2026-03-20 ユニバーシティ・カレッジ・ロンドン（UCL）
＜関連情報＞
- https://www.ucl.ac.uk/news/2026/mar/pain-relief-could-be-more-effective-certain-times-day
- https://www.science.org/doi/10.1126/science.aeg1907
- https://www.science.org/doi/10.1126/science.aee6177
- https://www.science.org/doi/10.1126/science.ady6455
時間経過に伴う痛み 2つの脳回路が慢性疼痛と時間の相互作用を促進する Pain across time Two brain circuits facilitate the interaction between chronic pain and time
Simon Beggs and Paul W. Frankland
Science Published:19 Mar 2026
DOI:https://doi.org/10.1126/science.aeg1907
Abstract
Pain is classically defined as a sensory experience, yet it also engages emotional and cognitive processes (1). When pain becomes chronic—persists or recurs beyond 3 months from injury—it is frequently accompanied by disability and emotional dysregulation (2). Among these comorbidities, depression, anxiety, and sleep disorders are the most prevalent, yet the mechanistic relationships linking pain chronicity to these affective consequences remain poorly understood. On page 1235 and 1236 of this issue, Wei et al. (3) and Ding et al. (4), respectively, report evidence of pain-related brain regulation at two opposite ends of the temporal spectrum. Wei et al. describe a neural circuit that accounts for daily fluctuations in pain sensitivity. Meanwhile, Ding et al. identify cellular and structural brain changes that contribute to the emergence of depression in chronic pain. These observations offer new insight into how chronic pain becomes coupled to affective and cognitive comorbidities.
慢性疼痛からうつ病へ：海馬歯状回における神経新生を介したミクログリアのリモデリング From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus
Ming Ding, Shitong Xiang, Yuqing Zhang, Lei Wei, […] , and Xiao Xiao
Science Published:19 Mar 2026
DOI:https://doi.org/10.1126/science.aee6177
Editor’s summary
Chronic pain and depression are mutually linked. Ding et al. explored the mechanistic link between chronic pain and depression in humans and rodents (see the Perspective by Beggs and Frankland). In patients and an animal model, early stages of chronic pain were found to be associated with an increase in hippocampal volume, whereas later stages were associated with decreased hippocampal volume. These changes in rats were followed by the development of depressive-like behavior. Mechanistically, the authors showed that microglial activation leads to dysregulation of hippocampal neurogenesis (producing volumetric changes), shifts in hippocampal physiology, and onset depressive-like behaviors. The study provides valuable insights into the role of the hippocampus in the development of comorbid depression in the context of chronic pain. —Mattia Maroso
Structured Abstract
INTRODUCTION
Chronic pain is a leading risk factor for depression and anxiety, yet the brain mechanisms that convert persistent sensory distress into affective dysfunction remain unclear. Neuroimaging studies have implicated the hippocampus in both pain and mood regulation, but it is unknown whether hippocampal alterations precede, accompany, or result from the emergence of affective symptoms. Resolving this temporal and mechanistic relationship is essential for explaining individual vulnerability to depression in chronic pain and for identifying intervention points that can prevent this transition.
RATIONALE
We hypothesized that chronic pain induces a staged remodeling process, rather than a uniform degenerative change, within the hippocampus. Specifically, we proposed that the dentate gyrus serves as a critical gate where persistent nociceptive input is initially accommodated through adaptive plasticity but later diverted into maladaptive circuit destabilization by interactions between adult-born neurons and microglia.
RESULTS
Integrating longitudinal human neuroimaging data from the UK Biobank with rodent models of neuropathic pain, we identified a conserved biphasic trajectory of hippocampal remodeling. During early stages of chronic pain, hippocampal volume increased and hippocampal-dependent cognitive performance improved, consistent with an adaptive response. As pain persisted, this phase transitioned to hippocampal atrophy, cognitive decline, and the emergence of anxiety- and depression-like behaviors.
At the cellular level, early chronic pain selectively increased activity of newborn neurons within the dentate gyrus and triggered targeted recruitment and remodeling of microglia in the neurogenic niche. These cell-type–specific changes progressively amplified local circuit excitability and disrupted network balance, marking a transition from adaptive hippocampal plasticity to maladaptive circuit remodeling. Functionally, distinct modes of dentate gyrus modulation produced divergent outcomes: Suppressing newborn neuron activity alleviated affective symptoms but impaired cognition, whereas microglial modulation prevented anxiety- and depression-like behaviors while preserving cognitive function. Together, these findings identify microglia as a key regulator of the pain-to-depression transition.
