Yuan Yuan

All Publications

• Deconstruction of a spino-brain-spinal cord circuit drives chronic mechanical pain. Research square Wang, Q., Lee, J. H., Nachtrab, G., Yuan, Y., Yuan, L., Qi, W., Mohr, M. A., Xiong, J., Horowitz, M. A., Chen, X. 2025

  Abstract

  Inflammation or nerve injury at periphery can cause chronic pain. Although the spinal cord-projecting neurons in the rostral ventromedial medulla (RVMSC neurons) are known can promote pain chronification1-4, the pathway by which peripheral injury signals drive these neurons is poorly understood5,6. Here we report a circuit loop that extends from spinal cord to ventral posterolateral thalamus and posterior complex of the thalamus, proceeds to primary somatosensory cortex; then returns to the spinal cord via lateral superior colliculus, which in turn connects to μ-opioid receptor expressing RVMSC neurons. Silencing any node along this multisynaptic circuit has minimal effect on nociception in healthy mice, but can eliminate mechanical hypersensitization and restore normal nociceptive response thresholds in mouse models of inflammatory and neuropathic pain. Repetitive, but not acute, activation of each node within this circuit in healthy mice is sufficient to cause robust chronic mechanical hypersensitization. Our findings elucidate a spino-brain-spinal circuit loop linking ascending and descending pathways that specifically drives chronic mechanical pain, and identify novel cellular targets for treating chronic pain.

  View details for DOI 10.21203/rs.3.rs-5292927/v1

  View details for PubMedID 41282163

  View details for PubMedCentralID PMC12633165

• Brain control of humoral immune responses amenable to behavioural modulation. Nature Zhang, X., Lei, B., Yuan, Y., Zhang, L., Hu, L., Jin, S., Kang, B., Liao, X., Sun, W., Xu, F., Zhong, Y., Hu, J., Qi, H. 2020; 581 (7807): 204-208

  Abstract

  It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.

  View details for DOI 10.1038/s41586-020-2235-7

  View details for PubMedID 32405000

• Salience processing by glutamatergic neurons in the ventral pallidum. Science bulletin Wang, F., Zhang, J., Yuan, Y., Chen, M., Gao, Z., Zhan, S., Fan, C., Sun, W., Hu, J. 2020; 65 (5): 389-401

  Abstract

  Organisms must make sense of a constant stream of sensory inputs from both internal and external sources which compete for attention by determining which ones are salient. The ability to detect and respond appropriately to potentially salient stimuli in the environment is critical to all organisms. However, the neural circuits that process salience are not fully understood. Here, we identify a population of glutamatergic neurons in the ventral pallidum (VP) that play a unique role in salience processing. Using cell-type-specific fiber photometry, we find that VP glutamatergic neurons are robustly activated by a variety of aversion- and reward-related stimuli, as well as novel social and non-social stimuli. Inhibition of the VP glutamatergic neurons reduces the ability to detect salient stimuli in the environment, such as aversive cue, novel conspecific and novel object. Besides, VP glutamatergic neurons project to both the lateral habenula (LHb) and the ventral tegmental area (VTA). Together, our findings demonstrate that the VP glutamatergic neurons participate in salience processing and therefore provide a new perspective on treating several neuropsychiatric disorders, including dementia and psychosis.

  View details for DOI 10.1016/j.scib.2019.11.029

  View details for PubMedID 36659230

• Whole-Brain Mapping of Monosynaptic Afferent Inputs to Cortical CRH Neurons. Frontiers in neuroscience Zhang, S., Lv, F., Yuan, Y., Fan, C., Li, J., Sun, W., Hu, J. 2019; 13: 565

  Abstract

  Corticotropin-releasing hormone (CRH) is a critical neuropeptide modulating the mammalian stress response. It is involved in many functional activities within various brain regions, among which there is a subset of CRH neurons occupying a considerable proportion of the cortical GABAergic interneurons. Here, we utilized rabies virus-based monosynaptic retrograde tracing system to map the whole-brain afferent presynaptic partners of the CRH neurons in the anterior cingulate cortex (ACC). We find that the ACC CRH neurons integrate information from the cortex, thalamus, hippocampal formation, amygdala, and also several other midbrain and hindbrain nuclei. Furthermore, our results reveal that ACC CRH neurons receive direct inputs from two neuromodulatory systems, the basal forebrain cholinergic neurons and raphe serotoninergic neurons. These findings together expand our knowledge about the connectivity of the cortical GABAergic neurons and also provide a basis for further investigation of the circuit function of cortical CRH neurons.

