Optogenetic Long-Term Depression Induction in the PVT-CeL Circuitry Mediates Decreased Fear Memory
Optogenetic Long-Term Depression Induction in the PVT-CeL Circuitry Mediates Decreased Fear Memory
复制标题
PVT-CeL 回路中的光遗传学长期抑郁诱导介导恐惧记忆减少
DOI：
10.1007/s12035-018-1407-z
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Bi, Lin-lin
中科院分区：
文献类型：
--
作者：
Chen, Ming;Bi, Lin-lin
恐惧学习的失调和大脑网络活动的异常可能是焦虑症的病因之一。尽管有人提出，丘脑室旁核（PVT）到杏仁核中央外侧核（CeL）通路的活动减少可以诱导习得性恐惧的减弱，但没有研究表明直接光遗传学激活PVT投射CeL的影响体内神经元对无条件恐惧相关行为或习得性恐惧表达的影响。控制参与焦虑的PVT-CeL通路的神经元活性的机制是罕见的。在这里，我们发现CeL神经元对CeL中PVT终末的光遗传学激发具有不同的反应：具有相对高兴奋性的神经元（~ 30%），具有相对低兴奋性的神经元（~ 60%），以及没有兴奋性的神经元（~ 10%）。接下来，我们通过在自由移动的小鼠中使用光遗传学和焦虑测定来探索PVT-CeL通路在非条件性和条件性恐惧相关行为中的作用。我们观察到，在高架十字迷宫测试和旷场测试中，投射PVT的细胞神经元的时间精确的光遗传学激活对无条件的恐惧相关行为没有影响。但是，光遗传学激活的细胞投射的PVT神经元增加了条件性恐惧的表达。然后，我们发现，在接受PVT传入的CeL中的光遗传学长期抑郁（LTD）诱导有效地产生了学习性恐惧的持续衰减。LTD可使兴奋性相对较高的神经元比例降低，兴奋性相对较低的神经元比例增加。综合这些结果，我们发现PVT-CeL通路的活性增加可能导致过度的学习性恐惧。对PVT传入光刺激反应较强的细胞可能是调节学习性恐惧表达输出的关键神经元。我们的光遗传学LTD方案可能会激发开发新的治疗焦虑症的方法，包括脑深部电刺激，以诱导相关脑区的可塑性。
The dysregulation of fear learning and abnormal activities of cerebral networks may contribute to the etiologies of anxiety disorders. Although it has been proposed that decreased activity in the paraventricular nucleus of the thalamus (PVT) to the lateral central nucleus of amygdala (CeL) pathway could induce an attenuation of learned fear, no study has shown the effect of the direct optogenetic activation of PVT projecting CeL neurons in vivo on unconditioned fear-related behaviors or learned fear expression. The mechanisms that control the neuronal activity of the PVT-CeL pathway involved in anxiety are rare. Here, we found that CeL neurons have varied responses to optogenetic excitation of PVT terminals in the CeL: neurons with relative high excitability(~ 30%), neurons with relative low excitability(~ 60%), and neurons with no excitability (~ 10%). We next explored the role of the PVT-CeL pathway in unconditioned and conditioned fear-related behaviors by using optogenetics and anxiety assays in freely moving mice. We observed that temporally precise optogenetic activation of the CeL-projecting PVT neurons had no effect on unconditioned fear-related behaviors on the elevated plus maze test and the open field test. But optogenetic activation of the CeL-projecting PVT neurons increased conditioned fear expression. We then found that optogenetic long-term depression (LTD) induction in the CeL receiving PVT afferents effectively exerted a persistent attenuation of learned fear. The percentage of neurons with relative high excitability was decreased by the LTD induction, and the percentage of neurons with relative low excitability was increased by the LTD induction. Taking these results together, we identify that increased activity of the PVT-CeL pathway could lead to as excessive learned fear. The CeL neurons with relative high responses to the photo-stimulation of PVT afferents in the CeL may be the key neurons that regulate the output of learned fear expression. Our optogenetic LTD protocol may inspire the development of novel treatments for anxiety disorders involving deep brain stimulation to induce plasticity at relevant brain areas.