The molecular neural mechanism underlying the acceleration of brain aging due to Dcf1 deficiency.

Owing to the continuous increase in human life expectancy, the management of aging-related diseases has become an urgent issue. The brain dominates the central nervous system; therefore, brain aging is a key area of aging-related research. We previously uncovered that dendritic cell factor 1 (Dcf1) maintains the stemness of neural stem cells and its expression in Drosophila can prolong lifespan, suggesting an association between Dcf1 and aging; however, the specific underlying neural mechanism remains unclear. In the present study, we show for the first time that hippocampal neurogenesis is decreased in aged Dcf1-/- mice, which leads to a decrease in the number of brain neurons and an increased number of senescent cells. Moreover, astrocytes proliferate abnormally and express elevated mRNA levels of aging-related factors, in addition to displaying increased activation of Akt and Foxo3a. Finally, behavioral tests confirm that aged Dcf1-/- mice exhibit a significant decline in cognitive abilities related to learning and memory. In conclusion, we reveal a novel mechanism underlying brain aging triggered by Dcf1 deficiency at the molecular, cellular, tissue, and behavioral levels, providing a new perspective for the exploration of brain aging.

CRYAA and GJA8 promote visual development after whisker tactile deprivation.

Deprivation of one sense can be followed by enhanced development of other senses via cross-modal plasticity mechanisms. To study the effect of whisker tactile deprivation on vision during the early stages of development, we clipped the bilateral whiskers of young mice and found that their vision was impaired but later recovered to normal levels. Our results demonstrate that inhibition of the PI3K/AKT/ERK signaling pathway caused short-term visual impairment during early development, while high expression levels of Crystallin Alpha A (CRYAA) and Gap Junction Protein Alpha 8 (GJA8) in the retina led to the recovery of developmental visual acuity. Interestingly, analysis of single-cell sequencing results from human embryonic retinas at 9-19 gestational weeks (GW) revealed that CRYAA and GJA8 display stage-specific peak expression during human embryonic retinal development, suggesting potential functions in visual development. Our data show that high expression levels of CRYAA and GJA8 in the retina after whisker deprivation rescue impaired visual development, which may provide a foundation for further research on the mechanisms of cross-modal plasticity and in particular, offer new insights into the mechanisms underlying tactile-visual cross-modal development.

MiR-4763-3p targeting RASD2as a Potential Biomarker and Therapeutic Target for Schizophrenia.

Existing diagnostic methods are limited to observing appearance and demeanor, even though genetic factors play important roles in the pathology of schizophrenia. Indeed, no molecular-level test exists to assist diagnosis, which has limited treatment strategies. To address this serious shortcoming, we used a bioinformatics approach to identify 61 genes that are differentially expressed in schizophrenia patients compared with healthy controls. In particular, competing endogenous RNA network revealed the important role of the gene RASD2, which is regulated by miR-4763-3p. Indeed, analysis of blood samples confirmed that RASD2 is downregulated in schizophrenia patients. Moreover, positron emission tomography data collected for 44 human samples identified the prefrontal and temporal lobes as potential key brain regions in schizophrenia patients. Mechanistic studies indicated that miR-4763-3p inhibits RASD2 by base-pairing with the 3' untranslated region of RASD2 mRNA. Importantly, RASD2 has been shown to interact with ß-arrestin2, which contributes to the regulation of the DRD2-dependent CREB response element-binding protein pathway in the dopamine system. Finally, results obtained with a mouse model of schizophrenia revealed that inhibition of miR-4763-3p function alleviated anxiety symptoms and improved memory. The dopamine transporters in the striatal regions were significantly reduced in schizophrenia model mice as compared with wild-type mice, suggesting that inhibition of miR-4763-3p can lessen the symptoms of schizophrenia. Our findings demonstrate that miR-4763-3p may target RASD2 mRNA and thus may serve as a potential biomarker and therapeutic target for schizophrenia, providing a theoretical foundation for further studies of the molecular basis of this disease.

Atp11b Deletion Affects the Gut Microbiota and Accelerates Brain Aging in Mice.

