Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal death.

GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.

Oxytocin alleviates cognitive and memory impairments by decreasing hippocampal microglial activation and synaptic defects via OXTR/ERK/STAT3 pathway in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction, characterized by cognitive and memory impairments closely linked to hippocampal dysfunction. Though it is well-known that SAE is a diffuse brain dysfunction with microglial activation, the pathological mechanisms of SAE are not well established and effective clinical interventions are lacking. Oxytocin (OXT) is reported to have anti-inflammatory and neuroprotective roles. However, the effects of OXT on SAE and the underlying mechanisms are not clear. METHODS: SAE was induced in adult C57BL/6J male mice by cecal ligation and perforation (CLP) surgery. Exogenous OXT was intranasally applied after surgery. Clinical score, survivor rate, cognitive and memory behaviors, and hippocampal neuronal and non-neuronal functions were evaluated. Cultured microglia challenged with lipopolysaccharide (LPS) were used to investigate the effects of OXT on microglial functions, including inflammatory cytokines release and phagocytosis. The possible intracellular signal pathways involved in the OXT-induced neuroprotection were explored with RNA sequencing. RESULTS: Hippocampal OXT level decreases, while the expression of OXT receptor (OXTR) increases around 24 h after CLP surgery. Intranasal OXT application at a proper dose increases mouse survival rate, alleviates cognitive and memory dysfunction, and restores hippocampal synaptic function and neuronal activity via OXTR in the SAE model. Intraperitoneal or local administration of the OXTR antagonist L-368,899 in hippocampal CA1 region inhibited the protective effects of OXT. Moreover, during the early stages of sepsis, hippocampal microglia are activated, while OXT application reduces microglial phagocytosis and the release of inflammatory cytokines, thereby exerting a neuroprotective effect. OXT may improve the SAE outcomes via the OXTR-ERK-STAT3 signaling pathway. CONCLUSION: Our study uncovers the dysfunction of the OXT signal in SAE and shows that intranasal OXT application at a proper dose can alleviate SAE outcomes by reducing microglial overactivation, suggests that OXT may be a promising therapeutic approach in managing SAE patients.

A putative loop connection between VTA dopamine neurons and nucleus accumbens encodes positive valence to compensate for hunger.

Dopamine (DA) signal play pivotal roles in regulating motivated behaviors, including feeding behavior, but the role of midbrain DA neurons in modulating food intake and neural circuitry mechanisms remain largely unknown. Here, we found that activating but not inhibiting ventral tegmental area (VTA) DA neurons reduces mouse food intake. Furthermore, DA neurons in ventral VTA, especially neurons projecting to the medial nucleus accumbens (NAc), are activated by refeeding in the 24 h fasted mice. Combing neural circuitry tracing, optogenetic, chemogenetic, and pharmacological manipulations, we established that the VTA→medial NAc→VTA loop circuit is critical for the VTA DA neurons activation-induced food intake reduction. Moreover, activating either VTA DA neurons or dopaminergic axons in medial NAc elevates positive valence, which will compensate for the hungry-induced food intake. Thus, our study identifies a subset of positive valence-encoded VTA DA neurons forming possible loop connections with medial NAc that are anorexigenic.