The role of zinc signalling in the amygdala

我们不断地将价格归因于我们在环境中导航时遇到的感觉信息--它是令人愉快和有益的，还是有害的和令人厌恶的？我们学会预测与这些经历相关的积极和消极结果，并做出适当的情感和行为反应，接近回报，逃离/避免危险。这对我们的生存至关重要。大脑的一个区域，杏仁核的基底外侧复合体(BLA)，接受密集的感觉输入，并被认为是编码刺激价所必需的。BLA中的神经元将投射发送到大脑的其他区域，这些区域负责做出适当的行为反应，并形成对厌恶事件和奖励关联的记忆。我的实验室感兴趣的是了解信号机制，通过这种机制，特定价态的情绪信息在这些大脑区域之间进行处理和传递。我们发现，BLA中含有大量独特地使用锌作为神经递质的神经元。我们还看到，在这些神经元靶向的大脑区域，它们的突触中锌含量非常高，这表明锌信号对于这些神经元建立的连接的正常功能很重要。这项提案中概述的实验旨在评估锌信号是否对处理由BLA神经元形成的回路中的情感相关信息至关重要。我们最近获得了一种小鼠，这种小鼠经过基因工程，允许我们选择性地针对使用锌作为神经递质的神经元，用可见的标志物对它们进行标记，使用光激活的通道增加或减少它们的活动，以及消除它们使用锌传递信号的能力。我们将分析这些小鼠的行为，同时以电路特有的方式操纵特定锌神经元的活动，同时控制它们释放锌的能力，同时它们暴露在消极或积极的实验环境中。通过这种方式，我们将能够理解锌神经元，它们在大脑中形成的电路，以及它们传递的锌信号，如何有助于杏仁核处理情感相关信息的功能。在我的学术生涯中，我大部分时间都在从事研究，旨在了解含锌神经元的作用，以及锌作为哺乳动物大脑中的神经递质的作用。作为世界锌神经生物学专家之一，收购这只革命性的基因工程小鼠为我提供了应用新的、最先进的细胞、生理、分子和基因技术来更好地理解锌信号在大脑功能中的基础作用的方法。

We are constantly attributing valence to sensory information that is encountered as we navigate our environment - is it pleasant and rewarding or noxious and aversive? We learn to predict positive and negative outcomes that are tied to those experiences, and make appropriate emotional and behavioural responses, to approach rewards and to escape/avoid danger. This is essential for our survival. One region of the brain, the basolateral complex of the amygdala (BLA), receives dense sensory inputs and is known to be necessary for encoding stimulus valence. Neurons in the BLA send projections to other regions of the brain that are responsible for making appropriate behavioural responses and for forming memories for aversive events and reward associations. My laboratory is interested in understanding the signaling mechanisms whereby valence-specific emotional information is processed and conveyed among these brain regions.     We have discovered that the BLA contains a large number of neurons that uniquely use zinc as a neurotransmitter. We also see that in regions of the brain that are targeted by these neurons, they have very high levels of zinc in their synapses, suggesting that signaling by zinc is important for the normal function of connections made by these neurons. The experiments outlined in this proposal are directed toward assessing whether zinc signaling is critical for processing of emotionally relevant information, in circuits formed by BLA neurons.     We have recently acquired a strain of mouse that has been genetically engineered to allow us to selectively target neurons that use zinc as a neurotransmitter, to label them with a visible marker, increase or decrease their activity using light-activated channels, as well as to eliminate their ability to convey a signal using zinc. We will analyze the behaviour of these mice while manipulating the activity of specific zinc neurons in a circuit-specific manner, at the same time controlling their ability to release zinc, while they are exposed to negative or positive experimental contexts. In this way we will be able to understand how zinc neurons, the circuits they form in the brain, and the zinc signals that they transmit, contribute to the function of the amygdala in processing emotionally relevant information.     I have devoted the majority of my academic life engaged in studies directed to understanding the role of zinc containing neurons, and zinc as a neurotransmitter in the mammalian brain. As one of the world's experts in zinc neurobiology, the acquisition of this revolutionary, genetically-engineered mouse provides me with the means to apply novel, state-of-the-art cellular, physiological, molecular and genetic techniques to developing a greater understanding of the fundamental role of zinc signaling in brain function.