Functional synaptic connectivity and plasticity in the mammalian striatum

哺乳动物纹状体的功能性突触连接和可塑性

• 批准号: RGPIN-2021-02712
• 负责人: Milnerwood, Austen
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742170
• 关键词: Functional; synaptic; connectivity; plasticity; mammalian

Brain function relies on neurons communicating at specialized junctions, synapses. During development, neurons need to form specific pathways to build the brain. After these set patterns of connectivity are established, the synapses between brain cells need to be able to change their connections and activity, in order for the brain (and animal) to acquire new abilities and memories, and use them effectively. This capacity, `synaptic plasticity', is believed to be the basis of all information storage and processing in the brain. Much has been learned of the mechanisms of synaptic plasticity, but most of our understanding comes from one brain region, the hippocampus, an area important for navigation and new memory formation. However, how synaptic plasticity works in other brain regions is relatively poorly described. The basal ganglia are brain regions that are critical for motor learning, skill acquisition, behavioral control, and emotional choices. The striatum is the gateway into the basal ganglia. Striatal neurons receive huge amounts of input fibers from all areas of the cortex and the thalamus, which carry sensory, motor, memory, and motivational information, and are modulated by dopamine, which predicts rewarding outcomes. It is the job of the striatum and to determine from all this information what actions to take in any scenario. This relies on experience, so synaptic plasticity in the striatum must occur throughout life, and is especially important during adolescence when the drive to learning new behaviours and risk-taking is high. Long-lasting synaptic plasticity changes such as increases (LTP) and decreases (LTD) in the strength of synapses are well characterized in (male) juvenile rodent hippocampus, but are less well understood in the striatum. This is in part because the striatum is more complex, and because few labs look at glutamate and dopamine inputs together; both of which need to be examined to understand their roles in striatal development and maturation. This project concerns part of my lab's efforts to understand striatal glutamate and dopamine synapse development and plasticity. We will do this in adolescent and adult mice male mice, and also in female mice, which may develop differently and have been largely unstudied. We use electrophysiology techniques to record synapse activity and LTP / LTD of glutamate inputs, and electrochemistry to measure dopamine release in brain slices. We use light to activate specific types of neurons, and drugs to examine the fundamental ways this brain region works. We will determine how sex differences may change the development and plasticity of the striatum which is lacking in the literature. This information is valuable to many areas of science outside our interests here; the striatum is involved in addiction, and many psychiatric, developmental, and degenerative conditions. Knowing how the striatum works will help guide many others who seek to understand how it fails.

大脑的功能依赖于神经元在特殊的连接处，即突触进行交流。在发育过程中，神经元需要形成特定的通路来构建大脑。在这些固定的连接模式建立之后，脑细胞之间的突触需要能够改变它们的连接和活动，以便大脑（和动物）获得新的能力和记忆，并有效地利用它们。这种被称为“突触可塑性”的能力被认为是大脑中所有信息存储和处理的基础。关于突触可塑性的机制，我们已经了解了很多，但我们大部分的理解都来自大脑的一个区域，海马体，这是一个对导航和新记忆形成很重要的区域。然而，突触可塑性是如何在大脑的其他区域起作用的，人们对其描述相对较少。基底神经节是大脑中对运动学习、技能习得、行为控制和情绪选择至关重要的区域。纹状体是基底神经节的入口。纹状体神经元接受来自皮质和丘脑所有区域的大量输入纤维，这些纤维携带感觉、运动、记忆和动机信息，并受多巴胺调节，多巴胺预测有益的结果。这是纹状体的工作，从所有这些信息中决定在任何情况下采取什么行动。这依赖于经验，所以纹状体中的突触可塑性必须贯穿一生，在学习新行为和冒险的动力很高的青春期尤为重要。长期突触可塑性的变化，如突触强度的增加（LTP）和减少（LTD），在（雄性）幼年啮齿动物海马中得到了很好的表征，但在纹状体中却知之甚少。这部分是因为纹状体更为复杂，而且很少有实验室同时研究谷氨酸和多巴胺的输入；这两者都需要检查，以了解它们在纹状体发育和成熟中的作用。这个项目是我实验室研究纹状体谷氨酸和多巴胺突触发育和可塑性的一部分。我们将在青春期和成年小鼠中进行实验雄性小鼠，以及雌性小鼠，它们的发育可能有所不同，在很大程度上还没有被研究过。我们使用电生理技术记录突触活动和谷氨酸输入的LTP / LTD，电化学技术测量脑切片中多巴胺的释放。我们使用光来激活特定类型的神经元，并使用药物来检查大脑区域工作的基本方式。我们将确定性别差异如何改变纹状体的发育和可塑性，这在文献中是缺乏的。这些信息对我们感兴趣之外的许多科学领域都很有价值；纹状体与成瘾以及许多精神、发育和退行性疾病有关。了解纹状体是如何工作的，将有助于指导其他试图理解纹状体是如何失效的人。