Dissection of cortico-amygdala circuits controlling aversive behavior using novel mono- and bi-synaptic retrograde viral tools

杏仁核长期以来一直被认为是协调后天和先天恐惧反应的中心区。虽然到目前为止，大多数研究都集中在杏仁核本身，以及它不同的解剖和功能不同的核之间的相互作用，但越来越清楚的是，杏仁核嵌入了整个大脑的环路，它从那里整合信息来调节厌恶行为的表达。特别是，杏仁核接受强大的皮质输入，这是根据不同物种和感觉模式的共同原则组织的：信息在皮质级联中从初级感觉皮质通过次级皮质区域流向更高级别的联合皮质，并沿着这一途径观察到与杏仁核的连接强度增加。然而，在识别的突触连接神经元(而不仅仅是区域间追踪)的水平上，我们对这些电路的组织方式知之甚少，它们在厌恶行为中向杏仁核提供的信息，以及这些信号对行为的哪些方面是必需的。在这里，我们的目标是开发新的单突触和双突触病毒跟踪工具，我们结合现有的转基因和病毒方法来针对嵌入在特定皮质网络中的神经元进行功能成像和光遗传操作，这些特定皮质网络与小鼠已识别的杏仁核神经元存在单突触和双突触连接。这将与解决后天和先天恐惧的范例相结合，以确定这些回路如何影响行为，使用从初级听觉皮质到次级听觉皮质再到杏仁核的信息流，以及从更高级别的关联皮质(岛叶皮质)到杏仁核的交流作为模型。除了这些具体目标外，我们预计新型病毒工具的开发和验证也将使未来能够解剖其他大脑区域的特定大规模网络。

The amygdala has long been established as a central area orchestrating learned and innate fear responses. While most research to date has focused on the amygdala itself, and interactions between its different anatomically and functionally distinct nuclei, it is becoming increasingly clear that the amygdala is embedded in brain-wide circuits from which it integrates information to regulate expression of aversive behaviors. In particular, the amygdala receives strong cortical input that is organized according to a common principle across different species and sensory modalities: information flows in cortical cascades from primary sensory cortex via secondary cortical areas towards higher order association cortex, with increasing connection strength to the amygdala observed along this pathway. However, we know very little about the organization of these circuits at the level of identified, synaptically connected neurons (rather than mere inter-area tracing), the information they supply to the amygdala during aversive behaviors, and for which aspects of behavior these signals are required. Here, our goal is to develop novel mono- and bi-synaptic viral tracing tools that we use in combination with existing transgenic and viral approaches to target functional imaging and optogenetic manipulations to neurons embedded within specific cortical networks that are mono- and bi-synaptically connected to identified amygdala neurons in the mouse. This will be combined with paradigms addressing learned and innate fear to determine how these circuits contribute to behavior, using information flow from primary to secondary auditory cortex and further to the amygdala and communication from a higher order association cortex (insular cortex) to the amygdala as models. In addition to these specific aims, we expect that the development and validation of the novel viral tools will also enable future dissection of specific large-scale networks in other brain areas.