Shanghai Center for Brain Science and Brain-Inspired Technology

Parkinson's disease (PD) is a prevalent neurodegenerative disorder accompanied by neuroinflammation. Many studies have demonstrated that interleukin-6 (IL-6) exhibits both anti-inflammatory and pro-inflammatory effects in the central nervous system, yet its role in PD remains controversial. In this study, Il6 -/- (knockout), Il6 +/-, and wild-type mice were utilized to investigate the impact of IL-6 on the pathology of MPTP- or α-SynucleinA53T-induced PD mice. Our findings revealed that Il6 deficiency exacerbated motor dysfunction in both female and male mice. MPTP intoxication resulted in earlier and more extensive injuries to the dopaminergic system and heightened glial reaction in the nigrostriatal pathway of female Il6 -/- mice compared with male Il6 -/- mice, which only displayed more severe dopaminergic neuronal loss at 7 days after MPTP administration. Toxic α-Synuclein overexpression in the substantia nigra region caused earlier motor dysfunction and aggravated dopaminergic neurodegeneration in female Il6 -/- mice. In Il6 +/- mice, MPTP-induced depletion of dopaminergic nerve fibers was unaffected, although astrocyte activation was attenuated. Moreover, intraperitoneal administration of recombinant IL-6 (rIL-6) partially ameliorated MPTP-induced motor dysfunction and striatal dopaminergic terminal depletion in both wild-type and knockout mice. Our findings underscore the crucial role of IL-6 in the inflammatory pathology of PD, highlighting sex-dependent differences, and suggest that rIL-6 holds potential promise for PD therapy.

The rapid advancement of spatial multi-omics technologies has unveiled opportunities for deciphering the intricate spatial heterogeneity; however, current computational approaches struggle to comprehensively integrate diverse molecular and spatial information. Here we propose 3d-OT, a deep geometry-aware framework that leverages spatial geometric and multi-omics information for feature extraction, spatial domains identification and heterogeneous slices alignment. 3d-OT utilizes modality fusion representation to align spatial slices, bridging the gap in spatial multi-omics alignment methods. Meanwhile, we handle nonrigid deformations in heterogeneous slice alignment through soft correspondence optimal transport, and the chamfer distance is introduced to quantify its performance. 3d-OT outperforms existing methods in capturing anatomical details of mouse brain cortex layers and tracking nonrigid deformations of heart and neural crest tissues at different resolutions. Finally, we construct the 3D spatiotemporal trajectory of mouse embryonic development. Overall, 3d-OT enables comprehensive understanding of existing spatial multi-omics data, offering a powerful computational tool to decipher the spatial complexity of biological tissues.

Tooth avulsion, a severe dental trauma prevalent among adolescents, is commonly treated with delayed replantation. However, this procedure is frequently complicated by root resorption, which can ultimately lead to tooth loss. Given that adolescent patients are not candidates for implant therapy, strategies to mitigate root resorption and prolong the survival of replanted teeth are critically needed. This study aimed to investigate the effect of chronic intermittent hypobaric hypoxia (CIHH) on root resorption following delayed tooth replantation and to elucidate its potential mechanisms. Human clinical specimens from non-replanted and replanted teeth were compared using X-ray and computed tomography (CT) for root resorption. In a rat model, animals were allocated to four groups: Non-replantation or Replantation, each under normobaric normoxic (NN) or chronic intermittent hypobaric hypoxia (CIHH, simulating 4,000 m altitude, 5 h/day) conditions. After one month, root resorption was assessed by micro-CT, and periodontal healing and osteoclast distribution were evaluated via histology. OPG and RANKL protein levels were quantified by IHC and Western blot. Furthermore, bone marrow-derived macrophages (BMMs) and bone mesenchymal stem cells (BMSCs) were isolated and induced to differentiate into osteoclasts and osteoblasts, with differentiation assessed by TRAP and ALP staining, respectively. Clinical specimens revealed that delayed replantation resulted in significant root resorption. In the rat model, delayed replanted tooth also exhibits obvious root absorption. However, CIHH treatment significantly attenuated root resorption, reduced the number of osteoclasts on the root surface. Importantly, CIHH significantly downregulated RANKL expression without significantly affecting OPG levels. Consistent with the in vivo findings, in vitro experiments demonstrated that CIHH markedly suppressed osteoclast differentiation from BMMs, but did not significantly affect the osteogenic differentiation capacity of BMSCs. CIHH mitigates root resorption after delayed tooth replantation, which is associated with reduced RANKL expression and decreased osteoclast presence.

Stress promotes the progression from borderline hypertension to sustained hypertension, but the mechanism remains unclear. We investigated the role of corticotropin-releasing factor (CRF)-expressing neurons in the central nucleus of amygdala (CeA) on arterial blood pressure (ABP) and sympathetic activity of borderline hypertensive rats (BHRs) subjected to chronic unpredictable mild stress (CUMS). CUMS induced sustained hypertension, and led to increased delta-FosB expression as well as enhanced spontaneous and evoked firing of CeA CRF-expressing neurons in BHRs. Furthermore, optogenetic activation of CeA CRF-expressing neurons significantly increased the sympathetic outflow and ABP in BHRs. Impaired GABAergic inhibition, a depolarizing shift of GABA reversal potential (EGABA), disrupted chloride homeostasis and increased NKCC1 expression were observed in CeA CRF-expressing neurons in BHRs subjected to CUMS. NKCC1 inhibition with bumetanide restored GABAergic inhibition and chloride homeostasis, normalized neuronal excitability, leading to reduced sympathetic vasomotor tone in CUMS BHRs. These results indicate that NKCC1-mediated disruption of chloride homeostasis in CeA CRF-expressing neurons contributes to elevated sympathetic activity and hypertension under chronic stress. These findings enhance our understanding of the neuronal and molecular mechanisms underlying stress-induced hypertension and reveal potential targets for its prevention and treatment.

Navigating human-populated environments without causing discomfort is a critical capability for socially-aware agents. While rule-based approaches offer interpretability through predefined psychological principles, they often lack generalizability and flexibility. Conversely, data-driven methods can learn complex behaviors from large-scale datasets, but are typically inefficient, opaque, and difficult to align with human intuitions. To bridge this gap, we propose RLSLM, a hybrid Reinforcement Learning framework that integrates a rule-based Social Locomotion Model, grounded in empirical behavioral experiments, into the reward function of a reinforcement learning framework. The social locomotion model generates an orientation-sensitive social comfort field that quantifies human comfort across space, enabling socially aligned navigation policies with minimal training. RLSLM then jointly optimizes mechanical energy and social comfort, allowing agents to avoid intrusions into personal or group space. A human-agent interaction experiment using an immersive VR-based setup demonstrates that RLSLM outperforms state-of-the-art rule-based models in user experience. Ablation and sensitivity analyses further show the model’s significantly improved interpretability over conventional data-driven methods. This work presents a scalable, human-centered methodology that effectively integrates cognitive science and machine learning for real-world social navigation.