{"id":4079,"date":"2025-11-03T08:42:54","date_gmt":"2025-11-03T08:42:54","guid":{"rendered":"https:\/\/www.caolaboratory.org.cn\/?p=4079"},"modified":"2026-04-10T07:31:16","modified_gmt":"2026-04-10T07:31:16","slug":"neuron%e2%94%82%e6%9b%b9%e9%b9%8f%e5%ae%9e%e9%aa%8c%e5%ae%a4%e5%8f%91%e7%8e%b0%e9%87%8d%e5%a4%8d%e5%88%bb%e6%9d%bf%e8%a1%8c%e4%b8%ba%e7%9a%84%e9%97%ad%e7%8e%af%e7%a5%9e%e7%bb%8f%e6%9c%ba%e5%88%b6-2","status":"publish","type":"post","link":"https:\/\/www.caolaboratory.org.cn\/?p=4079","title":{"rendered":"Neuron | Peng Cao\u2019s Laboratory Discovers the Neural Mechanism Behind Repetitive Stereotyped Behaviors"},"content":{"rendered":"\n

In daily life, people perform various physiologically repetitive stereotyped behaviors (such as washing hands and brushing teeth) to meet normal life needs. In psychiatric disorders like autism and obsessive-compulsive disorder (OCD), patients often exhibit pathological repetitive stereotyped behaviors. These pathological behaviors are seen as a window into understanding the mechanisms of these disorders and have attracted the attention of many researchers. When human autism and OCD gene mutations were introduced into the mouse genome, researchers were surprised to find that the \u201cdiseased\u201d mice also exhibited pathological repetitive stereotyped behaviors, such as prolonged repetitive self-grooming. [1-4]<\/strong> Self-grooming is an instinctive behavior in humans and animals that helps to remove foreign objects (like dirt) from the body, and it has significant biological importance. Research into the neural mechanisms underlying such instinctive behaviors may reveal the underlying logic behind repetitive stereotyped behaviors. Previous studies have mainly focused on brain regions, including the “cortex-striatum” circuit regulating self-grooming behaviors. [5-7]<\/strong> However, the neural mechanisms through which the brain and spinal cord coordinate to initiate repetitive stereotyped behaviors are still unclear.<\/p>\n\n\n\n

On December 21, 2021, Peng Cao\u2019s laboratory at the Beijing Institute of Life Sciences published a study titled A Brain-to-Spinal Sensorimotor Loop for Repetitive Self-Grooming<\/em> in the renowned neuroscience journal Neuron<\/em>. This study discovered that in the caudal part of the spinal trigeminal nucleus (Sp5C), neurons expressing cerebellin-2 (Cbln2) form a descending neural pathway projecting to the spinal cord, playing an important role in maintaining repetitive self-grooming behaviors. Inactivation of the Cbln2+ Sp5C neurons blocked sensory- and stress-induced repetitive self-grooming. Activation of these neurons triggered repetitive forelimb movements similar to self-grooming. Further investigation showed that Cbln2+ Sp5C neurons receive inputs from sensory neurons in the trigeminal ganglion and neurons in the hypothalamic paraventricular nucleus. These neurons form a descending pathway to the spinal cord, controlling motor and interneurons in the cervical spinal cord, making them a necessary and sufficient condition for repetitive self-grooming behavior. These results suggest that the brain-spinal coordination plays a critical role in repetitive stereotyped behaviors. The authors proposed an intriguing closed-loop neural mechanism model: each instance of self-grooming activates the Cbln2+ Sp5C neurons, which further promote the next cycle of self-grooming behavior, forming a feedback-driven closed-loop mechanism that sustains the occurrence of repetitive stereotyped behaviors.<\/p>\n\n\n\n

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1. Establishing Three Induced Behavioral Paradigms and Quantitative Methods for Measuring Repetitive Self-Grooming<\/strong><\/strong><\/p>\n\n\n\n

The researchers first used three different external stimuli to induce repetitive self-grooming behaviors: corn oil applied to the face (sensory stimulus), subcutaneous injection of capsaicin (chemical stimulus), and foot shock (stress-induced stimulus). All three methods resulted in repetitive self-grooming behaviors directed toward the mouse’s face. To quantitatively analyze these behaviors, the researchers embedded miniature magnets in the mouse forelimbs and placed the mouse in an electromagnetic field. The generated electromagnetic signals tracked repetitive forelimb movements, which corresponded to repetitive self-grooming behaviors.<\/p>\n\n\n\n

