Synaptic mechanisms of amygdala-dependent behaviors

恐惧行为是由杏仁核驱动的，在精神疾病期间可能会变得适应不良。我们的主要目标是了解杏仁核回路如何触发恐惧行为，以及这种功能在从正常状态到病理状态的过渡过程中如何变化。这些知识将提供有助于开发与病理性恐惧相关的精神障碍治疗方法的信息。 杏仁核通过分析传入的信息并触发防御反应来运作。我们研究的第一个问题是杏仁核如何在突触水平上区分来自大脑不同区域的信号，这些信号处理感觉信息，以及提供执行控制的信号。为了解决这个问题，人们需要通过选择性地刺激来自特定大脑区域的纤维来询问特定的输入。为了解决这个问题，我们建立了基于视蛋白的技术，用于选择性激活或沉默杏仁核的输入从皮层区TeA，传递感觉信息，并从前扣带皮层，这是牵连的影响，疼痛和认知。这两种输入都针对相同的杏仁核神经元，并在杏仁核内混合。我们发现这两条通路的突触可塑性有显著差异。虽然来自嗅周皮层的突触传递（LTP）的长时程增强需要抑制GABA α受体介导的抑制，但ACC-杏仁核通路中的LTP则不需要。此外，切断外囊和杏仁核之间的联系，即使在GABA α受体介导的抑制的存在下，也能在嗅周皮层的输入中产生LTP。此外，我们发现这两个输入表现出不同的连接杏仁核抑制神经元。ACC输入在激活表达5-羟色胺受体3的中间神经元方面更有效，而TeA输入在招募囊周细胞方面更有效。这些发现有有趣的影响：第一，多巴胺依赖性抑制神经元的外囊似乎门的可塑性杏仁核输入从嗅周皮质，而在基底外侧核门高度精炼的信息ACC内的多巴胺依赖性的中间神经元。 我们继续研究杏仁核去抑制的机制，并专注于局部微电路的多巴胺能调制。使用interneuron-specific线的转基因Cre-mice，我们选择性地激活小白蛋白阳性神经元在基底外侧杏仁核，并发现多巴胺选择性地抑制GABA释放对主细胞，但不对interneurons。 我们目前的目标是确定神经调质如何通过其突触特异性效应控制基底外侧杏仁核抑制和兴奋之间的平衡。

Fear behaviors, which are driven by the amygdala, can become maladaptive during mental illness. Our main goal is to understand how amygdala circuitry triggers fear behaviors and how this function changes during transition from normal to pathological states. This knowledge will provide information that will help in developing treatments for mental disorders associated with pathological fear. Amygdala operates by analyzing incoming information and triggering defensive responses. The first question of our investigation is how amygdala distinguishes, at the synaptic level, between signals which arrive from different areas of the brain, those which process sensory information, and those which provide executive control. To address this question, one needs to interrogate a specific input by selectively stimulating fibers coming from a specific brain area. To address this question we established opsin-based techniques for selective activation or silencing of amygdala inputs from cortical area TeA which transmits sensory information, and from the anterior cingulate cortex, which is implicated in affect, pain and cognition. Both inputs target same amygdala neurons and are intermingled inside amygdala. We found significant difference in synaptic plasticity between the two pathways. While long-term potentiation of synaptic transmission (LTP) in the input from perirhinal cortex required suppression of GABAa receptor-mediated inhibition, LTP in the ACC-amygdala pathway did not. Moreover, severing connections between external capsule and amygdala enabled LTP in the input from perirhinal cortex even in the presence of GABAa receptor-mediated inhibition. In addition, we found that these two inputs exhibit differential connectivity to the amygdala inhibitory neurons. The ACC input was more effective in activating interneurons that express serotonin receptor 3, whereas the TeA input was more effective in recruiting the pericapsular cells. These findings have interesting implications: first, dopamine-dependent inhibitory neurons of the external capsule appear to gate plasticity in the amygdala input from perirhinal cortex, whereas serotonin-dependent interneurons inside the basolateral nucleus gate the highly refined information from ACC. We continued to investigate the mechanisms responsible for amygdala disinhibition and focused on dopaminergic modulation of local microcircuits. Using interneuron-specific lines of transgenic Cre-mice, we selectively activated parvalbumin positive neurons in the basolateral amygdala and found that dopamine selectively suppressed GABA release towards principal cells, but not towards interneurons. Our current goal is to determine how neuromodulators, through their synapse-specific effcts, control the balance between inhibition and excitation in the basolateral amygdala nucleus.