Yasuhisa Tamura

Insufficient sleep and circadian misalignment increase inflammatory agents. This triggers neuroinflammation and can result in health issues including depression, dementia, lifestyle-related diseases, and industrial accidents. Lactoferrin (LF) confers neuroprotective effects, which are derived from its anti-inflammatory, antioxidant, and iron metabolic properties; however, its roles in acute neuroinflammation and circadian rhythm disruption are yet to be elucidated. Therefore, we aimed to test the effects of LF on rat neuroinflammation and sleep and jetlag in humans. Rats received 7 days of an oral liposomal bovine LF (L-bLF) or vehicle followed by polyriboinosinic:polyribocytidylic acid (poly I:C) peritoneal injections (n = 5–6). Compared with the rats given poly I:C only, the rats given L-bLF and poly I:C had lower Il1b, Tnf, Casp1, Nfe212, Gclm, and Sod2 expression in the hippocampus. This open-label pilot study was carried out on tour conductors performing regular international tour responsibilities, and the data were compared between the initial tour without L-bLF intake and the subsequent tour with L-bLF intake. In the tour with L-bLF intake, L-bLF administration started from one week before the trip and was continued during the trip. In both periods, the tour conductors experienced limited sleep; however, both subjective and objective sleep quality was significantly better with the oral L-bLF intake than without. Overall, we found that prophylactic L-bLF supplementation reduced neuroinflammation in rat hippocampi and improved sleep quality and jetlag in tour conductors.

Alpha-glycerylphosphorylcholine (αGPC) is a precursor of acetylcholine and can increase acetylcholine concentration in the brain. In addition, αGPC has a role in cholinergic function as well as monoaminergic transmission, including dopaminergic and serotonergic systems. These monoaminergic systems are related to feelings and emotions, including motivation, reward processing, anxiety, and depression. However, the precise effects of αGPC on human feelings and emotions remain to be elucidated. In this study, we investigated changes in the subjective feelings of healthy volunteers using the KOKORO scale before and after administering αGPC. Thirty-nine volunteers participated in a single-blind, placebo-controlled design. Participants completed a KOKORO scale test to quantify self-reported emotional states, three times each day for two weeks preceding treatment and then for a further two weeks while self-administering treatment. αGPC treatment show a tendency to increase motivation during the intervention period. Furthermore, motivation at night was significantly higher in the αGPC group than in the placebo group (p < 0.05). However, αGPC did not show any effects on anxiety. These data suggest that αGPC can be used to increase motivation in healthy individuals.

NG2 immunoreactive cells (NG2 cells) are found in the brain and peripheral tissues including the skin, intestinal tracts, and bladder. In a previous study, we observed the presence of NG2 cells in the stomach using bioluminescence imaging techniques in NG2-firefly luciferase (fLuc) transgenic (Tg) rats. Here, we aimed to identify and characterize NG2 cells in the adult rat stomach. Immunohistochemical studies showed that NG2 cells were mainly present in the lamina propria and most of the cells were gastric telocytes, co-expressing CD34, and platelet-derived growth factor receptor alpha (PDGFRα), with a small oval-shaped cell body and extremely long and thin cellular prolongations. In the rat stomach, NG2-expressing telocytes comprised two subpopulations: NG2+/CD34+/PDGFRα+ and NG2+/CD34+/PDGFRα-. Furthermore, we showed that the expression of NG2 gene in the aged rat stomach decreased relative to that of the young rat stomach and the decline of NG2 expression in aged rats was mainly observed in NG2+/CD34+/PDGFRα+ telocytes. These findings suggested age-related alterations in NG2+/CD34+/PDGFRα+ telocytes of rat stomach.

The hair cycle consists of three different phases: anagen (growth), catagen (regression), and telogen (resting). During the anagen phase, hair follicle stem cells (HFSCs) in the bulge and the secondary hair germ proliferate and generate the outer and inner root sheath cells and the hair shafts. We previously identified NG2-immunoreactive (NG2+) cells as HFSCs in both regions of the hair follicles. Recently, the interaction between the hair cycle and the cutaneous immune system has been re-examined under physiological and pathological conditions. However, the roles of NG2+ HFSCs in the skin’s immune system remain completely elucidated. In the present study, we investigated whether the elimination of NG2+ HFSCs affects the induction of allergic contact dermatitis, using a herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) suicide gene system. When the GCV solution was applied to the skin of NG2-HSVtk transgenic (Tg) rats during the depilation-induced anagen phase, NG2+ HFSCs in the Tg rat skin induced apoptotic cell death. Under exposure of a hapten, the selective ablation of NG2+ HFSCs during the anagen phase aggravated the sensitization phase of allergic contact dermatitis. These findings suggest that NG2+ HFSCs and their progeny have immunosuppressive abilities during the anagen phase.

