Natural variation and genetic covariance in adult hippocampal neurogenesis

Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB/BXA, n = 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1/CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis

Neuronal stem cells and adult neurogenesis

In many fields of modern medicine and medically oriented biology the growing interest in stem cells has fundamentally changed the perception of what is therapeutically possible. In principle, stem cell biology has introduced cellular replacement strategies even to fields where classical organ transplantation, such as heart and kidney, was impossible — most notably neurobiology (Gage 2000)

Three-dimensional ultrastructural and immunohistochemical study of immature neurons in the subgranular zone of the rat dentate gyrus

The present study is devoted to three dimensional ultrastructural organization of mitotically dividing immature neurons in dentate gyrus using biophysical approaches. In adult vertebrate brain, cell proliferation persists throughout life mainly in dentate gyrus of the hippocampus (DG) and olfactory bulb. Neurogenesis has been demonstrated using tagged thymidine analogues incorporated into the S phase of the cell cycle, but these may also detect repaired DNA in postmitotic neurons. Recent retroviral labelling has shown that neuronal progenitors/neuroblasts divide and produce functional neurons. Providing ultrastructural evidence of mitotically active cells has proven problematical, not only because of technical issues of identifying dividing cells at electron microscope level, but also because it is difficult to demonstrate unequivocally that neurons identified in the electron microscope are really post mitotic. However by characterising post mitotic cells labelled with BrdU and doublecortin and comparing these with post mitotic cells reconstructed in 3 dimensions from ultrathin serial sections, we have been able to illustrate individual mitotic elements and phases of cells within the GC layer of adult rat dentate gyrus. Here we show dividing cells in metaphase within clusters of immature GCs in subgranular zone (SGZ). These reconstructions provide ultrastructural confirmation that cells expressing doublecortin (DCX), a microtubule associated protein expressed in migrating neurons, localize as clusters in the subgranular zone (SGZ) of dentate gyrus (DG) in the hippocampus during all animal life. Such DG cells with clear synaptic specializations, somatic spines and basal dendrites are exclusive to immature GC that appear to reenter the cell cycle, suggesting the possibility that newly generated neurons within the DG might arise not only from precursors, but also from clusters of immature GC

Anatomical perspectives on adult neural stem cells

The concept of stem cells within the adult brain is not new. However, only recently have scientific techniques become sufficiently advanced to identify them although this remains problematic and the technology is still developing. Nevertheless, it is now generally recognized that stem cells are restricted to two germinal regions within the intact brain. From here they can migrate to specific destinations where they integrate with existing circuitry. Their identity remains controversial but a growing body of evidence suggests it may have an astrocytic phenotype. Within the germinal regions the stem cells are confined to a niche environment and are capable of responding to environmental signals generated locally in an autocrine or paracrine fashion. The niche environment is also modulated by more generalized systemic and physiological activity. These observations are exciting in their own right and form the basis of this review. They are also beginning to alter how we think about neural injury and disease and to impact on the development of novel therapies

Impact of diet on adult hippocampal neurogenesis

Research over the last 5 years has firmly established that learning and memory abilities, as well as mood, can be influenced by diet, although the mechanisms by which diet modulates mental health are not well understood. One of the brain structures associated with learning and memory, as well as mood, is the hippocampus. Interestingly, the hippocampus is one of the two structures in the adult brain where the formation of newborn neurons, or neurogenesis, persists. The level of neurogenesis in the adult hippocampus has been linked directly to cognition and mood. Therefore, modulation of adult hippocampal neurogenesis (AHN) by diet emerges as a possible mechanism by which nutrition impacts on mental health. In this study, we give an overview of the mechanisms and functional implications of AHN and summarize recent findings regarding the modulation of AHN by diet