In 2012,we published the first special issue on the mecha-nisms of pain and itch in Neuroscience Bulletin[1],cover-ing peripheral[2,3],central[4],and glial[5]mechanisms.In 2018,the second special issue expanded on these topics[6],featuring single-cell profiling and in vivo Ca2+imag-ing of primary sensory neurons[7,8],and illustrating how nociceptors regulate pain,itch,and infection[9].It also highlighted spinal neurocircuits of pain[10]and itch[11],glial contributions[12],sex differences[13],and supraspinal mechanisms underlying pain and empathy[14,15].Over the past seven years,significant advances have been made in neuroglial and neuroimmune interactions and supraspi-nal circuits.Thus,this third special issue—comprising one review,eleven original articles,and one research highlight[16-28]—timely summarizes recent progress in pain and itch research.
The anterior cingulate cortex (ACC) has recently been proposed as a key player in the representation of itch stimuli. However, to date, little is known about the contribution of specific ACC interneuron populations to itch processing. Using c-Fos immunolabeling and in vivo Ca2+ imaging, we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide (VIP)-expressing interneuron activity in the ACC. Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch. Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis. Together, this study highlights the importance of ACC VIP+ neurons in modulating itch-related affect and behavior, which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.
The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (Ih) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.
Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.
Astrocytes in the spinal dorsal horn (SDH) exhibit diverse reactive phenotypes under neuropathic conditions, yet the mechanisms driving this diversity and its implications in chronic pain remain unclear. Here, we report that spared nerve injury (SNI) induces marked upregulation of both complement component 3 (C3⁺, A1-like) and S100 calcium-binding protein A10 (S100A10⁺, A2-like) astrocyte subpopulations in the SDH, with elevated microglial cytokines including interleukin-1α, tumor necrosis factor-α, and complement component 1q. Transcriptomic, immunohistochemical, and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype. Fibroblast growth factor 8 (FGF8), a neuroprotective factor via FGFR3, mitigated microglia-induced C3⁺ astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice. These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.
Neuropathic pain, a debilitating condition caused by dysfunction of the somatosensory nervous system, remains difficult to treat due to limited understanding of its molecular mechanisms. Bioinformatics analysis identified cerebellin 2 (CBLN2) as highly enriched in human and murine proprioceptive and nociceptive neurons. We found that CBLN2 expression is persistently upregulated in dorsal root ganglia (DRG) following spinal nerve ligation (SNL) in mice. In addition, transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription. SNL also induced SOX11 upregulation, with SOX11 and CBLN2 co-localized in nociceptive neurons. The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes, including upregulation of numerous NF-κB downstream targets. Consistently, CBLN2 activated NF-κB signaling, and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity, proinflammatory cytokines and chemokines production, and neuronal hyperexcitability. Together, these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.
Chronic pain, frequently comorbid with neuropsychiatric disorders, significantly impairs patients' quality of life and functional capacity. Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis. This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels: (1) Peripheral Sensitization: CCL2/CCR2 modulates TRPV1, Nav1.8, and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain. (2) Spinal Cord Central Sensitization: CCL2/CCR2 contributes to NMDAR-dependent plasticity, glial activation, GABAergic disinhibition, and opioid receptor desensitization. (3) Supraspinal Central Networks: CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions, including the ACC, CeA, NAc, and hippocampus, and it also increases pain sensitization through the descending facilitation system. Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed, highlighting novel avenues for chronic pain management.
Parkinson's disease(PD)is a neurodegenerative disorder characterized by α-Synuclein(α-Syn)aggregation and dopa-minergic neuron degeneration[1].While traditionally con-sidered a central nervous system(CNS)disorder,growing evidence suggests α-Syn pathology in the peripheral organs such as skin,minor salivary glands,submandibular glands,and so on[1].Recent studies have primarily focused on the gastrointestinal tract,supporting the hypothesis that α-Syn may propagate from the gut to the brain in a prion-like man-ner[2,3].However,in a groundbreaking study published in Nature Neuroscience,Xin Yuan et al.have provided a novel perspective on the peripheral origins of PD,revealing for the first time the critical role of the kidney in the pathological transmission and initiation of α-Syn(Fig. 1)[4].Moreover,their findings open new avenues for investigating PD patho-genesis and potential therapeutic interventions.
