A developmental brain-wide screen identifies retrosplenial cortex as a key player in the emergence of persistent memory.

Memories formed early in life are short-lived while those formed later persist. Recent work revealed that infant memories are stored in a latent state. But why they fail to be retrieved is poorly understood. Here we investigated brain-wide circuit mechanisms underlying infantile amnesia in mice. We performed a screen that combined activity-dependent neuronal tagging at different postnatal ages, tissue clearing and light sheet microscopy. We observed striking developmental transitions in the organization of fear memory networks and changes in the activity and functional connectivity of the retrosplenial cortex (RSP) that aligned with the emergence of persistent memory. 7 days after learning, chemogenetic reactivation of tagged RSP ensembles enhanced memory in adults but not in infants. But after 33 days, reactivating infant-tagged RSP ensembles recovered forgotten memories. These studies show that RSP ensembles store latent infant memories, reveal the time course of RSP functional maturation, and suggest that immature RSP functional networks contribute to infantile amnesia.

Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis is a disease caused by autoantigen-responsive immune cells that disrupt the myelin in the central nervous system (CNS). Although immunosuppressive drugs are used to suppress symptoms, no definitive therapy exists. As in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis, a partial sequence of the myelin oligodendrocyte glycoprotein (MOG35-55) was identified as a causative autoantigen. This suggests that the induction of immune tolerance that is specific to MOG35-55 would be a fundamental treatment for EAE. We previously reported that lipid nanoparticles (LNPs) containing an anionic phospholipid, phosphatidylserine (PS), in their lipid composition, can be used to deliver mRNA and that this leads to proteins of interest to be expressed in the spleen. In addition to the targeting capability of PS, PS molecules avoid activating the immune system. Physiologically, the recognition of PS on apoptotic cells suppresses immune activation against these cells by releasing cytokines, such as interleukin-10 (IL-10) and transforming growth factor (TGF)-ß that negatively regulate immunity. In this study, we tested whether mRNA delivery of autoantigens to the spleen by PS-LNPs causes the expression of MOG35-55 antigens with minimal immune stimulation and whether this could be used to treat an EAE model by inducing immune tolerance.

Logistics and distribution of small extracellular vesicles from the subcutaneous space to the lymphatic system.

Small extracellular vesicles (sEVs) are small, cell-derived particles with sizes of approximately 100 nm. Since these particles include cargos such as host cell-derived proteins, messenger RNAs, and micro RNAs, they serve as mediators of cell-cell communication. While the analysis of the pharmacokinetic of sEVs after the intravenous injection have been reported, the lymphatic transport of sEVs remains unclear. The objective of this study was to provide insights into the intra-lymphatic trafficking and distribution of sEVs when they are injected into an interstitial space both in normal skin tissue and in cancerous tissue. When sEVs were Subcutaneously administered into the tail base and the tumor tissue, they preferably accumulated in the lymph nodes (LNs), rather than in the liver and the spleen. The findings reported herein show that the lymphatic transport of sEVs was drastically changed in model mice, in which a surgical treatment was used to modify to allow the dominant lymphatic flow from the footpad directly to the axillary LN via the inguinal LN. Based on the results, we conclude that when sEVs are injected into the subcutis space, they are preferably delivered to the LN via the lymphatic system. Further, the extent of accumulation of sEVs in the LN after subcutaneous injection was reduced when they were preliminarily incubated with Proteinase K. These results suggest that the lymphatic drainage of sEVs in normal skin tissue is regulated by membrane proteins on their surface. This reduction, however, was not observed in the case of cancer tissue. This discrepancy can be attributed to the presence of highly permeable lymphatic vessels in the tumor tissue. Further, the major cell subtypes that captured sEVs in the LN were LN-resident medullary sinus macrophages. These collective findings indicate that the lymphatic drainage of sEVs are mediated by proteins and, that they may appear to contribute to the control of the function of immune-responsive cells in the LNs.

Inter-rater reliability of the Oral Assessment Guide for oral cancer patients between nurses and dental hygienists: the difficulties in objectively assessing oral health.

PURPOSE: Perioperative oral care is effective for the prevention and reduction of complications following surgery. However, oral cancer patients' oral health is often poor. During hospitalization, oral cancer patients frequently receive oral care from ward nurses as well as professional oral care from dental hygienists. Maintenance of good oral hygiene in these patients ideally requires cooperation between nurses and dental hygienists. Consequently, communication tools used to share information about the status of patients' oral health are needed. One such tool is the Oral Assessment Guide (OAG). However, the inter-rater reliability of the OAG has not been consistently reported; therefore, we examined this between nurses and dental hygienists. METHODS: Participants comprised 76 patients hospitalized for oral cancer treatment. After surgery, a nurse and a dental hygienist performed oral assessments using the OAG. Comparative statistical analyses were conducted to examine differences and consistencies in the scores of nurses and dental hygienists. RESULTS: Although almost all patients' oral health status was poor, none were given the worst score in the mucous membrane or gingiva categories. Further, the tongue, saliva, mucous membrane, gingiva, and teeth/denture categories had low κ coefficients, indicating poor nurse-dental hygienist inter-rater reliability. In contrast, the κ coefficients and agreement rates for voice and swallowing were high. Dental hygienists' scores were significantly higher for the tongue, gingiva, and teeth/denture categories than were nurses' scores. CONCLUSIONS: This study showed low nurse-dental hygienist inter-rater reliability for the OAG and highlighted the difficulties in objectively assessing patients' symptoms and oral health conditions. Therefore, rather than only relying on an objective assessment of symptoms by a clinician, assessments should also include patients' subjective reporting of symptoms. OAG will likely be used until a new assessment tool is developed. Objective assessment training and/or user manual development may be required to improve the reliability of OAG. The present training of one lesson a year is insufficient, and efforts should be made to improve this to get more reliable outcomes.