Anthony D. Tramontin

Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.

The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.

Noggin Antagonizes BMP Signaling to Create a Niche for Adult Neurogenesis

Large numbers of new neurons are born continuously in the adult subventricular zone (SVZ). The molecular niche of SVZ stem cells is poorly understood. Here, we show that the bone morphogenetic protein (BMP) antagonist Noggin is expressed by ependymal cells adjacent to the SVZ. SVZ cells were found to express BMPs as well as their cognate receptors. BMPs potently inhibited neurogenesis both in vitro and in vivo. BMP signaling cell-autonomously blocked the production of neurons by SVZ precursors by directing glial differentiation. Purified mouse Noggin protein promoted neurogenesis in vitro and inhibited glial cell differentiation. Ectopic Noggin promoted neuronal differentiation of SVZ cells grafted to the striatum. We thus propose that ependymal Noggin production creates a neurogenic environment in the adjacent SVZ by blocking endogenous BMP signaling.

A unified hypothesis on the lineage of neural stem cells.

For many years, it was assumed that neurons and glia in the central nervous system were produced from two distinct precursor pools that diverged early during embryonic development. This theory was partially based on the idea that neurogenesis and gliogenesis occurred during different periods of development, and that neurogenesis ceased perinatally. However, there is now abundant evidence that neural stem cells persist in the adult brain and support ongoing neurogenesis in restricted regions of the central nervous system. Surprisingly, these stem cells have the characteristics of fully differentiated glia. Neuroepithelial stem cells in the embryonic neural tube do not show glial characteristics, raising questions about the putative lineage from embryonic to adult stem cells. In the developing brain, radial glia have long been known to produce cortical astrocytes, but recent data indicate that radial glia might also divide asymmetrically to produce cortical neurons. Here we review these new developments and propose that the stem cells in the central nervous system are contained within the neuroepithelial → radial glia → astrocyte lineage.

Adult Ependymal Cells Are Postmitotic and Are Derived from Radial Glial Cells during Embryogenesis

Ependymal cells on the walls of brain ventricles play essential roles in the transport of CSF and in brain homeostasis. It has been suggested that ependymal cells also function as stem cells. However, the proliferative capacity of mature ependymal cells remains controversial, and the developmental origin of these cells is not known. Using confocal or electron microscopy (EM) of adult mice that received bromodeoxyuridine (BrdU) or [3H]thymidine for several weeks, we found no evidence that ependymal cells proliferate. In contrast, ependymal cells were labeled by BrdU administration during embryonic development. The majority of them are born between embryonic day 14 (E14) and E16. Interestingly, we found that the maturation of ependymal cells and the formation of cilia occur significantly later, during the first postnatal week. We analyzed the early postnatal ventricular zone at the EM and found a subpopulation of radial glia in various stages of transformation into ependymal cells. These cells often had deuterosomes. To directly test whether radial glia give rise to ependymal cells, we used a Cre-lox recombination strategy to genetically tag radial glia in the neonatal brain and follow their progeny. We found that some radial glia in the lateral ventricular wall transform to give rise to mature ependymal cells. This work identifies the time of birth and early stages in the maturation of ependymal cells and demonstrates that these cells are derived from radial glia. Our results indicate that ependymal cells are born in the embryonic and early postnatal brain and that they do not divide after differentiation. The postmitotic nature of ependymal cells strongly suggests that these cells do not function as neural stem cells in the adult.

Seasonal plasticity in the adult brain

Seasonal plasticity of structure and function is a fundamental feature of nervous systems in a wide variety of animals that occupy seasonal environments. Excellent examples of seasonal brain changes are found in the avian song control system, which has become a leading model of morphological and functional plasticity in the adult CNS. The volumes of entire brain regions that control song increase dramatically in anticipation of the breeding season. These volumetric changes are induced primarily by vernal increases in circulating sex steroids and are accompanied by increases in neuronal size, number and spacing. In several species, these structural changes in the song control circuitry are associated with seasonal changes in song production and learning. Songbirds provide important insights into the mechanisms and behavioral consequences of plasticity in the adult brain.

Oestrogen regulates male aggression in the non–breeding season

Extensive research has focused on territorial aggression during the breeding season and the roles of circulating testosterone (T) and its conversion to 17β–oestradiol (E2) in the brain. However, many species also defend territories in the non–breeding season, when circulating T–levels are low. The endocrine control of non–breeding territoriality is poorly understood. The male song sparrow of Washington State is highly territorial year–round, but plasma T is basal in the non–breeding season (autumn and winter). Castration has no effect on aggression in autumn, suggesting that autumnal territoriality is independent of gonadal hormones. However, non–gonadal sex steroids may regulate winter territoriality (e.g. oestrogen synthesis by brain aromatase). In this field experiment, we treated wild non–breeding male song sparrows with a specific aromatase inhibitor (fadrozole, FAD) using micro–osmotic pumps. FAD greatly reduced several aggressive behaviours. The effects of FAD were reversed by E2 replacement. Treatment did not affect body condition or plasma corticosterone, suggesting that all subjects were healthy. These data indicate that E2 regulates male aggression in the non–breeding season and challenge the common belief that aggression in the non–breeding season is independent of sex steroids. More generally, these results raise fundamental questions about how sexual and/or aggressive behaviours are maintained in a variety of model vertebrate species despite low circulating levels of sex steroids or despite castration. Such nonclassical endocrine mechanisms may be common among vertebrates and play an important role in the regulation of behaviour.

