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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761348
• 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.

大脑功能依赖于神经元在专门的连接点，突触上进行交流。在发育过程中，神经元需要形成特定的通路来构建大脑。在建立了这些连接模式之后，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，并有效地使用它们。这种能力，即"突触可塑性"，被认为是大脑中所有信息储存和处理的基础。关于突触可塑性的机制，我们已经了解了很多，但我们大多数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，突触可塑性如何在其他大脑区域工作的描述相对较少。基底神经节是对运动学习、技能获得、行为控制和情感选择至关重要的大脑区域。纹状体是进入基底神经节的通道。纹状体神经元从皮层和丘脑的所有区域接收大量的输入纤维，这些纤维携带感觉、运动、记忆和动机信息，并受到多巴胺的调制，多巴胺预测奖励结果。这是纹状体的工作，并从所有这些信息中确定在任何情况下采取什么行动。这依赖于经验，因此纹状体中的突触可塑性必须在整个生命中发生，并且在青春期尤其重要，因为此时学习新行为和冒险的动力很高。持久的突触可塑性变化，如增加（LTP）和减少（LTD）的突触强度的特点是在（男性）青少年啮齿动物海马，但不太了解纹状体。这部分是因为纹状体更复杂，而且很少有实验室同时研究谷氨酸和多巴胺的输入;这两者都需要进行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雄性小鼠和雌性小鼠中进行这项研究，这些小鼠可能发育不同，并且在很大程度上未被研究。我们使用电生理学技术记录突触活动和谷氨酸输入的LTP/LTD，并使用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，并使用药物来检查这个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的科学领域之外的许多领域都很有价值;纹状体与成瘾以及许多精神病，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许多其他人试图了解它是如何失败的。