Role of cholecystokinin-expressing interneurons in the oscillatory control of experience-dependent fear behavior

项目摘要 脑振荡活动的一个重要功能作用得到以下观察结果的支持： 在特定的频率与特定的行为和精神状态，包括恐惧的状态。的精确 这些相关性的机械基础尚不清楚。实现更深入的机械理解需要 识别特定类型的神经元，介导特定模式之间的因果关系， 振荡活动和特定的行为和精神状态。不同的振荡活动模式 在基底外侧杏仁核（BLA）中检测到的表达与抑制的经验- 依赖性恐惧行为引起对依赖经验的恐惧的抑制的振荡活动 行为由位于BLA中的表达小清蛋白（PV+）的中间神经元控制。PV+中间神经元 对BLA回路的振荡活动和功能输出进行强有力的控制， 它们在BLA投射神经元的索马上形成的突触。BLA中的体周抑制性突触 也由表达胆囊收缩素的中间神经元（CCK+中间神经元）产生。根据以前的调查结果， BLA中的CCK+中间神经元可以发挥与PV+中间神经元在BLA中所起的作用相反的作用。 BLA关于经验依赖性恐惧行为的振荡控制。本研究的目的是 为了确定BLA中的CCK+中间神经元是否控制引起行为增加的振荡活动， 经验依赖性恐惧的表达。为了达到这一目标，小鼠将受到情境恐惧 条件反射、情境恐惧消退和情境恐惧恢复。CCK+中间神经元在BLA的这些 将用光遗传学方法使小鼠沉默。假设沉默CCK+中间神经元可以减少 恐惧记忆的行为表达，如通过观察冻结行为所测量的，并且也减少 引起依赖于经验的恐惧行为的振荡活动，通过记录局部场来测量 BLA的潜力。此外，将记录并分析BLA中单个单元的加标活性 为了确定可能是振荡和 行为改变这项研究的完成将增加对大脑如何 振荡控制经验依赖的恐惧行为，并可能导致改善治疗选择， 患有过度恐惧的患者，例如由于创伤后应激障碍。

PROJECT SUMMARY An important functional role for oscillatory brain activity is supported by the observation that brain oscillations at specific frequencies correlate with specific behavioral and mental states, including states of fear. The precise mechanistic basis for these correlations is unclear. Achieving a deeper mechanistic understanding requires the identification of specific types of neurons that mediate causal relationships between specific patterns of oscillatory activity and specific behavioral and mental states. Different patterns of oscillatory activity have been detected in the basolateral amygdala (BLA) during the expression versus the suppression of experience- dependent fear behavior. Oscillatory activity that causes the suppression of experience-dependent fear behavior is controlled by parvalbumin-expressing (PV+) interneurons located in the BLA. PV+ interneurons exert strong control over both oscillatory activity and functional output of BLA circuits through inhibitory synapses that they make onto the soma of BLA projection neurons. Perisomatic inhibitory synapses in the BLA are also made by interneurons that express cholecystokinin (CCK+ interneurons). Based on previous findings, CCK+ interneurons in the BLA could play a role that is opposite from the role played by PV+ interneurons in the BLA with regards to the oscillatory control of experience-dependent fear behavior. The goal of this study is to determine if CCK+ interneurons in BLA control oscillatory activity that causes increased behavioral expression of experience-dependent fear. To achieve this goal, mice will be subjected to contextual fear conditioning, contextual fear extinction, and contextual fear retrieval. CCK+ interneurons in the BLA of these mice will be silenced with an optogenetic approach. Silencing CCK+ interneurons is hypothesized to decrease the behavioral expression of the fear memory, as measured by observing freezing behavior, and to also decrease oscillatory activity that causes experience-dependent fear behavior, as measured by recording local-field potentials in the BLA. In addition, the spiking activity of single-units in the BLA will be recorded and analyzed in order to identify neuronal mechanisms that might underlie the relationship between oscillatory and behavioral changes. Completion of this study will increase the mechanistic understanding of how brain oscillations control experience-dependent fear behavior, and might lead to improved treatment options for patients suffering from excessive fear, for example as a result of post-traumatic stress disorder.