On August 16, 2024, a research paper titled “A thalamic nucleus reuniens–lateral septum–lateral hypothalamus circuit for comorbid anxiety–like behaviors in chronic itch” was published online in Science Advances. This collaborative study involved Researcher Ming-Gang Liu from Oujiang Laboratory, Employing cutting-edge techniques across neuronal, synaptic, and circuit levels, the study systematically investigated the role of GABAergic neurons in the lateral septum (LS) in regulating anxiety-like behaviors induced by chronic itch, along with their upstream and downstream projection circuit mechanisms. This research offers new perspectives for the comprehensive treatment of chronic itch complicated by anxiety.
Itch is an unpleasant sensation that triggers the urge to scratch. Under physiological conditions, it represents acute itch that alerts the body to imminent or existing threats. By inducing scratching to remove potentially harmful foreign substances from the skin, it serves protective and warning functions. However, when itch persists and escalates into chronic itch, it loses its original protective significance and instead becomes a debilitating clinical condition severely impacting patients' physical and mental health. Beyond exacerbating the itching sensation through repeated scratching and subsequent skin damage, long-term chronic pruritus often triggers accompanying complications such as anxiety, depression, and other emotional disorders. These further deteriorate patients' quality of life and increase socioeconomic burdens. Unfortunately, due to limited understanding of the neural mechanisms underlying chronic pruritus and its comorbidities, current clinical treatments remain severely constrained. Anxiety, the most common and prevalent comorbidity in chronic pruritus, has been documented in various dermatological conditions and systemic diseases causing persistent itching. Prolonged, recurrent anxiety exacerbates the abnormal sensation of itch, ultimately forming a vicious cycle of itch-anxiety-increased itch. Nevertheless, fundamental neurobiological research on how chronic pruritus induces anxiety remains relatively scarce.
In this study, researchers first established a chronic itch model of contact dermatitis induced by diphenylcyclopropenone (DCP). They found that DCP sensitization followed by two weeks of continuous administration stably induced pronounced anxiety-like behavior in adult C57BL/6J mice. Second, researchers employed fiber optic recording to detect calcium signaling changes in GABAergic neurons within the LS region during scratching and anxiety-like states in DCP-sensitized mice. They observed no significant alterations in calcium signaling during scratching. However, calcium levels markedly increased when mice transitioned from the enclosed arms to the open arms of a elevated plus maze. These fiber optic recording results were consistent with behavioral outcomes from direct manipulation of LS GABAergic neurons. Based on these findings, the authors propose that LS GABAergic neurons specifically mediate chronic itch-induced anxiety-like behavior without affecting scratching behavior.
Subsequently, the authors employed viral tracing, patch-clamp electrophysiology, and projection circuit-specific chemogenetic manipulation to investigate the upstream and downstream projections of LS GABAergic neurons contributing to DCP-induced anxiety. They sought to elucidate the neural circuit mechanisms by which the LS mediates distinct anxiety states. By performing c-fos detection in traced upstream projection brain regions, the authors identified the thalamic reuniens nucleus (Re) as the upstream brain region for chronic itch-induced anxiety-like behavior and the prefrontal cortex (PFC) as the upstream region for acute restraint-induced anxiety-like behavior. The study revealed that DCP treatment significantly enhanced synaptic plasticity in excitatory projections from Re to LS and increased excitability of Re neurons projecting to LS. Selective inhibition of ReàLS projections using chemogenetic methods specifically blocked chronic itch-induced anxiety-like behavior. Conversely, inhibiting PFCàLS projections specifically blocked acute restraint-induced anxiety-like behavior.
Finally, the authors investigated downstream projections from the LS. Viral tracing and in vitro patch-clamp recordings revealed that GABAergic neurons in the LS primarily project to GABAergic neurons in the lateral hypothalamus (LH). Selective inhibition of LSàLHGABA projections via a viral co-injection strategy significantly alleviated chronic itch-induced anxiety-like behavior without affecting scratching behavior. The authors further identified a distinct population of LS neurons that both receive projections from the reticular formation (Re) and project to the LH. Inhibiting this LS neuron population similarly blocked chronic itch-induced anxiety-like behavior.
In summary, this study provides a comprehensive investigation of the brain regions, neurons, synapses, and circuit mechanisms underlying chronic itch and its anxiety-like comorbidity. It elucidates the cell type and circuit-specific mechanisms by which the LS regulates anxiety induced by chronic itch, It identifies unique neural mechanisms underlying chronic itch-induced anxiety distinct from other anxiety models, reveals synaptic plasticity alterations in the LS and specific projection circuits caused by chronic itch, and explores strategies to reverse these abnormalities and anxiety-like behaviors. Ultimately, it deciphers a neural circuit regulating chronic itch-induced anxiety-like behavior: Re→LS→LH (Figure1). These findings provide a scientific theoretical basis for deepening understanding of the neural mechanisms of chronic itch and the circuit mechanisms underlying the itch-anxiety vicious cycle, while also offering new clues and insights for the clinical treatment of chronic itch.
Manuscript URL：
https://www.science.org/doi/10.1126/sciadv.adn6272
