前庭神经核-臂旁核通路介导前庭功能损伤诱发焦虑症的神经生物学机制研究

Vestibular dysfuntion induced anxiety disorder is very common in the clinical practice. Chronic anxiety will delay vestibular rehabilitation or even severe psychiatric disorders such as depression. But the mechanisms underlying this comorbidity remains unclear, making effective treatments difficult. Previous neuroanatomical studies has proved that vestibular nuclei (VN) have bilateral connections with the regulation center of anxiety-parabrachial nucleus (PBN). Our preliminary studies have demonstrated elevated anxiety levels through behavioral tests and elevated concentrations of all or part of monoamine neurotransmitters in medial VN after vestibular impairment. We also noted increased expression of c-fos in PBN. We therefore hypothesize that VN-PBN neural pathway may mediate the vestibular dysfunction-related anxiety. In this research, we first use the animal model of vestibular dysfunction to observe the activity of different sub-nuclei and types of neurons of VN and PBN after vestibular impairment through c-Fos immunohistochemical staining. Then we apply optogenetical and phamacogenetical technology combined with behavioral study to see the anxiety-related behavioral changes following the activation/inhibition of different types of neurons. Through this research we will explore the role of VN-PBN neural pathway in the mediation of vestibular dysfunction-related anxiety through behavioral, immunohistochemical and phamacogenetical methods, in order to clarify the mechanism underlying the comorbidity of vestibular dysfunction and anxiety, thus providing theoretical basis for new treatments.

前庭功能损伤继发焦虑症在临床上较常见，长期焦虑会延缓前庭功能恢复，甚至诱发抑郁等精神疾患。但目前前庭功能损伤导致焦虑症的具体作用机制仍不明确。已有研究证实前庭神经核和介导焦虑的重要核团臂旁核之间有密切交互支配。我们前期研究发现前庭功能损伤后动物焦虑水平上升，且前庭神经内侧核部分单胺类神经递质浓度显著增加，臂旁核c-fos表达显著增加。因此我们推测前庭神经核-臂旁核通路介导了前庭功能损伤诱发焦虑的病理生理过程。本项目拟利用转基因小鼠构造前庭功能损伤模型，结合免疫组化、光遗传学及化学遗传学操控神经元活性、特异性神经元示踪技术和焦虑行为评价等方法，研究前庭神经核和臂旁核神经环路在调控前庭功能损伤导致焦虑症中的作用，并明确不同类型神经元对焦虑行为的影响。预期结果将深入揭示前庭功能损伤导致焦虑症的神经生物学机制，为探索新的治疗手段提供理论依据。

前庭功能损伤继发焦虑症在临床上较常见，长期焦虑会导致睡眠障碍，延缓前庭功能恢复，甚至诱发抑郁等精神疾患。但目前前庭功能损伤导致焦虑症的具体作用机制仍不明确。已有研究证实前庭神经核和介导焦虑和恐惧的重要核团臂旁核之间有密切交互支配。本项目进行了臂旁核（PB）相关环路活性变化对恐惧/焦虑的影响，首先进行PB-孤束核（NTS）神经通路调节脑波的作用方式及神经通路研究，发现NTS可以促进非快眼睡眠（NREM）期脑波的同步化，而且是通过PB起作用的。我们发现腹侧（vHPC）和背侧海马（dHPC）的激活（化学遗传学手段）会影响条件恐惧的强化，同时增强恐惧记忆的消除。此外还通过化学遗传学手段发现觉醒状态下激活与PB密切相关的杏仁核背外侧核（BLA）可能抑制条件恐惧记忆的消除。最后我们发现初始电压对峰值电压Vh的影响是随着prestin的密度增大而增大的，可能和内耳毛细胞发育早期的分子成熟过程有关。