  View details for DOI 10.3389/fnins.2019.00565

  View details for PubMedID 31213976

  View details for PubMedCentralID PMC6558184

• Central Processing of Itch in the Midbrain Reward Center. Neuron Su, X. Y., Chen, M., Yuan, Y., Li, Y., Guo, S. S., Luo, H. Q., Huang, C., Sun, W., Li, Y., Zhu, M. X., Liu, M. G., Hu, J., Xu, T. L. 2019

  Abstract

  Itch is an aversive sensation that evokes a desire to scratch. Paradoxically, scratching the itch also produces a hedonic experience. The specific brain circuits processing these different aspects of itch, however, remain elusive. Here, we report that GABAergic (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) are activated with different temporal patterns during acute and chronic itch. DA neuron activation lags behind GABA neurons and is dependent on scratching of the itchy site. Optogenetic manipulations of VTA GABA neurons rapidly modulated scratching behaviors through encoding itch-associated aversion. In contrast, optogenetic manipulations of VTA DA neurons revealed their roles in sustaining recurrent scratching episodes through signaling scratching-induced reward. A similar dichotomy exists for the role of VTA in chronic itch. These findings advance understanding of circuit mechanisms of the unstoppable itch-scratch cycles and shed important insights into chronic itch therapy.

  View details for DOI 10.1016/j.neuron.2019.03.030

  View details for PubMedID 31000426

• Reward Inhibits Paraventricular CRH Neurons to Relieve Stress. Current biology : CB Yuan, Y., Wu, W., Chen, M., Cai, F., Fan, C., Shen, W., Sun, W., Hu, J. 2019; 29 (7): 1243-1251.e4

  Abstract

  Chronic, uncontrollable stress can lead to various pathologies [1-6]. Adaptive behaviors, such as reward consumption, control excessive stress responses and promote positive health outcomes [3, 7-10]. Corticotrophin-releasing hormone (CRH) neurons in paraventricular nucleus (PVN) represent a key neural population organizing endocrine, autonomic, and behavioral responses to stress by initiating hormonal cascades along the hypothalamic-pituitary-adrenal (HPA) axis and orchestrating stress-related behaviors through direct projections to limbic and autonomic brain centers [11-18]. Although stress and reward have been reported to induce changes of c-Fos and CRH expression in PVN CRH neurons [19-23], it has remained unclear how these neurons respond dynamically to rewarding stimuli to mediate the stress-buffering effects of reward. Using fiber photometry of Ca2+ signals within genetically identified PVN CRH neurons in freely behaving mice [24-26], we find that PVN CRH neurons are rapidly and strongly inhibited by reward consumption. Reward decreases anxiety-like behavior and stress-hormone surge induced by direct acute activation of PVN CRH neurons or repeated stress challenge. Repeated stress upregulates glutamatergic transmission and induces an N-methyl-D-aspartate receptor (NMDAR)-dependent burst-firing pattern in these neurons, whereas reward consumption rebalances the synaptic homeostasis and abolishes the burst firing. Anatomically, PVN CRH neurons integrate widespread information from both stress- and reward-related brain areas in the forebrain and midbrain, including multiple direct long-range GABAergic afferents. Together, these findings reveal a hypothalamic circuit that organizes adaptive stress response by complementarily integrating reward and stress signals and suggest that intervention in this circuit could provide novel methods to treat stress-related disorders.

  View details for DOI 10.1016/j.cub.2019.02.048

  View details for PubMedID 30853436

• High frequency stimulation induces sonic hedgehog release from hippocampal neurons. Scientific reports Su, Y., Yuan, Y., Feng, S., Ma, S., Wang, Y. 2017; 7: 43865

  Abstract

  Sonic hedgehog (SHH) as a secreted protein is important for neuronal development in the central nervous system (CNS). However, the mechanism about SHH release remains largely unknown. Here, we showed that SHH was expressed mainly in the synaptic vesicles of hippocampus in both young postnatal and adult rats. High, but not low, frequency stimulation, induces SHH release from the neurons. Moreover, removal of extracellular Ca2+, application of tetrodotoxin (TTX), an inhibitor of voltage-dependent sodium channels, or downregulation of soluble n-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) proteins, all blocked SHH release from the neurons in response to HFS. Our findings suggest a novel mechanism to control SHH release from the hippocampal neurons.

  View details for DOI 10.1038/srep43865

  View details for PubMedID 28262835

  View details for PubMedCentralID PMC5338313