Glucocorticoid Receptor Down-Regulation Affects Neural Stem Cell Proliferation and Hippocampal Neurogenesis.

Dysregulation of the hypothalamic-pituitary-adrenal axis and abnormalities in the glucocorticoid receptor (GR) have been linked to major depressive disorder. Given the critical role of GR in stress response regulation, we investigated the impact of GR changes on neural stem cells (NSCs) proliferation and hippocampal neurogenesis. Stress response was induced using dexamethasone (DEX), a GR agonist, which led to reduced proliferation of neural stem cells and neural progenitor cells, as well as decreased expression of GR. Additionally, a reduction of serum concentration within the culture media resulted in suppressed cell proliferation, accompanied by decreased GR expression. The association between GR expression and cell proliferation was further confirmed through GR siRNA knockdown and overexpression experiments. Furthermore, in vivo studies utilizing young male C57BL/6 mice demonstrated that corticosterone (CORT) (35 µg/ml) administered through drinking water for four weeks induced depression-like behavior, as indicated by increased immobility times in forced swimming and tail suspension tests. CORT exposure led to reduced GR and nestin expression levels, along with diminished numbers of BrdU-positive cells in the hippocampi, indicating impaired hippocampal neurogenesis. Taken together, our findings provide the first evidence that stress-induced downregulation of GR negatively affects neurogenesis by inhibiting NSCs proliferation.

CYFIP2 p.Arg87Cys Causes Neurological Defects and Degradation of CYFIP2.

Here, we report the generation and comprehensive characterization of a knockin mouse model for the hotspot p.Arg87Cys variant of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) gene, which was recently identified in individuals diagnosed with West syndrome, a developmental and epileptic encephalopathy. The Cyfip2+/R87C mice recapitulated many neurological and neurobehavioral phenotypes of the patients, including spasmlike movements, microcephaly, and impaired social communication. Age-progressive cytoarchitectural disorganization and gliosis were also identified in the hippocampus of Cyfip2+/R87C mice. Beyond identifying a decrease in CYFIP2 protein levels in the Cyfip2+/R87C brains, we demonstrated that the p.Arg87Cys variant enhances ubiquitination and proteasomal degradation of CYFIP2. ANN NEUROL 2023;93:155-163.

Anti-Inflammatory Effect of IKK-Activated GSK-3ß Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3ß, and GSK-3ß plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3ß inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP+-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD.

Kinematically aligned total knee arthroplasty restores more native medial collateral ligament strain than mechanically aligned total knee arthroplasty.

PURPOSE: Kinematically aligned total knee arthroplasty (KA TKA) targets restoration of patient-specific alignment and soft tissue laxity. However, whether KA TKA reproduces native soft tissue strain remains unclear. This cadaveric study tested the hypothesis that KA TKA would better restore the quantitative strain and strain distribution of medial collateral ligament (MCL) to the native healthy knee compared to mechanically aligned (MA) TKA. METHODS: Twenty-four fresh-frozen cadaver knees (12 pairs) were mounted on a customized knee squatting simulator to measure MCL strain during flexion. For each pair, one knee was assigned to KA TKA and the other to MA TKA. During KA TKA, the amount of femur and tibia resected was equivalent to implant thickness without MCL release using the calipered measuring technique. MA TKA was performed using conventional measured resection techniques. MCL strain was measured using a video extensometer (Mercury® RT RealTime tracking system, Sobriety s.r.o, Czech Republic). MCL strain and strain distribution during knee flexion were measured, and the measurements compared between native and post-TKA conditions. RESULTS: Mean and peak MCL strain were similar between KA TKA and native knees at all flexion angles (p > 0.1 at all flexion angles) while mean strain at all flexion angles and peak strain at ≥ 60º of MA TKA were approximately twice those of the native knees (p < 0.05 at ≥ 60º of flexion). In addition, greater MCL strain was observed in 4 of 12 regions of interest (ROI) after MA TKA (M1, M2, P1 and P2) compared to the native knee, whereas after KA TKA, MCL strain measurements were similar at all but 1 ROI (P2). CONCLUSIONS: KA TKA restored a more native amount and distribution of MCL strain compared to MA TKA. These findings provide clues for understanding why patients may experience better performance and more normal knee sensations after KA TKA compared to MA TKA. LEVEL OF EVIDENCE: Therapeutic study, Level I.

A single chemosensory GPCR is required for a concentration-dependent behavioral switching in C. elegans.

