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， 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、学习和习惯形成的学习，通过调节短期和长期的 可塑性在两个水平在基底神经节，在轴突终端在纹状体，并从体树突区 这些行为共同决定了哪些中型多刺神经元（MSN）突触将活动传递给 黑质网状（SNr）黑丘脑神经元，整合基底神经节电路并驱动神经元的活动。 控制行为的皮层 轴突终末突触囊泡胞吐释放的DA作用于多个突触前和突触后部位 它们一起改变纹状体黑质dii-ecf和纹状体苍白间接MSN活性。传输 sonnatodendritic区域知之甚少，部分原因是它们缺乏常规的突触囊泡， 而是表达VMAT 2的神经分泌细胞器。体树突DA释放也出现 有多个控制黑质丘脑活动的靶点，但目前对这种突触知之甚少。 我们的假设是，体树突DA的释放使突触的频率依赖性选择成为可能。 纹状体黑质直接通路的终末。我们|ab已经开发出光学技术来测量 单个突触末梢，包括表征DA的荧光假神经递质（FFN） 释放和突触囊泡融合探针FM 1-43到纹状体黑质突触。我们的初步证据 表明体树突DA释放通过突触前D1受体选择纹状体黑质突触， 频率依赖性的方式，使用经典方法检测不到的效果。我们将与 爱德华兹实验室使用突变小鼠，应该缺乏体细胞多巴胺释放，Krietzer实验室谁拥有 开发了选择性激活DA、纹状体黑质和苍白球黑质通路以及von：Zastrow的方法， 他们正在探索干扰MSN神经元上Dl信号的方法，包括安非他明 （AMPH），

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),