Next, the researchers used different volumes of corn oil to induce facial self-grooming in mice. They found that the duration of this behavior was dependent on the volume of the oil. Further, using TrkB-CreER, TH-2A-CreER, and Mrgprb4-TdTomato-2A-Cre mice, the researchers injected AAV-DIO-EGFP-2A-TeNT vectors into the trigeminal ganglion to inactivate specific neuron types. They found that inactivating the TrkB+ sensory neurons in the trigeminal ganglion significantly reduced the duration of self-grooming induced by corn oil, suggesting that TrkB+ neurons in the trigeminal ganglion are involved in the repetitive self-grooming induced by corn oil.<\/p>\n\n\n\n

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Figure 1<\/strong> Repetitive stereotyped behavior induction and quantitative analysis of self-grooming (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

2. Cbln2+ Sp5C Neurons Are the Key Neuronal Subtype for Facial Self-Grooming<\/strong><\/strong><\/p>\n\n\n\n

Next, the researchers examined the central mechanisms underlying self-grooming behavior. Sensory neurons in the trigeminal ganglion project to the brainstem, where they form the trigeminal nerve complex. This complex includes the principal trigeminal nucleus (Pr5) and the spinal trigeminal nucleus (Sp5). The caudal part of the spinal trigeminal nucleus (Sp5C) is structurally similar to the spinal dorsal horn, hence often referred to as the medullary dorsal horn. Previous studies have shown that neurons in this region, which express Cbln2, PV, CCK, and NPY, are involved in processing mechanical stimuli. The researchers used chemogenetic inhibition techniques to target specific neuronal subtypes (Cbln2+, PV+, CCK+, NPY+) in the Sp5C. They found that inhibiting Cbln2+ Sp5C neurons led to a significant reduction in the duration of self-grooming behavior induced by corn oil, capsaicin, and stress, while inhibition of other neuronal subtypes had no significant impact. This suggests that Cbln2+ Sp5C neurons are critical for regulating this behavior.<\/p>\n\n\n\n

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Figure 2<\/strong> Cbln2+ Sp5C neurons are the key neuronal subtype for facial self-grooming (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

3. Activation of Cbln2+ Sp5C Neurons Triggers Forelimb Movements Similar to Self-Grooming<\/strong><\/strong><\/p>\n\n\n\n

The researchers then injected AAV-DIO-ChR2-2A-mCherry vectors into the Sp5C of Cbln2-IRES-Cre mice and embedded optical fibers. They found that optogenetic activation of Cbln2+ Sp5C neurons induced repetitive forelimb movements similar to self-grooming. The frequency of this movement depended on the intensity and frequency of the laser. Additionally, chemogenetic activation of Cbln2+ Sp5C neurons also triggered repetitive stereotyped self-grooming behavior, which was reduced by the antidepressant fluoxetine.<\/p>\n\n\n\n

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Figure 3<\/strong> Activation of Cbln2+ Sp5C neurons triggers forelimb movements similar to self-grooming (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

4. Morphological and Physiological Properties of Cbln2+ Sp5C Neurons<\/strong><\/strong><\/p>\n\n\n\n

The researchers further analyzed the morphology and physiology of Cbln2+ Sp5C neurons. They found that these neurons are primarily glutamatergic. Using calcium imaging, they observed that Cbln2+ Sp5C neurons showed oscillatory calcium signals when self-grooming behavior was induced by corn oil. However, the calcium signal was delayed relative to the self-grooming behavior, suggesting that these neurons participate in maintaining, rather than initiating, the behavior. Additionally, these neurons showed a preference for responding to mechanical stimuli on the same side of the face.<\/p>\n\n\n\n

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Figure 4<\/strong> Morphological and physiological properties of Cbln2+ Sp5C neurons (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

5. Inputs and Outputs of Cbln2+ Sp5C Neurons<\/strong><\/strong><\/p>\n\n\n\n

Using rabies virus tracing, the researchers discovered that Cbln2+ Sp5C neurons receive inputs from LTMRs and TRPV1+ sensory neurons in the trigeminal ganglion, as well as inputs from the primary somatosensory cortex (S1) and the paraventricular hypothalamic nucleus (PVH). They also found that these neurons project to the ventral posterior medial nucleus (VPM) of the thalamus, the lateral parabrachial nucleus (LPB), and the ventral horn of the spinal cord. These projections were organized into two separate groups in the Sp5C, with the projections to LPB and the spinal cord playing distinct roles.<\/p>\n\n\n\n

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Figure 5<\/strong> Inputs and outputs of Cbln2+ Sp5C neurons (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

6. Critical Role of Cbln2+ Sp5C Neurons Projecting to the Spinal Cord in Facial Self-Grooming<\/strong><\/strong><\/p>\n\n\n\n

