Saturation of Synaptic Plasticity at Individual Dendritic Spines

单个树突棘突触可塑性的饱和

• 批准号: 10505839
• 负责人: Juan C Flores
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505839
• 关键词: AMPA Receptors; Affect; Alzheimer' s Disease; Animal Model; Bioenergetics; Brain; Calcium; Cells; Chemosensitization; Data; Dendrites; Dendritic Spines; Disease Progression; Down Syndrome; Drug Addiction; Environment; Excitatory Synapse; Exhibits; Fluorescence Resonance Energy Transfer; Foundations; Fragile X Syndrome; Frequencies; Functional disorder; Glutamates; Goals; Growth; Hippocampus (Brain); Human; Image; Impairment; Individual; Knock-out; Knowledge; Lead; Learning; Learning Disabilities; Mitochondria; Molecular; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Organism; Pattern; Pharmacology; Phase; Play; Positioning Attribute; Process; Regulation; Research; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Slice; Stimulus; Surface; Synapses; Synaptic plasticity; Testing; Time; Training; Variant; Vertebral column; Work; autism spectrum disorder; calmodulin-dependent protein kinase II; experience; experimental study; falls; imaging study; improved; knockout animal; learning outcome; mitochondrial dysfunction; nervous system disorder; neuronal circuitry; new therapeutic target; post-doctoral training; postsynaptic; pre-doctoral; response; sensor; synaptic function; targeted treatment; transmission process; two-photon

Abstract The ability of organisms to learn is crucial for them to survive and adapt to new environments. Learning relies on the brain’s capacity to change the connections between neurons to alter circuit functions, or synaptic plasticity. Dysfunction in the regulation of synaptic plasticity, or ability of the brain to change in response to stimuli, has been implicated in neurological disorders like Alzheimer’s disease, autism spectrum disorder and drug addiction. Much of the research on the synaptic plasticity associated with learning has focused on dendritic spines, membranous protrusions that are the postsynaptic sites of excitatory transmission in the cortex. Notably, learning in humans is improved when breaks are incorporated into learning sessions, in a process called spaced learning. Notably, spaced training increases learning in rodent models of Fragile X, Angelman’s and Down syndromes, which are learning impaired. One idea is that the need for breaks is due to a temporary saturation of plasticity at the synapses involved in this learning. Indeed, it has been shown that saturation of potentiation leads to impairment of learning in animal models. After an initial stimulation leads to circuit potentiation, a second stimulus is unable to produce potentiation unless the intervals between stimuli were increased. However, the mechanisms that lead to saturation of plasticity remain poorly defined. The goal of this proposal is to determine the cellular and molecular mechanisms by which this saturation occurs. My current data show that saturation of synaptic strengthening occurs at individual synapse level and that the saturation occurs via postsynaptic mechanisms. My data also demonstrate that saturation of synaptic strengthening at individual spines can be overcome by increased levels of stimulation and that saturation is also release over time as spines stimulated 60 minutes after their initial stimulation are able to exhibit further synaptic strengthening. Finally, my data show that CaMKII activity is reduced in spines which are experiencing saturation. Using 2-photon (2p) imaging, 2p glutamate uncaging, calcium imaging and conditional single cell knock out animals, I propose to rigorously investigate the molecular and cellular mechanisms that drive saturation of plasticity at individual spines. The results of these experiments will further our knowledge of synaptic plasticity and its limitations and could elucidate novel drug targets for the treatment of neurological disorders and learning disabilities. After completing my dissertation, I intend to pursue a postdoctoral position studying the role of mitochondrial signaling and dysfunction in neurodegenerative diseases. The proposed experiments and training plan will provide a strong foundation for my transition to postdoctoral training and will support me in my long-term goal of an academic research position.

抽象的 生物体的学习能力对于它们生存和适应新环境至关重要。学习靠 大脑改变神经元之间的连接以改变回路功能或突触可塑性的能力。 突触可塑性调节功能障碍，或大脑响应刺激而改变的能力， 与阿尔茨海默病、自闭症谱系障碍和毒瘾等神经系统疾病有关。 与学习相关的突触可塑性的大部分研究都集中在树突棘上， 膜突起是皮质中兴奋性传递的突触后部位。值得注意的是，学习 当休息被纳入学习课程中时，人类的能力就会得到改善，这一过程称为间隔学习。 值得注意的是，间隔训练可以增强脆性 X 型、安杰曼氏综合症和唐氏综合症啮齿动物模型的学习能力， 那些有学习障碍的人。一种想法是，需要断裂是由于塑性暂时饱和 参与这种学习的突触。事实上，已经表明，增强饱和会导致 动物模型中的学习障碍。初始刺激导致电路增强后，第二次刺激 除非增加刺激之间的间隔，否则无法产生增强作用。然而，这些机制 导致塑性饱和的原因仍然不明确。该提案的目标是确定蜂窝 以及发生这种饱和的分子机制。我目前的数据显示突触的饱和度 强化发生在单个突触水平，并且饱和通过突触后机制发生。 我的数据还表明，单个棘突触强化的饱和度可以通过以下方式克服： 刺激水平增加，并且饱和度也会随着时间的推移而释放，因为在 60 分钟后刺激脊柱 他们最初的刺激能够表现出进一步的突触强化。最后，我的数据显示 CaMKII 处于饱和状态的脊柱活动减少。使用 2 光子 (2p) 成像，2p 谷氨酸 脱笼、钙成像和条件单细胞敲除动物，我建议严格研究 驱动单个脊柱可塑性饱和的分子和细胞机制。这些结果 实验将加深我们对突触可塑性及其局限性的了解，并可以阐明新药物 治疗神经系统疾病和学习障碍的目标。完成我的论文后，我 打算攻读博士后职位，研究线粒体信号传导和功能障碍的作用 神经退行性疾病。拟议的实验和培训计划将为 我向博士后培训的过渡，并将支持我实现学术研究职位的长期目标。