CONCLUSION
By resolving distinct modes of dentate gyrus modulation, we show that microglia act as critical and therapeutically tractable regulators of the transition from chronic pain to affective disorders. Our findings reveal that this transition is governed not by hippocampal hyperactivity per se but rather by microglia-dependent remodeling that determines whether adaptive plasticity is sustained or diverted into maladaptive circuit states. Targeting microglial activation preserves hippocampal structure and cognitive function while preventing affective pathology, positioning microglia as a selective leverage point for interrupting the progression from chronic pain to mood disorders.
Dentate gyrus–centered hippocampal remodeling during the transition from chronic pain to affective disorders.This schematic illustrates a biphasic hippocampal response to chronic pain. Early pain induces transient hippocampal expansion and cognitive enhancement, followed by hippocampal atrophy and affective dysfunction. Dysregulated interactions between newborn neurons and microglia within the dentate gyrus drive this transition, highlighting microglial remodeling as a selective therapeutic target. E/I, excitatory-inhibitory.
Abstract
Chronic pain often evolves into depression and anxiety, yet mechanisms linking sensory distress to affective dysfunction remain unclear. Integrating human neuroimaging from the UK Biobank with a rodent model, we uncovered biphasic hippocampal remodeling. Hippocampal volume increased during early pain stages, with paradoxical cognitive improvements, but declined with comorbid depression. In rodents, the dentate gyrus (DG) acted as a hub governing this transition: Lesions of DG prevented affective symptoms. Elevated DG activity was linked to hyperactive newborn neurons and microglial recruitment and remodeling, leading to circuit imbalance. Whereas suppressing newborn neuron activity alleviated emotional pathology at the expense of cognition, microglial modulation selectively restored affective behavior without cognitive cost. These findings reveal microglia-mediated hippocampal remodeling as a key mechanism linking chronic pain to mood disorders.
視床下部時計は概日性疼痛を制御する Hypothalamic clock governs circadian pain
Hong-Rui Wei, Qianqian Lou, Le-Xian Li, Lan Tang , […] , and Zhi Zhang
Science Published:19 Mar 2026
DOI:https://doi.org/10.1126/science.ady6455
Editor’s summary
Pain perception in humans has been shown to be subject to circadian modulation. Wei et al. identified a multisynaptic circuit involved in circadian chronic pain modulation in mice (see the Perspective by Beggs and Frankland). The authors showed that increased γ-aminobutyric (GABA) signaling activity in the suprachiasmatic nucleus during the daytime, or rest phase, inhibited neurons in the subparaventricular zone, leading to disinhibition of glutamatergic neurons in the paraventricular nucleus. This in turn enhanced GABAergic tone in the ventrolateral periaqueductal gray, a region that has been well established for its role in modulating responses to pain. At night, the active phase, reduced suprachiasmatic nucleus activity weakened this cascade, decreasing nociceptive sensitivity. These results offer a mechanistic basis for the fluctuations in pain sensitivity observed in chronic pain patients. —Mattia Maroso
Structured Abstract
INTRODUCTION
Pain sensitivity in humans exhibits daily fluctuations. Patients with neuropathic pain or rheumatoid arthritis frequently experience an exacerbation of symptoms in the evening. However, the neural mechanisms underlying circadian pain remain poorly understood. Although rhythmic variations have been reported in the central nervous system, evidence supporting a direct correlation between circadian rhythms in neuronal activity and pain sensitivity is still limited.
RATIONALE
Research on circadian pain has largely focused on characterizing its perceptual and clinical manifestations, but the recognition of circadian pain rhythms has not been matched by mechanistic insight. Although the functions of many pain-processing brain regions have been characterized, their diurnal activity patterns under pathological pain conditions are poorly defined. Crucially, it is unknown whether and how the central circadian clock orchestrates pain-related regional activities to drive circadian pain.
