Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
Mol Neurobiol. 2019 Jul;56(7):4855-4865. doi: 10.1007/s12035-018-1407-z. Epub 2018 Nov 7.
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.
恐惧学习失调和大脑网络异常活动可能是焦虑症的病因。虽然有人提出，丘脑室旁核（PVT）到杏仁外侧中央核（CeL）通路的活动减少可能会导致习得性恐惧的减弱，但没有研究表明直接光遗传学激活 PVT 投射到 CeL 的神经元在体内对无条件恐惧相关行为或习得性恐惧表达的影响。控制焦虑相关 PVT-CeL 通路神经元活动的机制很少。在这里，我们发现 CeL 神经元对 PVT 末端在 CeL 中的光遗传学兴奋有不同的反应：兴奋性相对较高的神经元（30%）、兴奋性相对较低的神经元（60%）和无兴奋性的神经元（~10%）。接下来，我们通过在自由活动的小鼠中使用光遗传学和焦虑测定法，探索了 PVT-CeL 通路在无条件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，对 CeL 投射 PVT 神经元进行时间精确的光遗传学激活对无条件恐惧相关行为没有影响。但是，光遗传学激活 CeL 投射 PVT 神经元增加了条件性恐惧表达。然后，我们发现 PVT 传入 CeL 的光遗传学长时程抑制（LTD）诱导有效地持久减弱了习得性恐惧。相对高兴奋性神经元的百分比因 LTD 诱导而减少，相对低兴奋性神经元的百分比因 LTD 诱导而增加。综合这些结果，我们确定 PVT-CeL 通路的活性增加可能导致过度的习得性恐惧。CeL 中对 PVT 传入光刺激有相对高反应的神经元可能是调节习得性恐惧表达输出的关键神经元。我们的光遗传学 LTD 方案可能会激发针对涉及相关大脑区域的深部脑刺激的新型焦虑症治疗方法的发展，以诱导可塑性。