SEASONAL PLASTICITY AND SEXUAL DIMORPHISM IN THE AVIAN SONG CONTROL SYSTEM: STEREOLOGICAL MEASUREMENT OF NEURON DENSITY AND NUMBER

Differences in neuron density and number are associated with seasonal plasticity and sexual dimorphism in the avian song control system. In previous studies, neuron density and number in this system have been quantified primarily through nonstereological approaches in thick tissue sections by using the nucleolus as the unit of count. The reported differences between seasons and sexes may be inaccurate due to biases introduced by neuron splitting during sectioning. We used the unbiased optical disector technique on tissue from three previous studies (two investigations of seasonal plasticity and one investigation of sexual dimorphism in avian song nuclei) to assess seasonal and sex differences in neuron density and number. In two song nuclei, HVc and the robust nucleus of the archistriatum (RA), the optical disector yielded intergroup differences in neuron density and number that coincided well with the three previous reports.

A field study of seasonal neuronal incorporation into the song control system of a songbird that lacks adult song learning

Adult songbirds can incorporate new neurons into HVc, a telencephalic song control nucleus. Neuronal incorporation into HVc is greater in the fall than in the spring in adult canaries (open-ended song learners) and is temporally related to seasonal song modification. We used the western song sparrow, a species that does not modify its adult song, to test the hypothesis that neuronal incorporation into adult HVc is not seasonally variable in age-limited song learners. Wild song sparrows were captured during the fall and the spring, implanted with osmotic pumps containing [3H]thymidine, released onto their territories, and recaptured after 30 days. The density, proportion, and number of new HVc neurons were all significantly greater in the fall than in the spring. There was also a seasonal change in the incorporation of new neurons into the adjacent neostriatum that was less pronounced than the change in HVc. This is the first study of neuronal recruitment into the song control system of freely ranging wild songbirds. These results indicate that seasonal changes in HVc neuronal incorporation are not restricted to open-ended song learners. The functional significance of neuronal recruitment into HVc therefore remains elusive.

Short Day Lengths Delay Reproductive Aging

Abstract Caloric restriction and hormone treatment delay reproductive senescence in female mammals, but a natural model of decelerated reproductive aging does not presently exist. In addition to describing such a model, this study shows that an abiotic signal (photoperiod) can induce physiological changes that slow senescence. Relative to animals born in April, rodents born in September delay their first reproductive effort by up to 7 mo, at which age reduced fertility is expected. We tested the hypothesis that the shorter day lengths experienced by late-born Siberian hamsters ameliorate the reproductive decline associated with advancing age. Short-day females (10L:14D) achieved puberty at a much later age than long-day animals (14L:10D) and had twice as many ovarian primordial follicles. At 10 mo of age, 86% of females previously maintained in short day lengths produced litters, compared with 58% of their long day counterparts. Changes in pineal gland production of melatonin appear to mediate the effects of day length on reproductive aging; only 30% of pinealectomized females housed in short days produced litters. Exposure to short days induces substantial decreases in voluntary food intake and body mass, reduced ovarian estradiol secretion, and enhanced production of melatonin. One or more of these changes may account for the protective effect of short day lengths on female reproduction. In delaying reproductive senescence, the decrease in day length after the summer solstice is of presumed adaptive significance for offspring born late in the breeding season that first breed at an advanced chronological age.

Hippocampal volume does not change seasonally in a non food-storing songbird.

Seasonal differences in hippocampal morphology have been reported in food-storing birds. Non food-storing species have not been investigated however. It is therefore unclear whether seasonal changes in the hippocampus are specifically related to food-storing or reflect a more general seasonal mechanism that occurs in both food-storing and non food-storing birds alike. We determined the volumes of the hippocampal formation and remaining telencephalon in the non-storing male song sparrow (Melospiza melodies morphna) in two experiments comparing birds collected in the spring and fall of 1992–94 (Experiment 1) and 1997 (Experiment 2). Although pronounced seasonal changes in song control nuclei such as the HVC and RA were previously reported for the same brains used in Experiment 1, we found that hippocampal volume did not change with season in either Experiment 1 or 2 for these song sparrow brains. These results suggest that seasonal changes in the hippocampus do not occur in this non food-storing species and may be specific to food-storing birds.