Maternal obesity impairs hippocampal BDNF production and spatial learning performance in young mouse offspring.

Maternal obesity may affect the child's long-term development and health, increasing the risk of diabetes and metabolic syndrome. In addition to the metabolic and endocrine systems, recent reports have indicated that maternal obesity also modulates neural circuit formation in the offspring. However, this not yet been fully investigated. Here, we examined the effect of diet-induced maternal obesity on hippocampal development and function in the mouse offspring. Adult female mice were fed either a normal diet (ND, 4% fat) or a high-fat diet (HFD, 32% fat) before mating and throughout pregnancy and lactation. After weaning, all offspring were fed with a normal diet. We found that HFD offspring showed increased lipid peroxidation in the hippocampus during early postnatal development. HFD offspring had less brain-derived neurotrophic factor (BDNF) in the hippocampus than ND offspring. BDNF has been shown to play crucial roles in neuronal differentiation, plasticity and hippocampus-dependent cognitive functions such as spatial learning and memory. Using retroviral labeling, we demonstrated that dendritic arborization of new hippocampal neurons was impaired in the young HFD offspring. Finally, we evaluated cognitive function in these offspring using hippocampus-dependent behavioral tasks. The Barnes maze test demonstrated that HFD offspring showed impaired acquisition of spatial learning in the young but not adult period. This study, using a mouse model, indicates that diet-induced maternal obesity impairs hippocampal BDNF production and spatial cognitive function in young offspring, possibly due to their metabolic and oxidative changes.

"Bio-communication" between mother and offspring: lessons from animals and new perspectives for brain science.

Early brain development has a tremendous impact on the success of humans throughout their lives. During early development, neural circuit formation proceeds in a strictly regulated manner. In addition to genetic and epigenetic programs, recent studies using animal models have demonstrated that certain maternal bio-active agents are essential for normal neural development, with deficiencies adversely affecting offspring brain function and behavior. On the basis of these findings, we propose a new viewpoint: that maternal bio-active substances support the development of the fetal and neonatal brain, and the subsequent expression and maintenance of higher brain functions. We term these molecular-based biological conversations between mother and offspring "bio-communications". Based on findings obtained primarily from animal models, we review the effects of maternal substances on the neural developments and functions. Clarifying the regulatory mechanisms of "bio-communications" will help improve understanding of the mechanisms of human brain functioning and neural development. In addition, these findings will be applied to elucidate the mechanisms of developmental disorders and to explore new medical therapies to treat them.

White matter activated glial cells produce BDNF in a stroke model of monkeys.

Lacunar-type stroke accounts for approximately a quarter of all ischemic strokes, and is the most common cause of vascular dementia. Despite its importance, there are few specific treatments for lacunar stroke, probably due largely to a lack of animal models. In this study, we developed a stroke model in a higher primate, the Macaque monkey. This was achieved by occluding the deep subcortical penetrating arteries with agarose spheres of mean diameters around 50 microm, and the appropriateness of this model as a lacunar-type stroke was verified by MRI. We observed widespread gliosis in the ipsilateral white matter (WM) of the stroke monkey. We also analyzed the expression of neurotrophins in the activated glial cells, and found that their expression of BDNF was stimulated in the affected WM following ischemic injury. Our results support the idea that WM glial cells play an active role in protecting and promoting the regeneration of nerve fibers in the affected WM of the ischemic brain, by producing BDNF. These findings may be useful for the development of new therapeutic strategies aimed at preventing or treating stroke.

Excitatory GABAergic activation of cortical dividing glial cells.

Adult neocortex contains dividing satellite glia population even though their characteristics and functions have still remained unknown. Nestin(+)/NG2(+) cells as major fraction of dividing glial cells express bicuculline-sensitive gamma-aminobutyric acid A (GABA(A)) receptors and receive GABAergic inputs. Due to their high [Cl(-)](i), GABAergic activation depolarized the cells and then induced Ca(2+) influx into them. To assess an effect of this GABAergic excitation, we looked for the expression of neurotrophic factors. Among them, we detected the expression of brain-derived neurotrophic factor (BDNF) on the cells. The level of BDNF expression was elevated after cortical ischemia, and this elevation was blocked by bumetanide, an inhibitor for NKCC1 that blocks the GABAergic depolarization. Furthermore, performing a modified adhesive removal test, we observed that the treatment of bumetanide significantly attenuated the recovery in somatosensory dysfunction. Our results may shed a light on satellite glia population in the cortex and imply their roles in the functional recovery after ischemic injuries.

Diet-induced obesity in female mice leads to peroxidized lipid accumulations and impairment of hippocampal neurogenesis during the early life of their offspring.