The majority of individuals maintain normal physiological and behavioral function despite experiencing severe trau-matic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulner-ability,often presenting as stress-related psychiatric con-ditions such as major depressive disorder(MDD)[1]. The global prevalence of MDD is surging unprecedentedly,con-tributing substantially to the global burden of disease and disability.Although current psychotherapeutic interventions and psychopharmacological treatments demonstrate moder-ate efficacy,approximately 30％-50％of MDD patients show inadequate response to conventional antidepressant therapies[2-4].Such unmet clinical needs call for discovering more effective treatments,particularly those targeted to the disor-der's underlying pathophysiology.
Dear Editor, Sleep and memory are highly linked across species.Sleep gates and stabilizes memory,critical for memory processing.Insufficient sleep impairs cognition acutely/chronically,in vertebrates and invertebrates[1,2].While key elements are characterized[3,4],how a single molecule integrates sleep and memory remains unknown.
Alzheimer's disease(AD),the leading cause of dementia,remains a formidable challenge to neurology.Despite dec-ades of research focused on amyloid-β(Aβ)and tau patholo-gies,most clinical trials targeting these molecules failed,highlighting the need for alternative strategies[1].Recent attention has turned to neuroinflammation,particularly the role of microglia,the brain's resident immune cells[1].Microglia are central to AD progression.They can degrade Aβ plaques and protect neurons,but may also exacerbate neurotoxicity through chronic inflammation[1].
Chronic pain affects over 30％of the global adult population,significantly impairing quality of life,physical function,and psychological well-being,while imposing a substantial personal and economic burden[1].As the global popula-tion continues to age,there is an urgent and unmet need to effectively prevent,assess,and manage chronic pain in older adults.Although age-related changes in pain perception,processing,and coping mechanisms have been increasingly recognized over recent decades,many aspects of the rela-tionship between aging and pain remain poorly understood.In addition,aging is associated with increased susceptibility to chronic pain conditions,particularly following peripheral nerve injury[2,3].
Dear Editor, Stress granules(SGs)are dynamic membraneless RNA-protein aggregates or organelles that are formed in response to various cellular stresses and disassemble rapidly with the decay of stresses[1].Under stressful conditions,pro-tein translation is often inhibited suddenly.The resulting untranslated messenger ribonucleoproteins interact with the so-called"nucleator proteins"(such as G3BP1/2 and TIA1)to form the core structure of SGs,which then grow or merge into mature SGs by sequestering untranslated mRNAs and misfolded proteins[2,3].
Cerebral edema is characterized by fluid accumulation, and the glymphatic system (GS) plays a pivotal role in regulating fluid transport. Using the Tenecteplase system, magnesium salt of salvianolic acid B/ginsenoside Rg1 (SalB/Rg1) was injected intravenously into mice 4.5 h after middle cerebral artery occlusion and once every 24 h for the following 72 h. GS function was assessed by Evans blue imaging, near-infrared fluorescence region II (NIR-II) imaging, and magnetic resonance imaging (MRI). SalB/Rg1 had significant effects on reducing the infarct volume and hemorrhagic transformation score, improving neurobehavioral function, and protecting tissue structure, especially inhibiting cerebral edema. Meanwhile, the influx/efflux drainage of GS was enhanced by SalB/Rg1 according to NIR-II imaging and MRI. SalB/Rg1 inhibited matrix metalloproteinase-9 (MMP-9) activity, reduced cleaved β-dystroglycan (β-DG), and stabilized aquaporin-4 (AQP4) polarity, which was verified by colocalization with CD31. Our findings indicated that SalB/Rg1 treatment enhances GS function and attenuates cerebral edema, accompanying the regulation of the MMP9/β-DG/AQP4 pathway.
Dear Editor, Autism is a neurodevelopmental disorder that poses a sig-nificant threat to human health,with its primary manifes-tations including social disability,impairments in verbal and non-verbal communication,and the presence of nar-row interests along with stereotypical repetitive behaviors.Recent research has shown that the Sox5 transcription factor plays a significant role in the axonal projection,migration,localization,and communication of newly generated neu-rons[1].Defects in the Sox5 gene are known to increase the risk of autism.A clinical study on 16 patients with Sox5 gene defects found that Sox5 haploinsufficiency is closely linked to key traits like developmental delay,language delay,behavioral problems,and minor deformities such as a pro-truding forehead and a wide,flat nasal bridge[2].In addi-tion,copy number variation studies of 1,461 individuals with autism spectrum disorder(ASD)revealed that roughly 11.6％had potentially significant genomic variations,includ-ing Sox5 gene deletion mutations[3].
