Localized astrogenesis regulates gyrification of the cerebral cortex.

The development and evolution of mammalian higher cognition are represented by gyrification of the laminar cerebral cortex and astrocyte development, but their mechanisms and interrelationships remain unknown. Here, we show that localized astrogenesis plays an important role in gyri formation in the gyrencephalic cerebral cortex. In functional genetic experiments, we show that reducing astrocyte number prevents gyri formation in the ferret cortex, while increasing astrocyte number in mice, which do not have cortical folds, can induce gyrus-like protrusions. Morphometric analyses demonstrate that the vertical expansion of deep pallial regions achieved by localized astrogenesis is crucial for gyri formation. Furthermore, our findings suggest that localized astrogenesis by a positive feedback loop of FGF signaling is an important mechanism underlying cortical folding in gyrencephalic mammalian brains. Our findings reveal both the cellular mechanisms and the mechanical principle of gyrification in the mammalian brain.

Glial cell type-specific gene expression in the mouse cerebrum using the piggyBac system and in utero electroporation.

Glial cells such as astrocytes and oligodendrocytes play crucial roles in the central nervous system. To investigate the molecular mechanisms underlying the development and the biological functions of glial cells, simple and rapid techniques for glial cell-specific genetic manipulation in the mouse cerebrum would be valuable. Here we uncovered that the Gfa2 promoter is suitable for selective gene expression in astrocytes when used with the piggyBac system and in utero electroporation. In contrast, the Blbp promoter, which has been used to induce astrocyte-specific gene expression in transgenic mice, did not result in astrocyte-specific gene expression. We also identified the Plp1 and Mbp promoters could be used with the piggyBac system and in utero electroporation to induce selective gene expression in oligodendrocytes. Furthermore, using our technique, neuron-astrocyte or neuron-oligodendrocyte interactions can be visualized by labeling neurons, astrocytes and oligodendrocytes differentially. Our study provides a fundamental basis for specific transgene expression in astrocytes and/or oligodendrocytes in the mouse cerebrum.

The origin and development of subcortical U-fibers in gyrencephalic ferrets.

In the white matter of the human cerebrum, the majority of cortico-cortical fibers are of short range, connecting neighboring cortical areas. U-fibers represent connections between neighboring areas and are located in the white matter immediately deep to the cerebral cortex. Using gyrencephalic carnivore ferrets, here we investigated the neurochemical, anatomical and developmental features of U-fibers. We demonstrate that U-fibers were derived from neighboring cortical areas in ferrets. U-fiber regions in ferrets were intensely stained with Gallyas myelin staining and Turnbull blue iron staining. We further found that U-fibers were derived from neurons in both upper and lower layers in neighboring areas of the cerebral cortex and that U-fibers were formed later than axons in the deep white matter during development. Our findings shed light on the fundamental features of U-fibers in the gyrencephalic cerebral cortex. Because genetic manipulation techniques for ferrets are now available, ferrets should be an important option for investigating the development, functions and pathophysiological changes of U-fibers.

FGF Signaling Directs the Cell Fate Switch from Neurons to Astrocytes in the Developing Mouse Cerebral Cortex.

During mammalian neocortical development, neural precursor cells generate neurons first and astrocytes later. The cell fate switch from neurons to astrocytes is a key process generating proper numbers of neurons and astrocytes. Although the intracellular mechanisms regulating this cell fate switch have been well characterized, extracellular regulators are still largely unknown. Here, we uncovered that fibroblast growth factor (FGF) regulates the cell fate switch from neurons to astrocytes in the developing cerebral cortex using mice of both sexes. We found that the FGF signaling pathway is activated in radial glial cells of the ventricular zone at time points corresponding to the switch in cell fate. Our loss- and gain-of-function studies using in utero electroporation indicate that activation of FGF signaling is necessary and sufficient to change cell fates from neurons to astrocytes. We further found that the FGF-induced neuron-astrocyte cell fate switch is mediated by the MAPK pathway. These results indicate that FGF is a critical extracellular regulator of the cell fate switch from neurons to astrocytes in the mammalian cerebral cortex.SIGNIFICANCE STATEMENT Although the intracellular mechanisms regulating the neuron-astrocyte cell fate switch in the mammalian cerebral cortex during development have been well studied, their upstream extracellular regulators remain unknown. By using in utero electroporation, our study provides in vivo data showing that activation of FGF signaling is necessary and sufficient for changing cell fates from neurons to astrocytes. Manipulation of FGF signaling activity led to drastic changes in the numbers of neurons and astrocytes. These results indicate that FGF is a key extracellular regulator determining the numbers of neurons and astrocytes in the mammalian cerebral cortex, and is indispensable for the establishment of appropriate neural circuitry.

Panax ginseng for Frailty-Related Disorders: A Review.

This review aims to understand the clinical efficacy of Panax ginseng (PG) for managing frailty-related disorders by reviewing meta-analyses, systematic reviews, and randomized clinical trial data. PG is widely used in traditional medicine, mainly in East Asia. It has traditionally been indicated for the collapse of qi or for abandoned conditions that manifest as shallow breathing, shortness of breath, cold limbs, profuse sweating, a low pulse rate, or weakness. In accordance with these indications, PG is used for managing conditions such as aging, inflammation, and cancer. PG is also used in some functional foods or supplements. Some studies have shown the effects of ginsenosides, which are the major constituents of PG. With regard to pharmacological activities of ginseng saponins, it has been presumed that these ginsenosides are metabolized into active forms by human intestinal microbiota after being taken orally. Therefore, we focused on reviewing the data of clinical studies on PG. Although there has been no study that directly investigated the effect of PG on frailty, a number of clinical studies have been conducted to investigate the efficacy and safety of PG and its interactions with other modern ginseng medications and ginseng-containing formulas. We searched the randomized controlled trial data from 1995 to 2018 and reviewed the potential effects of PG on frailty-related disorders. We reviewed the effects of PG on glucose metabolism, fatigue, hypertension, cardiovascular disorders, chronic obstructive pulmonary disease, renal function, cognitive function, and immune function. Our review showed some evidence for the usefulness of ginseng, which suggests that it has the potential to be used for the management of aging-related and frailty symptoms, such as fatigue and hypertension. The main limitation of this review is that no study has directly investigated the effect of PG on frailty. Instead we investigated frailty-related disorders, and the limitations of the available studies were small sample sizes and a poor methodological quality; besides, only a few studies targeted elderly people, and few included placebo controls. Larger, well-designed studies are needed to determine the effect of PG on frailty in the future.