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论文题名(中文):

 重复性自我梳理行为的脑-脊髓感觉运动神经环路    

姓名:

 程欣宇    

论文语种:

 chi    

学位:

 博士    

学位类型:

 学术学位    

学校:

 北京协和医学院    

院系:

 北京生命科学研究所    

专业:

 生物学-生物化学与分子生物学    

指导教师姓名:

 曹鹏    

论文完成日期:

 2024-04-30    

论文题名(外文):

 A brain to spinal sensorimotor loop for repetitive self-grooming    

关键词(中文):

 口面部自我梳理行为 神经环路 感觉刺激 自闭症 动物模型    

关键词(外文):

 orofacial self grooming behavior neural circuits sensory stimuli obsessive compulsive disorder (OCD) animal model    

论文文摘(中文):

自我梳理行为是一种先天性的本能行为,在物种间具有高度的保守性。它常用于维持身体清洁,并在调节体温、社交繁殖、缓解压力和抵抗病原等方面起着重要作用。过度的重复性自我梳理行为是一种病理性的表现,会引起动物毛发脱落,表皮受损等表型。这种行为也能够在患有精神类疾病的人群中观察到,常被诊断为重度的刻板行为。研究中往往将自我梳理行为的出现频率作为评估动物焦虑水平的指标之一,并在此基础上础建立了多种疾病动物模型,包括自闭症谱系障碍(ASD)强迫症(OCD)、抽动秽语综合征(TS)等。深入探究自我梳理行为的产生和调控机制能够为多种精神类疾病的治疗提供依据。
神经生物学研究发现,典型的自我梳理行为遵循高度的模式化,包括特定的行为类型和顺序,称为链式自我梳理行为。而脑干会影响这一行为中动作的完整执行中脑和脊髓的连接对这种节律性运动模式起着重要作用。此外,目前对于自我梳理行为的研究多集中于前脑,其中纹状体、伏隔核和大脑皮层的损伤和缺失都会对自我梳理行为产生不同程度的影响。位于边缘系统的杏仁核和下丘脑中的神经内分系统也参与对自我梳理行为的调控。这些研究表明自我梳理行为的产生可能依赖大脑中多个核团的共同作用,但对其发生的充分必要条件仍不明确,还缺乏分子细胞层面具体证据。
为此,在本研究中,我们利用电磁感应系统开发了一种能够定量测量小鼠重复性口面部自我梳理行为的行为范式和统计方法。并借助光遗传、化学遗传和光纤记录等经典神经科学研究方法确定了三叉神经复合体尾侧核(the caudal pant of thespinal trigeminalnucleus,Sp5C)中表达小脑肽-2 基因(Cerebellin-2.Cbln2t)的神经元作为关键的神经元调控口面部自我梳理行为,并进一步结合神经元顺向追踪技术和伪狂犬病毒逆向示踪技术,确定了其整合不同来源的多种刺激,包括三叉神经节(trigeminal ganglions,TG)中表达酪氨酸激酶受体B的神经元接受的机械刺激、TG中表达辣椒素受体的神经元接受的化学刺激,以及下丘脑室旁核中表达促肾上腺皮质激素释放激素的神经元接受的压力应激刺激,并向脊髓传导引起口面部的自我梳理行为,而这一行为本身产生的面部机械刺激,又作为输入诱导产生新一轮的面部自我梳理行为,形成感觉运动环路维持重复性面部自我梳理行为持续进行。
这一研究结果在分子细胞层面上揭示了自我梳理行为依赖的神经环路,对于症状为严重刻板行为的精神类疾病提供了可能的治疗靶点,同时感觉运动环路也为行为的神经环路研究提供了新的思路。

论文文摘(外文):

Self-grooming behavior is an innate and instinctive trait, displaying a high degree ofconservation across species. It is commonly employed for bodily cleanliness and plays apivotal role in daily life, including the regulation of body temperature, social reproductionstress relief, and resistance to pathogens.


Excessive repetitive self-grooming behavior is a pathological manifestation that canlead to phenotypic outcomes such as hair loss and epidermal damage in animals. Thisbehavior is also observed in populations suffering from psychiatric disorders and is oftendiagnosed as severe stereotypic behavior. In research, the frequency of self-groomingbehavior is often used as an indicator to assess the level of anxiety in animals. Based onthis, various animal models for diseases have been established, including autism spectnimmdisorders (ASD), obsessive-compulsive disorder (OCD), Tourette syndrome (TS) and etcDelving into the mechanisms underlying the emergence and regulation of self-groomingbehavior can provide a foundation for the treatment of various psychiatric disorders.

Neurobiological research has found that typical self-grooming behavior shows a highlevel of patterning, including specific behavior types and sequences, called syntactic chainpattern. The absence of the brainstem affects the complete execution of the actions in thisbehavior, and the connection between the midbrain and spinal cord plays an important rolein this rhythmic movement pattem. Cuently, research on self-grooming behaviorpredominantly focuses on the forebrain, and the damage of the striatum, accumbensnucleus, and cortex can impact self-grooming behavior. In the limbic system, the amygdalaand the neuroendocrine systems of hypothalamus are also involved in the regulation ofself-grooming behavior. These findings indicate that the generation of self-groomingbehavior could rely on the cooperation of multiple nucleus in the brain. However, thesufficient and necessary conditions for the self-grooming behavior are still unclear, and there is still a lack of detailed cellular and molecular evidence in this issue.


In this study, we developed a behavioral paradigm and statistical methods forquantitatively measuring repetitive orofacial self-grooming behavior in mice using an electromagnetic induction system. And with the help of classic neuroscience researchmethods such as optogenetics, chemogenetics, and fiber photometry, we identified neuronsexpressing gene cerebelline-2 (Cbin2) in the caudal part of the spinal trigeminal nucleus(Sp5C) as crucial neurons regulating orofacial self-grooming behavior. Furthermore, usinganterograde tracing and pseudorabies vins retrograde tracing techniques, we deteminedthat it integrates multiple stimuli from different sources and conducts them to the spinalcord to elicit orofacial self-grooming, These stimuli include mechanical stimuli receivedby neurons expressing tyrosine kinase receptor B (TrkB) in the trigeminal ganglia (TG)chemical stimuli received by neurons expressing transient receptor potential vanilloid 1(TRPV1) in TG, and stress stimuli received by neurons expressing corticotropin releasing hormone (CRH)in the paraventricular hypothalamic nucleus PVH).The mechanicalstimulation generated by this behavior on the face will induce a new round of orofacialself-grooming behavior, thereby forming a sensorimotor loop to maintain the continuationof repetitive orofacial self-grooming behavior.

This results reveal the neural circuits dependent on self-grooming behavior at thecellular and molecular level, and provide a possible therapeutic target for mental illnesseswhose syptoms are severe stereotyped behaviors. At the same time, the sensorimotorcircuit also provides new ideas for the study of neural circuits of behavior.

开放日期:

 2024-05-31    

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