Maternal obesity may affect the child's long-term development and health. However, there is little information about the involvement of maternal obesity in the brain development of offspring. Here, we investigated the effects of maternal obesity on the hippocampal formation of offspring. Adult female mice were fed either a normal diet (ND, 4% fat) or a high-fat diet (HFD, 32% fat) 6 wk before mating and throughout pregnancy and the majority of lactation. We found that infants from HFD-fed dams (HFD offspring) showed obesity and hyperlipidemia during suckling. In HFD offspring, lipid peroxidation was promoted in serum and the hippocampal dentate gyrus, where neurogenesis takes place throughout postnatal life. Using a BrdU-pulse labeling study, we showed that malondialdehyde, a product of peroxidized lipids, reduced the proliferation of hippocampal progenitor cells in vitro and that neurogenesis in HFD offspring during postnatal development was similarly lowered relative to the ND animals. These results indicated that maternal obesity impairs hippocampal progenitor cell division and neuronal production in young offspring possibly due to metabolic and oxidative changes.

Migration and differentiation of neural cell lines transplanted into mouse brains.

In the past few years, the plasticity of the regional specification of the CNS has been widely debated on the results from in utero transplantation. Two different results are reported with this transplantation method. One is that the distribution of transplanted cells is dependent on the donor origin, and the other is that the distribution is independent on the donor cell origin. The present study attempted to examine closely the plasticity of the regional specification by in utero transplantation method with clonal neural cell lines, 2Y-3t and 2Y-5o2b. These lines were established from a cerebellum of an adult p53-deficient mouse. Our results showed that transplanted cells migrated into various regions of the CNS and supported the independent distribution. Moreover, different distribution patterns of transplanted cells were observed between host sexes. Labeled cells were localized around the ventricle of neonatal host brains, where they were undifferentiated. In 2-3 weeks after birth, labeled cells were found in the brain parenchyma and some of them took neuronal morphology. In the rostral migratory stream (RMS), cells with unipolar or bipolar morphology were still undifferentiated. In other regions, labeled cells were often associated with blood vessels; the soma were on the surface of vessels, extending processes or neurites into surrounding brain parenchyma. Time-lapse imaging demonstrated that they were migrating with blood vessels.

GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells.

Hippocampal activity influences neurogenesis in the adult dentate gyrus; however, little is known about the involvement of the hippocampal circuitry in this process. In the subgranular zone of the adult dentate gyrus, neurogenesis involves a series of differentiation steps from radial glia-like stem/progenitor (type-1) cells, to transiently amplifying neuronal progenitor (type-2) cells, to postmitotic neurons. In this study, we conducted GFP-targeted recordings of progenitor cells in fresh hippocampal slices from nestin-GFP mice and found that neuronal progenitor (type-2) cells receive active direct neural inputs from the hippocampal circuitry. This input was GABAergic but not glutamatergic. The GABAergic inputs depolarized type-2 cells because of their elevated [Cl(-)](i). This excitation initiated an increase of [Ca(2+)](i) and the expression of NeuroD. A BrdU-pulse labeling study with GABA(A)-R agonists demonstrated the promotion of neuronal differentiation via this GABAergic excitation. Thus, it appears that GABAergic inputs to hippocampal progenitor cells promote activity-dependent neuronal differentiation.

Developmental shift in bidirectional functions of taurine-sensitive chloride channels during cortical circuit formation in postnatal mouse brain.

Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in the developing mammalian cerebral cortex, however, few studies have reported its neurobiological functions during development. In this study, by means of whole-cell patch-clamp recordings, we examined the effects of taurine on chloride channel receptors in neocortical neurons from early to late postnatal stages, which cover a critical period in cortical circuit formation. We show here that taurine activates chloride channels in cortical neurons throughout the postnatal stages examined (from postnatal day 2 to day 36). The physiological effects of taurine changed from excitatory to inhibitory due to variations in the intracellular Cl- concentration during development. An antagonist blocking analysis also demonstrated a developmental shift in the receptor target of taurine, from glycine receptors to GABAA receptors. Taken together, these results may reflect genetically programmed, bidirectional functions of taurine. At the early developmental stage, taurine acting on glycine receptors would serve to promote cortical circuit formation. As cortical circuit has to be regulated in the later stages, taurine would serve as a safeguard against hyperexcitable circuit.

Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus.

Neurogenesis in the dentate gyrus of the adult mammalian hippocampus has been proven in a series of studies, but the differentiation process toward newborn neurons is still unclear. In addition to the immunohistochemical study, electrophysiological membrane recordings of precursor cells could provide an alternative view to address this differentiation process. In this study, we performed green fluorescent protein (GFP)-guided selective recordings of nestin-positive progenitor cells in adult dentate gyrus by means of nestin-promoter GFP transgenic mice, because nestin is a typical marker for precursor cells in the adult dentate gyrus. The patch-clamp recordings clearly demonstrated the presence of two distinct subpopulations (type I and type II) of nestin-positive cells. Type I cells had a lower input resistance value of 77.1 M(Omega) (geometric mean), and their radial processes were stained with anti-glial fibrillary acidic protein antibody. On the other hand, type II nestin-positive cells had a higher input resistance value of 2110 MOmega and expressed voltage-dependent sodium current. In most cases, type II cells were stained with anti-polysialylated neural cell adhesion molecule. Taken together with a bromodeoxyuridine pulse-chase analysis, our results may reflect a rapid and dynamic cell conversion of nestin-positive progenitor, from type I to type II, at an early stage of adult neurogenesis in the dentate gyrus.