Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour.

Iron accumulation in the substantia nigra is recognized as a hallmark of Parkinson’s disease (PD). Therefore, reducing accumulated iron and associated oxidative stress is considered a promising therapeutic strategy for PD. However, current iron chelators have poor membrane permeability and lack cell-type specificity. Here we identified GSK-J4, a histone demethylase inhibitor with the ability to cross blood brain barrier, as a potent iron suppressor. Only a trace amount of GSK-J4 significantly and selectively reduced intracellular labile iron in dopaminergic neurons, and suppressed H₂O₂ and 6-OHDA-induced cell death in vitro. The iron-suppressive effect was mainly mediated by inducing an increase in the expression of the iron exporter ferroportin-1. In parallel, GSK-J4 rescued dopaminergic neuron loss and motor defects in 6-OHDA-induced PD rats, which was accompanied by reduction of oxidative stress. Importantly, GSK-J4 rescued the abnormal changes of histone methylation, H3K4me3 and H3K27me3 during 6-OHDA treatment although the iron-suppressive and neuroprotective effects were sensitive to H3K4me3 inhibition only. Also, upregulating H3K4me3 increased ferroportin-1 expression and neuroprotection. Taken together, we demonstrate a previously unappreciated action of GSK-J4 on cell-specific iron suppression and neuroprotection via epigenetic mechanism. Compared with conventional iron chelators, this compound has a stronger therapeutic potential for PD.

Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment.

Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures. Currently, the associations among skin microbiota, circulating metabolites, and epilepsy are still not well studied. In this study, we applied univariate and two-step Mendelian randomization analysis using single nucleotide polymorphisms as instrumental variables to analyze the possible associations. Five skin microbiota (asv022, asv008, bacillales, clostridiale, and micrococcaceae) and four circulating metabolites were found to be associated with epilepsy. Our results also showed that leucine level (p-value = 0.0487, OR = 1.067) and glutamine level (p-value = 0.0372, OR = 1.065) show a slight increased association with epilepsy, while phospholipids in medium LDL (p-value = 0.0302, OR = 0.9308) and ratio of saturated fatty acids (p-value = 0.0309, OR = 0.9017) appear to show a slight inverse correlation with epilepsy. In addition, the heterogeneity test and horizontal pleiotropy analysis indicated these results are robust in different situations. By mapping analysis, 54 genes were associated with at least two metabolites. By functional analysis, these genes were enriched in the immune-related pathways, which may have systemic effects on brain function. Our results provide a novel insight for understanding possible mechanisms of some epilepsy associations, which by further study might provide avenues for therapy research.