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Neuromodulatory Control of Cerebellar Synaptic Processing and Sensory Input

小脑突触处理和感觉输入的神经调节控制

基本信息

批准号：
9898477
负责人：
COURT A HULL
金额：
$ 34.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898477
关键词：
Acetylcholine Acute Affect Agonist Anatomy Animals Architecture Brain Calcium Calibration Cell Nucleus Cells Cerebellar Cortex Cerebellum Cognitive Cytoplasmic Granules Data Electrophysiology (science)Elements Eye Face Fiber Future Genetic Glutamates Golgi Apparatus Image In Vitro Interneurons Investigation Learning Life Lobule Microinjections Modernization Monitor Motor Motor output Movement Mus Neuromodulator Neurons Neurotransmitters Pharmacology Physiological Physiology Play Population Preparation Proteins Reflex action Regulation Sensory Serotonin Signal Transduction Site Slice Source Specificity Synapses Synaptic plasticity System Testing Viral Walking Work Writing cell type cholinergic crystallinity experimental study flexibility genetic approach granule cell in vivo insight mossy fiber motor learning neural circuit neuroregulation neurotransmission optogenetics receptor receptor expression sensory input sensory integration sensory stimulus serotonin receptor synaptic inhibition two-photon

项目摘要

Sensorimotor integration in the cerebellum is essential for refining motor output. Much of this integration occurs at the initial stage of cerebellar processing, in the granule cell layer where mossy fibers carrying diverse sensory and motor information converge. While these computations have been thought to occur through rigid, anatomically defined circuits, recent evidence suggests that granule cell layer integration can be contextually modified. Neuromodulators represent a strong candidate for such regulation, and anatomical studies have revealed prominent cholinergic and serotonergic projections into the cerebellar granule cell layer. However, it is unknown how these neuromodulators act at the cellular and circuit level to control sensory and motor integration. Our preliminary data reveal that Golgi cells, interneurons that provide the sole source of inhibition to the granule cell layer, express receptors for both acetylcholine (ACh) and serotonin (5-HT). We find that these neuromodulators bi-directionally regulate the excitability of Golgi cells: ACh suppresses Golgi cell spiking while 5-HT elevates spiking. In addition, we find that granule cells are depolarized by ACh. This suggests that ACh may generally act to increase excitability in the granule cell layer. Using a combination of modern physiological, genetic and anatomical approaches in the mouse, we will test the following aims: In Aim 1 we will use an in vitro brain slice preparation to identify the sites of ACh and 5-HT receptor expression on the major cell classes of the granule cell layer: the granule cells, Golgi cells and mossy fibers. Using targeted application of neuromodulatory agonists and specific pharmacology, we will determine how these neuromodulators directly impact cellular excitability both acutely and after prolonged exposure. In Aim 2, we will use retrograde tracing to identify the sources of cerebellar cholinergic and serotonergic inputs. This will allow us to identify whether these neuromodulatory inputs are part of a larger, brain-wide system, and under what conditions they are active. Localizing the afferent neuromodulatory nuclei will also allow viral delivery of optogenetic proteins, and thus investigation of the effect of endogenously released neuromodulators on the intact granule cell circuit. In particular, we will test the hypothesis that ACh acts to increase excitability in the granule cell layer while 5-HT acts to decrease it. Then in Aim 3, we will test how these neuromodulatory effects on excitability regulate granule cell layer integration of sensory and motor input in vivo. We will use multi-unit electrophysiology and two-photon imaging to determine how activation of cholinergic and serotonergic inputs alter the activity of the population of granule cells. In particular, we will present sensory stimuli with graded intensity to test the hypothesis that ACh and 5-HT change the gain of the granule cell network. Together, these experiments will reveal the synaptic and circuit mechanisms that support context-dependent processing in the cerebellum. In the future, we hope to extend these studies to determine how these mechanisms support context-specific learning in behaving animals.

小脑的感觉运动整合对于改善运动输出至关重要。这在很大程度整合发生在小脑处理的初始阶段，在颗粒细胞层，苔藓纤维承载着不同的感觉和运动信息。虽然这些计算一直被认为是通过刚性的、解剖学定义的电路发生的，最近，有证据表明，颗粒细胞层的整合可以根据环境而改变。神经调质代表了这种调节的强有力的候选者，并且解剖学研究显示出突出的胆碱能和胆碱能投射到小脑颗粒细胞层.然而，尚不清楚这些神经调质如何在细胞和回路水平上起作用，控制感觉和运动的整合我们的初步数据显示，高尔基体细胞，中间神经元为颗粒细胞层提供唯一的抑制源，表达两种受体乙酰胆碱（ACh）和5-羟色胺（5-HT）。我们发现这些神经调质调节高尔基体细胞的兴奋性：ACh抑制高尔基体细胞的峰化，而5-HT升高扣球此外，我们发现颗粒细胞被ACh去极化。这表明ACh 一般可用于增加颗粒细胞层的兴奋性。结合使用现代生理学，遗传学和解剖学方法在小鼠中，我们将测试以下目标：在目标1中，我们将使用体外脑切片制备来鉴定ACh的位点和5-HT受体在颗粒细胞层的主要细胞类别上的表达：颗粒细胞、高尔基体细胞和苔藓纤维。使用神经调节激动剂的靶向应用，具体药理学，我们将确定这些神经调节剂如何直接影响细胞急性和长时间暴露后的兴奋性。在目标2中，我们将使用逆行追踪来确定小脑胆碱能和胆碱能输入的来源。这将使我们能够确定这些神经调节输入是否是更大的全脑系统的一部分，在什么条件下它们是活跃的。定位传入神经调节核也将允许光遗传蛋白的病毒递送，从而研究内源性在完整的颗粒细胞回路上释放神经调质。特别是，我们将测试假设ACh的作用是增加颗粒细胞层的兴奋性，而5-HT的作用是然后在目标3中，我们将测试这些神经调节作用如何影响兴奋性。调节体内感觉和运动输入的颗粒细胞层整合。我们将使用多单元电生理学和双光子成像，以确定如何激活胆碱能和多巴胺能输入改变颗粒细胞群的活性。特别是要呈现具有分级强度的感觉刺激以检验ACh和5-HT改变的假设颗粒细胞网络的增益。总之，这些实验将揭示突触和小脑中支持上下文相关处理的电路机制。在未来，我们希望扩展这些研究，以确定这些机制如何支持上下文特定的学习行为动物。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.

DOI：
10.1073/pnas.1809382115
发表时间：
2018-10-09
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Behesti H;Fore TR;Wu P;Horn Z;Leppert M;Hull C;Hatten ME
通讯作者：
Hatten ME

The cerebellum influences vocal timing.

小脑影响发声时间。