突触前和突触后的多个部位 这共同改变了纹状体黑质dii-ECF和纹状体苍白质间接MSN的活性。传输自 Sonnatendritic区域知之甚少，部分原因是它们缺乏传统的突触小泡，但 而是表达VMAT2的神经分泌细胞器。也出现了躯体树突状DA释放 有多个靶点控制黑质丘脑的活动，但目前对这种突触知之甚少。 我们的假设是，躯体树突状细胞DA的释放能够实现突触的频率依赖性选择 纹状体黑质直接通路的终末。我们的|ab已经开发出光学技术来测量 个别突触终末，包括表征DA的荧光假神经递质(FFN) 释放突触小泡融合探针FM1-43至纹状体黑质突触。我们的初步证据 提示躯体树突状细胞DA释放通过突触前D1受体选择纹状体黑质突触。 与频率相关的方式，这是使用经典方法无法检测到的效果。我们将与 爱德华兹实验室使用了应该缺乏躯体突触DA释放的突变小鼠，克里策实验室 开发了选择性激活DA、纹状体和苍白球通路的方法，以及von：Zastrow 实验室，他们正在探索干扰MSN神经元上的DL信号的方法，包括苯丙胺 (安培)， 相关性(请参阅说明)： 多巴胺神经传递在药物依赖中的作用已经得到了很好的证实，但准确的方法是通过 目前还不清楚它改变了导致这种疾病的突触，特别是在多巴胺所在的中脑 释放是必需的，但释放的分子机制与大多数其余部分不同 中枢神经系统。我们成功地确定了这种释放是如何发生的，以及它相关的突触效应。

The importance of ventral midbrain (VM) dopamine (DA) synaptic activity is clear from their roles in motor, learning and behavioral disorders, including drug dependence. These synapses contribute to the normal execution of motor sequences, learning, and habit formation learning by mediating short- and long-terhi plasticity at two levels in the basal ganglia, at axon terminals in the striatum, and from somatodendritic areas Together, those actions determine which medium spiny neurons (MSN) synapses transfer activity to substantia nigra reticulara (SNr) nigrothalamic neurons that integrate basal ganglia circuitry and drive the cortex to control behavior, DA released by synaptic vesicle exocytosis from axon terminals acts at multiple pre- and postsynaptic sites that together alter striatonigral dii-ecf and striatopallidal indirect MSN activity. Transmission from sonnatodendritic regions is poorly understood, in part because they lack conventional synaptic vesicles but rather presunned neurosecretory organelles that express VMAT2. Somatodendritic DA release also appears to haVe multiple targets that control nigrothalamic activity, but little is known currently about such synapses. Our hypothesis is that somatodendritic DA release enables frequency-dependent selection of synaptic terminals ofthe striatonigral direct pathway. Our |ab has developed opticaltechniques to measure activity at individual synaptic terminals, including, fluorescent false neurotransmitters (FFNs) that characterize DA release and the synaptic vesicle fusion probe FM 1-43 to striatonigral synapses. Our preliminary evidence indicates that somatodendritic DA release selects striatonigral synapses via presynaptic D1 receptors in a frequency-dependent manner, an effect not detectable using classical methods. We will work with the Edwards lab using mutant mice that Should lack somatodendhtic DA release, the Krietzer lab who have developed means to selectively activate DA, striatonigral and pallidonigral pathways, and the von: Zastrow lab, who are exploring means to interfere with Dl signalling on the MSN neurons, including by amphetamine (AMPH), RELEVANCE (See instructions): The role of dopamine neurotransmission in drug dependence is well established, but the precise means by Which it alters synapses leading to this disorder is unclear, particularly in the midbrain where dopamine release is required but is released using different molecular mechanisms than in most of the rest of the central nervous system. We wiN determine how this release occurs and its relevant synaptic effects.