Synaptic mechanisms of amygdala-dependent behaviors

杏仁核依赖性行为的突触机制

• 批准号: 8556968
• 负责人: Alexei Morozov
• 金额: $ 102.24万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8556968
• 关键词: Address; Affect; Amygdaloid structure; Anterior; Area; Behavior; Brain; Cell Nucleus; Cells; Cognition; Disinhibition; Dopamine; Equilibrium; Exhibits; External Capsule; Fiber; Fright; Goals; Interneurons; Investigation; Knowledge; Long-Term Potentiation; Mediating; Mental disorders; Mus; Neuromodulator; Neurons; Opsin; Pain; Parvalbumins; Pathway interactions; Recruitment Activity; Sensory; Sensory Process; Serotonin; Serotonin Receptors 5-HT-3; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Transgenic Organisms; base; cingulate cortex; executive function; gamma-Aminobutyric Acid; inhibitory neuron; interest; receptor; response

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.

由杏仁核驱动的恐惧行为在精神疾病期间可能会成为适应不良的行为。我们的主要目标是了解杏仁核电路如何触发恐惧行为以及该功能在从正常状态到病理状态的过渡过程中如何变化。这些知识将提供信息，有助于开发与病理恐惧相关的精神障碍治疗方法。 杏仁核通过分析传入信息并触发防御反应来运作。我们调查的第一个问题是杏仁核如何在突触层面上区分来自大脑不同区域的信号，处理感官信息的信号以及提供执行控制的信号。为了解决这个问题，需要通过选择性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OPSIN的技术，用于从皮质区域茶中选择性激活或沉默的杏仁核输入，从而传递感官信息，并从前扣带回皮质中，这与情感，疼痛和认知有关。这两个输入都靶向相同的杏仁核神经元，并在杏仁核内混合。我们发现两种途径之间的突触可塑性显着差异。虽然来自周围皮层的输入中突触传播（LTP）的长期增强需要抑制GABAA受体介导的抑制作用，但ACC-杏仁核途径中的LTP却没有。此外，即使在GABAA受体介导的抑制作用的情况下，外部胶囊和杏仁核之间的切断的连接也启用了来自周围皮层的输入的LTP。此外，我们发现这两个输入表现出与杏仁核抑制性神经元的差异连通性。 ACC输入在激活表达5-羟色胺受体3的中神经元方面更有效，而茶输入在募集周围细胞方面更有效。这些发现具有有趣的含义：首先，外部囊的多巴胺依赖性抑制性神经元似乎在杏仁核皮质的杏仁核输入中可构栅性可塑性，而基底核核内的羟色胺依赖性中间神经元来自ACC的高度精制信息。 我们继续研究导致杏仁核抑制作用的机制，并着重于局部微电路的多巴胺能调节。使用转基因Cre-cre鼠的间神经元特异性线，我们在基底外侧杏仁核中有选择地激活白蛋白蛋白阳性神经元，发现多巴胺选择性地抑制了GABA对主要细胞的释放，而不是对中间神经元的释放。 我们目前的目标是确定神经调节剂如何通过其突触特异性效果来控制基底外侧杏仁核中抑制和激发之间的平衡。