RESULTS
Mice with neuropathic pain exhibit differentially diurnal and nocturnal responses to pain, showing higher pain sensitivity at zeitgeber time 5 (ZT5, 5 hours after light onset) in the daytime (the resting phase of mice) and lower at ZT14 in nighttime (the active phase of mice). Fiber photometry recordings and chemogenetic modulations reveal that the rhythmic activity of vasoactive intestinal peptide neurons in the suprachiasmatic nucleus (SCNVIP) is higher at ZT5 and lower at ZT14 in neuropathic pain mice, which corresponds to concomitant changes in nociceptive sensitivity.
Fos-TRAPed neuronal labeling and in vivo recordings demonstrate that the activity of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAGGABA) is higher at ZT5 compared to ZT14. The retrograde tracing reveals that vlPAGGABA neurons are innervated by glutamatergic neurons in the paraventricular nucleus (PVNGlu), which exhibit distinct daily rhythms in neuropathic pain mice, characterized by elevated activity at ZT5 and reduced activity at ZT14. Optogenetic manipulations show that the rhythmic PVNGlu→vlPAGGABA circuit activity entrains rhythmic pain sensitivity of mice with neuropathic pain.
Photoactivation of SCNVIP neuronal terminals in the PVN at ZT5 and local SCNVIP neurons at ZT14 induced opposite pain behavioral effects. Triple retrograde tracing and fiber photometry recordings indicate that the activity of PVN-projecting GABAergic neurons in the subparaventricular zone (SPZGABA) exhibits a synchronized, but inverse, pattern of rhythmicity relative to SCNVIP neuronal activity. Ablation of SPZGABA neurons establishes the SPZ as an essential inhibitory relay in the SCN→SPZ→PVN→vlPAG circuit for maintaining daily rhythms in pain sensitivity of neuropathic pain mice.
vlPAGGABA neuronal rhythmicity drives daily rhythms of the descending analgesia system via the vlPAG→rostral ventromedial medulla (RVM)→spinal cord circuit. At ZT5, the decreased activity of RVM-innervated GABAergic neurons in the spinal cord (SCGABA) leads to increased activity of ascending ventral posterolateral nucleus (VPL)–projecting glutamatergic neurons in the spinal cord (SCGlu) that they target, thereby inducing higher pain sensitivity of mice with neuropathic pain.
CONCLUSION
Mice exhibit daily rhythms in pain sensitivity, accompanied with rhythmic activity of the endogenous descending analgesia system, which is coordinated by the hypothalamic master clock. This study explains how the circadian system influences the pain modulation system to generate time-of-day–dependent pain behaviors, offering a mechanistic framework for chronotherapeutic strategies in pain management.
Mechanisms underlying circadian pain.
Differences in the activity of the SCN→SPZ→PVN→vlPAG→RVM→SC circuit between day and night phases mediate daily rhythms in pain-related behaviors under conditions of neuropathic pain. In the daytime, higher SCNVIP neuronal activity triggers stronger inhibitory inputs to SPZGABA neurons, increasing the activity of vlPAG-projecting PVNGlu neurons, in turn stimulating vlPAGGABA neuronal activity, inducing increased ascending SCGlu neuronal activity via the vlPAGGlu→RVM→SCGABA→SCGlu circuit, and finally leading to higher pain sensitivity in mice with neuropathic pain. At night, decreased SCNVIP activity results in lower ascending SCGlu neuronal activity through this circuit, thereby decreasing pain sensitivity. [Figure created with BioRender.com]
Abstract
Chronic pain exhibits circadian rhythms in humans, but the mechanisms underlying such rhythmicity remain unclear. Here, we found daily oscillations in the nociceptive thresholds in a mouse model of neuropathic pain, driven by a rhythmic circuit from the master clock in the hypothalamus to the descending analgesia system. In the daytime (resting phase), higher vasoactive intestinal peptide (VIP) neuronal activity in suprachiasmatic nucleus (SCNVIP) activates a signaling pathway involving the paraventricular nucleus (PVN) and the ventrolateral periaqueductal gray (vlPAG), ultimately increasing nociceptive sensitivity. At night (active phase), reduced SCNVIP neuronal activity decreases pain sensitivity through this polysynaptic circuit. This study identified a circuit for regulating pain rhythmicity that might be targeted to improve chronic pain management.
