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

项目总结 脑振荡的观察支持了脑振荡活动的一个重要功能作用 特定频率与特定的行为和精神状态相关，包括恐惧状态。精准的 这些关联的机制基础尚不清楚。要实现更深层次的机械性理解，需要 识别调节特定模式之间的因果关系的特定类型的神经元 振荡活动和特定的行为和精神状态。不同的振荡活动模式一直是 在杏仁基底外侧核(BLA)检测到的表达与经验抑制- 依赖恐惧行为。导致抑制依赖经验的恐惧的振荡活动 行为由位于BLA的小白蛋白表达(PV+)中间神经元控制。PV+中间神经元 通过抑制对BLA电路的振荡活动和功能输出进行强有力的控制 它们在BLA投射神经元胞体上形成的突触。大脑白质中的周围型抑制性突触 也由表达CCK+的中间神经元(CCK+中间神经元)产生。根据之前的调查结果， BLA内CCK+中间神经元可能发挥与PV+中间神经元相反的作用。 关于经验依赖的恐惧行为的振荡控制的BLA。这项研究的目标是 确定BLA中CCK+中间神经元是否控制导致行为增强的振荡活动 表达依赖经验的恐惧。为了实现这一目标，老鼠将受到背景恐惧的影响 条件反射、情景恐惧消退和情景恐惧恢复。脑白质中CCK+中间神经元的分布 小鼠将被光遗传学方法压制住。假设CCK+中间神经元沉默减少 通过观察冻结行为来测量恐惧记忆的行为表达，并且也减少 引起经验依赖型恐惧行为的振荡活动，通过记录局部场来测量 血乳酸中的潜势。此外，还将记录和分析BLA中单个单位的尖峰活动 为了找出可能构成振荡和运动之间关系的神经机制 行为上的改变。这项研究的完成将增加对大脑如何机制的理解 振荡控制依赖于经验的恐惧行为，并可能导致改善治疗方案 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.