Hair growth occurs periodically in a cycle that consists of three different phases: growth, regression, and resting. The length of each phase is regulated by both intrinsic and extrinsic factors throughout life, and influenced by physiological and pathological conditions. Elongation of the resting phase and shortening of the growth phase occur during physiological ageing and in baldness, respectively. In vivo discrimination of each phase of the hair cycle can be used to research for regeneration of hair follicles as well as to evaluate the efficacy of hair regrowth treatments in the same individual. Here we show that NG2+ epithelial cells in the hair follicles encompass bulge stem cells, and that the number of hair follicle NG2 cells underwent dramatic changes during the hair cycle. Transgenic rats with expression of firefly luciferase gene in NG2 cells were generated to monitor the hair cycle in vivo. Hair follicle NG2 cells were clearly visualized via bioluminescence imaging to study each phase of the hair cycle in the rats, from infancy to old age.

Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique and has been widely used in metabolomics. However, the intrinsic low sensitivity of NMR prevents its applications to systems with limited sample availabilities. In this study, a new experimental approach is presented to analyze mass-scarce samples in limited volumes of less than 300 nL with simple handling. The sample is loaded into the glass capillary, and this capillary is then inserted into a Kel-F rotor. The experimental performance of the capillary-inserted rotor (capillary-insert) is investigated on an isotropic solution of sucrose by the use of a high-resolution micro-sized magic angle spinning (HRµMAS) probe. The acquired NMR signal’s sensitivity to a given sample amount is comparable or even higher in comparison to that recorded by the standard solution NMR probe. More importantly, this capillary-insert coupled with the HRµMAS probe allows in-depth studies of heterogeneous samples as the MAS removes the line broadening caused by the heterogeneity. The NMR analyses of mass-limited cultured neurospheres have been demonstrated, resulting in high quality spectra where numerous metabolites are unambiguously identified.

Neural stem cells are present in 2 neurogenic regions, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), and continue to generate new neurons throughout life. Adult hippocampal neurogenesis is linked to a variety of psychiatric disorders such as depression and anxiety, and to the therapeutic effects of antidepressants, as well as learning and memory. In vivo imaging for hippocampal neurogenic activity may be used to diagnose psychiatric disorders and evaluate the therapeutic efficacy of antidepressants. However, these imaging techniques remain to be established until now. Recently, we established a quantitative positron emission tomography (PET) imaging technique for neurogenic activity in the adult brain with 3′-deoxy-3′-[¹⁸F]fluoro-L-thymidine ([¹⁸F]FLT) and probenecid, a drug transporter inhibitor in blood-brain barrier. Moreover, we showed that this PET imaging technique can monitor alterations in neurogenic activity in the hippocampus of adult rats with depression and following treatment with an antidepressant. This PET imaging method may assist in diagnosing depression and in monitoring the therapeutic efficacy of antidepressants. In this commentary, we discuss the possibility of in vivo PET imaging for neurogenic activity in adult non-human primates and humans.

Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3′-deoxy-3′-[¹⁸F]fluoro-l-thymidine ([¹⁸F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [¹⁸F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [¹⁸F]FLT combined with probenecid, an inhibitor of drug transporters at the blood–brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [¹⁸F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. SIGNIFICANCE STATEMENT Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.

NG2-expressing progenitor cells (NG2 cells) [ 1 , 2 ] are often located adjacent to neuronal somata in the central nervous system [ 3 ]. We have evaluated the microstructure of their cell adhesion by comparing that with other glial cells, using a transmission electron microscope (TEM) and a scanning electron microscopes (SEM) as well as an optical microscope. Following the identification of structural feature of NG2 cells by immuno-electron microscope, the adhesion manner of glial cells including NG2 cells and neurons was observed using a TEM. The TEM image indicated that many NG2 progenitor cells cut deep into the cytoplasm of neurons. Furthermore, the 3D reconstruction of microstructure of the cell adhesion manner using a SEM revealed a partial disappearance of plasma membrane separating...