Neuropathic pain is a chronic condition caused by damage or dysfunction in the nervous system. While the spleen may influence neuropathic pain, its role has been poorly understood. This study demonstrates that the spleen plays a crucial role in regulating neuropathic pain through the bed nucleus of the stria terminalis (BNST) - paraventricular nucleus of the hypothalamus (PVN) neural circuit in a chronic constriction injury (CCI) mouse model. Splenectomy, splenic denervation, or splenic sympathectomy significantly increased the mechanical withdrawal threshold (MWT) and reduced macrophage infiltration in the dorsal root ganglia (DRG) of CCI mice. Pseudorabies virus injections into the spleen revealed connections to the BNST and PVN in the brain. Chemogenetic inhibition of the BNST-PVN circuit increased macrophage infiltration in the DRG and decreased the MWT; these effects were reversed by splenectomy, splenic denervation, or sympathectomy. These findings underscore the critical role of the spleen, regulated by the BNST-PVN circuit, in neuropathic pain.
Microglial functions are linked to Ca2+ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer's disease (AD), but how ER Ca2+ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca2+ transients in controls and normalized Ca2+ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca2+ receptors in both homeostatic and AD microglia, providing insights into microglial Ca2+ malfunctions in AD.
Empathy is crucial for communication and survival for individuals. Whether empathy in pain contagion shows sex differences and its underlying mechanisms remain unclear. Here, we report that pain contagion can occur in stranger female rats, but not in stranger males. Blocking oxytocin receptors in the anterior cingulate cortex (ACC) suppressed pain contagion in female strangers, while oxytocin administration induced pain contagion in male strangers. In vitro, corticosterone reduces neuronal activation by oxytocin. During male stranger interactions, higher corticosterone decreased oxytocin receptor-positive neuronal activity in the ACC, suppressing pain contagion. These findings highlight the role of oxytocin in pain contagion and suggest that sex differences in empathy may be determined by the balance of oxytocin and corticosterone in the ACC. This study suggests an approach for the treatment of certain mental disorders associated with abnormal empathy, such as autism and depression.
Humans and animals have a fundamental ability to use experiences and environmental information to organize behavior. It often happens that humans and animals make decisions and prepare actions under uncertain situations. Uncertainty would significantly affect the state of animals' minds, but may not be reflected in behavior. How to "read animals' mind state" under different situations is a challenge. Here, we report that neuronal activity in the medial prefrontal cortex (mPFC) of rats can reflect the environmental uncertainty when the task situation changes from certain to uncertain. Rats were trained to perform behavioral tasks under certain and uncertain situations. Under certain situations, rats were required to simply repeat two nose-poking actions that each triggered short auditory tone feedback (single-task situation). Whereas under the uncertain situation, the feedback could randomly be either the previous tone or a short musical rhythm. No additional action was required upon the music feedback, and the same secondary nose-poking action was required upon the tone feedback (dual-task situation); therefore, the coming task was uncertain before action initiation. We recorded single-unit activity from the mPFC when the rats were performing the tasks. We found that in the dual task, when uncertainty was introduced, many mPFC neurons were actively engaged in dealing with the uncertainty before the task initiation, suggesting that the rats could be aware of the task situation change and encode the information in the mPFC before the action of task initiation.
Social working memory (SWM)-the ability to maintain and manipulate social information in the brain-plays a crucial role in social interactions. However, research on SWM is still in its infancy and is often treated as a unitary construct. In the present study, we propose that SWM can be conceptualized as having two relatively independent components: "externally oriented SWM" (e-SWM) and "internally oriented SWM" (i-SWM). To test this external-internal hypothesis, participants were tasked with memorizing and ranking either facial expressions (e-SWM) or personality traits (i-SWM) associated with images of faces. We then examined the neural correlates of these two SWM components and their functional roles in empathy. The results showed distinct activations as the e-SWM task activated the postcentral and precentral gyri while the i-SWM task activated the precuneus/posterior cingulate cortex and superior frontal gyrus. Distinct multivariate activation patterns were also found within the dorsal medial prefrontal cortex in the two tasks. Moreover, partial least squares analyses combining brain activation and individual differences in empathy showed that e-SWM and i-SWM brain activities were mainly correlated with affective empathy and cognitive empathy, respectively. These findings implicate distinct brain processes as well as functional roles of the two types of SWM, providing support for the internal-external hypothesis of SWM.