Animals detect and discriminate countless environmental chemicals for their well-being and survival. Although a single chemical can trigger opposing behavioral responses depending on its concentration, the mechanisms underlying such a concentration-dependent switching remain poorly understood. Here, we show that C. elegans exhibits either attraction or avoidance of the bacteria-derived volatile chemical dimethyl trisulfide (DMTS) depending on its concentration. This behavioral switching is mediated by two different types of chemosensory neurons, both of which express the DMTS-sensitive seven-transmembrane G protein-coupled receptor (GPCR) SRI-14. These two sensory neurons share downstream interneurons that process and translate DMTS signals via distinct glutamate receptors to generate the appropriate behavioral outcome. Thus, our results present one mechanism by which an animal connects two distinct types of chemosensory neurons detecting a common ligand to alternate downstream circuitry, thus efficiently switching between specific behavioral programs based on ligand concentration.

Splice-dependent trans-synaptic PTPδ-IL1RAPL1 interaction regulates synapse formation and non-REM sleep.

Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.

Continuous quadratus lumborum block as part of multimodal analgesia after total hip arthroplasty: a case report.

BACKGROUND: Commonly used epidural or systemic analgesics for pain control after hip surgery carry risk for potential adverse effects. In contrast, the quadratus lumborum block (QLB) utilizes a simple and easy fascial plane technique and provides a wide area of sensory blockade. Thus, the QLB may be beneficial as analgesia after total hip arthroplasty. CASE: Here, we report the case of an 83-year-old man who received a continuous transmuscular QLB as part of a multimodal analgesia after hardware removal and total hip arthroplasty. The patient received a continuous infusion of 0.2% ropivacaine at 8 ml/h through an indwelling catheter in addition to patient-controlled analgesia with intravenous fentanyl and oral celecoxib. The patient's pain scores did not exceed 4, and no additional analgesics were required until postoperative day 5. CONCLUSIONS: Transmuscular QLB may be a suitable option for multimodal analgesia after total hip arthroplasty.

NGL-1/LRRC4C-Mutant Mice Display Hyperactivity and Anxiolytic-Like Behavior Associated With Widespread Suppression of Neuronal Activity.

Netrin-G ligand-1 (NGL-1), encoded by Lrrc4c, is a post-synaptic adhesion molecule implicated in various brain disorders, including bipolar disorder, autism spectrum disorder, and developmental delay. Although previous studies have explored the roles of NGL-1 in the regulation of synapse development and function, the importance of NGL-1 for specific behaviors and the nature of related neural circuits in mice remain unclear. Here, we report that mice lacking NGL-1 (Lrrc4c-/- ) show strong hyperactivity and anxiolytic-like behavior. They also display impaired spatial and working memory, but normal object-recognition memory and social interaction. c-Fos staining under baseline and anxiety-inducing conditions revealed suppressed baseline neuronal activity as well as limited neuronal activation in widespread brain regions, including the anterior cingulate cortex (ACC), motor cortex, endopiriform nucleus, bed nuclei of the stria terminalis, and dentate gyrus. Neurons in the ACC, motor cortex, and dentate gyrus exhibit distinct alterations in excitatory synaptic transmission and intrinsic neuronal excitability. These results suggest that NGL-1 is important for normal locomotor activity, anxiety-like behavior, and learning and memory, as well as synapse properties and excitability of neurons in widespread brain regions under baseline and anxiety-inducing conditions.

Multimodal analgesia with multiple intermittent doses of erector spinae plane block through a catheter after total mastectomy: a retrospective observational study.

BACKGROUND: Although case reports have suggested that the erector spinae plane block (ESPB) may help analgesia for patients after breast surgery, no study to date has assessed its effectiveness. This retrospective observational study analyzed the analgesic effects of the ESPB after total mastectomy. METHODS: Forty-eight patients were divided into an ESPB group (n = 20) and a control group (n = 28). Twenty patients in the control group were selected by their propensity score matching the twenty patients in the ESPB group. Patients in the ESPB group were injected with 30 mL 0.375% ropivacaine, followed by catheter insertion for further injections of local anesthetics every 12 hours. Primarily, total fentanyl consumption was compared between the two groups during the first 24 hours postoperatively. Secondary outcomes included pain intensity levels (visual analogue scale) and incidence of postoperative nausea and vomiting (PONV). RESULTS: Median cumulative fentanyl consumption during the first 24 hours was significantly lower in the ESPB (33.0µg; interquartile range [IQR], 27.0-69.5µg) than in the control group (92.8µg; IQR, 40.0-155.0µg) (P = 0.004). Pain level in the early postoperative stage (<3 hr) and incidence of PONV (0% vs. 55%) were also significantly lower in the ESPB group compared to the control (P = 0.001). CONCLUSIONS: Intermittent ESPB after total mastectomy reduces fentanyl consumption and early postoperative pain. ESPB is a good option for multimodal analgesia after breast surgery.