The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including Atp11b, results in a variety of neurological diseases. The results of our analysis demonstrate that there was a shift in the abundance of certain gut microbiota in Atp11b-knockout (KO) mice. Specifically, there was an increase in pro-inflammatory bacteria that accelerate aging and a decrease in probiotics that delay aging. Consequently, an enhanced oxidative stress response was observed, which was characterized by a reduction in the superoxide dismutase (SOD) activity and an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, our data demonstrate that there was a decrease in the number of cells in the dentate gyrus (DG) region of the hippocampus, and aggravation of aging-related pathological features such as senescence ß-galactosidase (SA-ß-Gal), p-HistoneH2AX (Ser139), and p16INK4. Moreover, KO mice show typical aging-associated behavior, such as memory impairment and slow pain perception. Taken together, we demonstrate a possible mechanism of aging induced by gut microbiota in Atp11b-KO mice, which provides a novel perspective for the treatment of aging through the microbiota-gut-brain axis.

Depression-like symptoms due to Dcf1 deficiency are alleviated by intestinal transplantation of Lactobacillus murine and Lactobacillus reuteri.

Depression, characterized by low mood, is a complex mental disorder that is a serious threat to human health. Depression is thought to be caused by a combination of genetic, environmental and psychological factors. However, the pathophysiology of depression remains unclear. In the present study, we found that Dcf1 knockout (KO) mice had depression-like symptoms and disruptive changes in gamma-aminobutyric acid (GABA) concentration and GABA receptor expression were found in the hippocampus of Dcf1 KO and WT mice. Furthermore, the gut microbiota composition of Dcf1 KO mice was significantly different from that of wildtype (WT) mice and Dcf1 KO mice showed lower Firmicutes and Lactobacillus content compared to WT mice. In addition, the depression-like behavior of Dcf1 KO mice was alleviated by the administration of microbiota. More surprisingly, after treatment with Lactobacillus murine and Lactobacillus reuteri, two Lactobacillus species with proportionally greater differences in content between the WT and KO groups, KO mice showed similar GABA content, as well as restored GABA-related receptor expression, as the WT group. Our data elucidated a possible mechanism of depression induction by gut microbiota in Dcf1 KO mice and provide a new avenue to explore the treatment of depression by gut microbiota.

A preliminary study on abnormal brain function and autistic behavior in mice caused by dcf1 deletion.

Autism is one of the urgent problems in neuroscience. Early research in our laboratory found that dcf1 gene-deficient mice exhibited autistic behavior. Reviewing the literature, we know that the caudate putamen (CPu) brain region is closely related to the occurrence of autism. In this study, we observed that the electrical signal in the abnormal brain region of adult mice was enhanced by using field potential detection for the corresponding brain region. We then used retrovirus markers to track neurons in the CPu brain region and found that there are neural projections in the hippocampus-CPu brain region. Therefore, we selected DREADDs (Designer receptors exclusively activated by designer drugs) to inhibit the abnormal brain region of the mouse and found, through behavioral testing, that this can inhibit the autistic behavior of mice. This research provides new evidence for the understanding of the cause of autism and has accumulated new basis for the treatment of autism. It has theoretical significance and potential application value for the understanding and treatment of autism.

Elucidating the Relationship Between Diabetes Mellitus and Parkinson's Disease Using 18F-FP-(+)-DTBZ, a Positron-Emission Tomography Probe for Vesicular Monoamine Transporter 2.

Diabetes mellitus (DM) and Parkinson's disease (PD) have been and will continue to be two common chronic diseases globally that are difficult to diagnose during the prodromal phase. Current molecular genetics, cell biological, and epidemiological evidences have shown the correlation between PD and DM. PD shares the same pathogenesis pathways and pathological factors with DM. In addition, ß-cell reduction, which can cause hyperglycemia, is a striking feature of DM. Recent studies indicated that hyperglycemia is highly relevant to the pathologic changes in PD. However, further correlation between DM and PD remains to be investigated. Intriguingly, polycystic monoamine transporter 2 (VMAT2), which is co-expressed in dopaminergic neurons and ß cells, is responsible for taking up dopamine into the presynaptic vesicles and can specifically bind to the ß cells. Furthermore, we have summarized the specific molecular and diagnostic functions of VMAT2 for the two diseases reported in this review. Therefore, VMAT2 can be applied as a target probe for positron emission tomography (PET) imaging to detect ß-cell and dopamine level changes, which can contribute to the diagnosis of DM and PD during the prodromal phase. Targeting VMAT2 with the molecular probe 18F-FP-(+)-DTBZ can be an entry point for the ß cell mass (BCM) changes in DM at the molecular level, to clarify the potential relationship between DM and PD. VMAT2 has promising clinical significance in investigating the pathogenesis, early diagnosis, and treatment evaluation of the two diseases.