Recently, the collaborative team of Xie Wei and Mu Mingdao fromthe Key Laboratory of Developmental Genes and Human Disease has, for the first time, identified a novel neural circuit originating from the paralemniscal nucleus (MPL) in the brainstem and composed of neurons expressing the neuropeptide Pth2. This circuit plays a critical role in encoding aversive stimuli and triggering anxiety-like behaviors. The findings were recently published online in Neuroscience Bulletin, the official journal of the Chinese Society for Neuroscience.
Rapid identification of environmental threats is crucial for animal survival. Although the novel neuropeptide Pth2 has been implicated in emotional regulation, the specific neural mechanisms underlying its function remain unclear.
This study focused on the dense population of Pth2 neurons within the brainstem MPL region, aiming to elucidate their functional and circuit basis in emotion-related behaviors. The research team first successfully constructed a Pth2-P2A-iCre gene-edited mouse model, enabling precise genetic labeling and manipulation of Pth2 neurons. Using fiber photometry calcium imaging, they observed that MPL Pth2 neurons exhibit rapid and sustained activation in mice exposed to aversive stimuli such as foot shocks, suggesting their involvement in encoding early threat information. To further establish their causal role, researchers employed chemogenetic methods to specifically activate MPL-Pth2 neurons, successfully inducing significant conditioned place aversion and anxiety-like behaviors in mice. This demonstrates that the activity of this neuronal population is sufficient to drive negative emotional states. Further neural circuit tracing experiments revealed that MPL-Pth2 neurons primarily project to brain regions closely associated with defensive behaviors, such as the paraventricular nucleus of the thalamus (PSTh) and the zona incerta (ZI), thereby structurally elucidating the potential pathways through which they regulate emotional behaviors. This study is the first to delineate a Pth2ergic neural pathway from the brainstem MPL to the diencephalon, which not only responds to aversive information at the perceptual level but also actively drives anxiety and aversion behaviors. This provides a new perspective for understanding the neural mechanisms underlying negative emotions and offers potential targets for intervention research related to psychiatric disorders.
The co-first authors of this paper are Zhang Zixu, an undergraduate student in the "Clinical Medicine 5+3" program at Southeast University School of Medicine andthe Key Laboratory of Developmental Genes and Human Disease; Geng Shuyan, a Ph.D. candidate; and Sun Chuanyao, a Ph.D. candidate from the School of Life Science and Technology at Southeast University. Graduate students Hu Shengru and Xu Tianxiang participated in the research as co-authors. Professor Xie Wei and Associate Professor Mu Mingdao are the corresponding authors. The research was supported by the National Key R&D Program of China (2030–"Brain Science and Brain-Like Research" Major Project), the National Natural Science Foundation of China, the Jiangsu Provincial Natural Science Foundation, and the Southeast University Medical Research Ascension Plan, among other funding sources. (School of Life Science and Technology)
Link to the original article: https://doi.org/10.1007/s12264-025-01548-4