What role do different interneurons in medial prefrontal cortex play in associative recognition memory?

内侧前额叶皮层的不同中间神经元在联想识别记忆中发挥什么作用？

• 批准号: BB/X000915/1
• 负责人: Zafar Bashir
• 金额: $ 86.89万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000915%2F1
• 关键词: What; role; do; different; interneurons

Associative recognition memory is the process that enables us to form normal, every-day memories. This allows us to remember where we parked the car, where we left our keys, or our phone. This type of memory is essential for us to be able to live our normal lives and underlies some of the first noticeable deficits that occur when cognitive decline or Alzheimer's disease begins to set in. Defining the brain processes which give rise to associative memory is important for understanding how the brain operates under normal conditions but is also important in beginning to understand the mechanisms that start to break down in old age or in Alzheimer's disease. Rodents such as rats and mice also use associative recognition memory in their normal lives, and we have shown that a number of different brain regions including the prefrontal cortex, hippocampus, and regions of the thalamus work together during associative recognition memory. These different regions work together with the prefrontal cortex to control the initial learning and then the remembering of the original memory. However, there are still many things that we don't know about how these brain regions operate. One of the questions we will answer is: how do inhibitory cells in the prefrontal cortex control the function of this brain region during associative memory? We propose that the hippocampus and the nuclei of the thalamus control different types of inhibitory cells in the prefrontal cortex and that the separate activation of the different inhibitory cells by these different brain regions separately brings about the initial encoding and then the retrieval of the memory. We will test these ideas in mice by selectively targeting and silencing the major types of interneurons in prefrontal cortex during different phases of memory. We will use advanced anatomical markers and light microscopy methods to detect whether the hippocampus and the thalamic connections to prefrontal cortex terminate on the different inhibitory cell types. Finally, we will examine how these different connections control activity of the different inhibitory cells and therefore control the function of the prefrontal cortex. The project is timely because we have only recently identified the different regions that work together to bring about the different phases of associative recognition memory and it is now possible to identify and selectively target different inhibitory cells while a mouse is performing a learning task. Furthermore, the anatomical methods have recently been developed that now allow us to identify which brain regions connect with which inhibitory cells and finally we can record from these cells to measure how their activity is controlled by the different brain regions that control associative memory. Overall, this work will provide a detailed mechanistic insight into how brain regions work collectively to bring about associative recognition memory.

联想识别记忆是使我们能够形成正常的日常记忆的过程。这使我们能够记住我们把车停在哪里，我们把钥匙或手机放在哪里。这种类型的记忆对于我们能够过正常的生活至关重要，并且是认知能力下降或阿尔茨海默病开始出现时出现的一些第一个明显缺陷的基础。定义产生联想记忆的大脑过程对于理解大脑在正常条件下如何运作很重要，但对于开始理解老年或阿尔茨海默病开始崩溃的机制也很重要。啮齿类动物，如大鼠和小鼠，在它们的正常生活中也使用联想识别记忆，我们已经证明，在联想识别记忆过程中，包括前额叶皮层、海马体和丘脑区域在内的许多不同的大脑区域都在一起工作。这些不同的区域与前额叶皮层一起控制最初的学习，然后是对原始记忆的记忆。然而，我们仍然不知道这些大脑区域是如何运作的。我们要回答的问题之一是：在联想记忆过程中，前额叶皮层中的抑制细胞是如何控制这一大脑区域的功能的？我们认为，海马和丘脑的核控制着前额叶皮层中不同类型的抑制性细胞，这些不同的大脑区域分别激活不同的抑制性细胞，从而分别产生最初的记忆编码，然后再提取记忆。我们将在小鼠中测试这些想法，方法是在记忆的不同阶段选择性地靶向和沉默前额叶皮层中主要类型的中间神经元。我们将使用先进的解剖学标记和光学显微镜方法来检测海马和丘脑与前额叶皮质的连接是否终止于不同的抑制细胞类型。最后，我们将研究这些不同的连接如何控制不同抑制细胞的活动，从而控制前额叶皮层的功能。该项目是及时的，因为我们最近才确定了协同工作以实现联想识别记忆的不同阶段的不同区域，现在可以在小鼠执行学习任务时识别并选择性地靶向不同的抑制细胞。此外，解剖学方法最近已经发展，现在允许我们识别哪些大脑区域与哪些抑制细胞连接，最终我们可以记录这些细胞，以测量它们的活动如何受到控制联想记忆的不同大脑区域的控制。总的来说，这项工作将提供一个详细的机制洞察大脑区域如何集体工作，带来联想识别记忆。