The researchers further tested whether activation of the Cbln2+ Sp5C neurons projecting to the spinal cord could induce self-grooming behavior. They found that chemogenetic activation of these neurons in the spinal cord could trigger repetitive facial self-grooming. Conversely, inhibiting these spinal projections significantly reduced the duration of self-grooming behavior induced by corn oil, capsaicin, and foot shock.<\/p>\n\n\n\n

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Figure 6<\/strong> Critical role of Cbln2+ Sp5C neurons projecting to the spinal cord in facial self-grooming behavior (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

7. Characterization of Spinal Projections of Cbln2+ Sp5C Neurons<\/strong><\/strong><\/p>\n\n\n\n

Through rabies virus tracing, the researchers identified the upstream inputs of the Cbln2+ Sp5C neurons projecting to the spinal cord. They found that these neurons integrate inputs from sensory neurons in the trigeminal ganglion, as well as inputs from PVH neurons. They also recorded calcium signals from these neurons during self-grooming behavior and found significant increases in calcium activity, particularly in response to mechanical stimuli on the same side of the face.<\/p>\n\n\n\n

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Figure 7<\/strong> Characterization of spinal projections of Cbln2+ Sp5C neurons (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

8. Conclusion and Proposal of a “Sensorimotor Closed-Loop” Model<\/strong><\/strong><\/p>\n\n\n\n

In conclusion, this study identifies the Cbln2+ Sp5C neurons and their spinal projections as critical components in repetitive stereotyped self-grooming behavior in mice. The study provides three main conclusions: (1) Cbln2+ Sp5C neurons, as a unique neuronal subtype, regulate instinctual self-grooming behavior. (2) The discovery of spinal projections from these neurons offers key insights into how brain-spinal coordination contributes to repetitive stereotyped behaviors. (3) The findings suggest that Cbln2+ Sp5C neurons may play a role in OCD-like behaviors in mouse models. The researchers propose a “sensorimotor closed-loop” model, where each instance of self-grooming activates Cbln2+ Sp5C neurons, promoting the next cycle of self-grooming behavior, thereby sustaining repetitive stereotyped behaviors.<\/p>\n\n\n\n

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Figure 8<\/strong> The “Sensorimotor Closed-Loop” Model (Image from: Xie et al., Neuron 2021)<\/p>\n\n\n\n

The study was conducted by Zhiyong Xie, Dapeng Li, Xinyu Cheng, Qing Pei, and Huating Gu, who are the co-first authors, along with important contributions from other lab members. Key collaborators include Dr. Yuanwu Ma from the Chinese Academy of Medical Sciences, Dr. Fan Zhang from Hebei Medical University, and Dr. Chen Zhang from Capital Medical University. The research was funded by the National Natural Science Foundation of China.<\/p>\n\n\n\n

References<\/strong><\/strong><\/p>\n\n\n\n

[1] Welch, J.M., Lu, J., Rodriguiz, R.M., Trotta, N.C., Peca, J., Ding, J.D., Feliciano, C., Chen, M., Adams, J.P., Luo, J., et al. (2007). Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894\u2013900<\/p>\n\n\n\n

[2] Shmelkov, S.V., Hormigo, A., Jing, D., Proenca, C.C., Bath, K.G., Milde, T., Shmelkov, E., Kushner, J.S., Baljevic, M., Dincheva, I., et al. (2010). Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat. Med. 16, 598\u2013602.<\/p>\n\n\n\n

[3] Peca, J., Feliciano, C., Ting, J.T., Wang, W., Wells, M.F., Venkatraman, T.N., Lascola, C.D., Fu, Z., and Feng, G. (2011). Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437-442.<\/p>\n\n\n\n

[4] Schmeisser, M.J., Ey, E., Wegener, S., Bockmann, J., Stempel, A.V., Kuebler, A., Janssen, A.L., Udvardi, P.T., Shiban, E., Spilker, C., et al. (2012). Autistic-like behaviours and hyperactivity in mice lacking ProSAP1\/Shank2. Nature 486, 256-260.<\/p>\n\n\n\n

[5] Ahmari, S.E., Spellman, T., Douglass, N.L., Kheirbek, M.A., Simpson, H.B., Deisseroth, K., Gordon, J.A., and Hen, R. (2013). Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science 340, 1234\u20131239.<\/p>\n\n\n\n

[6] Burguiere, E., Monteiro, P., Feng, G., and Graybiel, A.M. (2013). Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 340, 1243\u20131246.<\/p>\n\n\n\n

[7] Yu, X., Taylor, A.M.W., Nagai, J., Golshani, P., Evans, C.J., Coppola, G., and Khakh, B.S. (2018). Reducing Astrocyte Calcium Signaling In Vivo Alters Striatal Microcircuits and Causes Repetitive Behavior. Neuron 99, 1170\u2013 1187.e9.<\/p>\n","protected":false},"excerpt":{"rendered":"

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