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.

在精神疾病期间，由杏仁核驱动的恐惧行为可能会变得不适应。我们的主要目标是了解杏仁核回路如何触发恐惧行为，以及这一功能在从正常状态向病理状态转变的过程中如何变化。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，那些处理感觉信息的信号，以及那些提供执行控制的信号。为了解决这个问题，人们需要通过有选择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，选择性地激活或抑制杏仁核的输入，这些输入来自传递感觉信息的皮质区TEA和与影响、疼痛和认知有关的前扣带皮质。这两种输入以相同的杏仁核神经元为目标，并混合在杏仁核内。我们发现这两条通路在突触可塑性方面存在显著差异。虽然从周边皮质传入的长时程增强突触传递(LTP)需要抑制GABAA受体介导的抑制，但ACC-杏仁核通路中的LTP不需要。此外，切断外囊和杏仁核之间的联系，即使在GABAA受体介导的抑制存在的情况下，也能使来自周边皮质的LTP进入。此外，我们发现这两种输入与杏仁核抑制神经元的连接方式不同。ACC能更有效地激活表达5-羟色胺受体3的中间神经元，而TEA能更有效地招募囊周细胞。这些发现具有有趣的意义：首先，外囊的多巴胺依赖的抑制神经元似乎在杏仁核周围皮质的输入中通向可塑性，而基底外侧核内的5-羟色胺依赖的中间神经元则通向来自ACC的高度精炼的信息。 我们继续研究杏仁核去抑制的机制，并将重点放在局部微电路的多巴胺能调制上。利用转基因Cre-小鼠的中间神经元特异性系，我们选择性地激活杏仁基底外侧核中的小白蛋白阳性神经元，发现多巴胺选择性地抑制向主细胞释放GABA，但不抑制向中间神经元释放GABA。 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应控制杏仁核基底外侧核抑制和兴奋之间的平衡。