NGL-1/LRRC4C Deletion Moderately Suppresses Hippocampal Excitatory Synapse Development and Function in an Input-Independent Manner.

Netrin-G ligand-1 (NGL-1), also known as LRRC4C, is a postsynaptic densities (PSDs)-95-interacting postsynaptic adhesion molecule that interacts trans-synaptically with presynaptic netrin-G1. NGL-1 and its family member protein NGL-2 are thought to promote excitatory synapse development through largely non-overlapping neuronal pathways. While NGL-2 is critical for excitatory synapse development in specific dendritic segments of neurons in an input-specific manner, whether NGL-1 has similar functions is unclear. Here, we show that Lrrc4c deletion in male mice moderately suppresses excitatory synapse development and function, but surprisingly, does so in an input-independent manner. While NGL-1 is mainly detected in the stratum lacunosum moleculare (SLM) layer of the hippocampus relative to the stratum radiatum (SR) layer, NGL-1 deletion leads to decreases in the number of PSDs in both SLM and SR layers in the ventral hippocampus. In addition, both SLM and SR excitatory synapses display suppressed short-term synaptic plasticity in the ventral hippocampus. These morphological and functional changes are either absent or modest in the dorsal hippocampus. The input-independent synaptic changes induced by Lrrc4c deletion involve abnormal translocation of NGL-2 from the SR to SLM layer. These results suggest that Lrrc4c deletion moderately suppresses hippocampal excitatory synapse development and function in an input-independent manner.

A case report of a tongue ulcer presented as the first sign of occult tuberculosis.

BACKGROUND: Tuberculosis (TB) is a serious infectious disease with considerable fatality, typically affecting the pulmonary system and, rarely, other body organs including the oral cavity. Due to the rarity of oral TB, it is frequently overlooked in differential diagnosis of oral lesions. Despite a declining trend in TB incidence in recent years, it is still a major public health problem with high contagiousness, thereby requiring the early diagnosis and prompt treatment. CASE PRESENTATION: A 57-year-old male patient presented with chief complaint of painful ulcer on tip of his tongue. He reported that the ulcer developed without any remarkable event such as mechanical trauma, vesicle formation or systemic illness. His past medical history revealed the TB over 40 years ago, which had reportedly healed after pharmacological treatments. As the ulceration persisted after topical steroid application and careful education about avoiding possible mechanical stimuli, biopsy was performed and histological finding showed typical findings of oral tuberculosis including intense granulomatous inflammatory features with small red rods of mycobacterial organisms as well as epithelioid cells and Langhans giant cells. After suitable antituberculosis treatments, oral tuberculosis ulcer was almost completely healed. We present a case of oral TB affecting tip of the tongue in a patient with a history of pulmonary TB and emphasize the understanding of intraoral manifestations for early diagnosis and prompt treatment of TB. CONCLUSIONS: The present case represented the importance of understanding oral tuberculosis manifestations for dental clinicians who might be frequently the first health care professionals to encounter various oral lesions.

Flavobacterium knui sp. nov., a novel member of the family Flavobacteriaceae.

A Gram-stain negative, non-motile, rod-shaped bacterial strain, designated 2-56T, was isolated from water and characterized taxonomically using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that strain 2-56T belongs to the family Flavobacteriaceae in the phylum Bacteroidetes and is closely related to Flavobacterium paronense KNUS1T (98.4%) and Flavobacterium collinsense 4-T-2T (96.7%). The G + C content of the genomic DNA of strain 2-56T was 33.4 mol%. The isolate contained MK-6 as the predominant respiratory quinone, and iso-C15:1 G (15.9%), iso-C15:0 (15.8%), iso-C17:0 3-OH (10.7%), and iso-C15:0 3-OH (9.6%) were the major fatty acids. The major polar lipids were phosphatidylethanolamine and an unidentified lipid. The phenotypic and chemotaxonomic data support the affiliation of strain 2-56T with the genus Flavobacterium. However, the DNA-DNA relatedness between the isolate and F. paronense and F. collinsense were 35.7 and 21.5%, respectively, clearly showing that strain 2-56T is not related to them at the species level. Strain 2-56T could be clearly differentiated from its close neighbours on the basis of its phenotypic, genotypic and chemotaxonomic features. Therefore, strain 2-56T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium knui sp. nov. is proposed. The type strain is 2-56T (= KCTC 62061T = JCM 32247T).