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Biomedical subjects

F H Gage

Publications and source records attributed to F H Gage.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regenerating the damaged central nervous system.

It is self-evident that the adult mammalian brain and spinal cord do not regenerate after injury, but recent discoveries have forced a reconsideration of this accepted principle. Advances in our understanding of how the brain develops have provided a rough blueprint for how we may bring about regeneration in the damaged brain. Studies in developmental neurobiology, intracellular signalling and neuroimmunology are bringing the regeneration field closer to success. Notwithstanding these advances, clear and indisputable evidence for adult functional regeneration remains to be shown.

Animals↗
PubMed2000

Vascular niche for adult hippocampal neurogenesis.

The thin lamina between the hippocampal hilus and granule cell layer, or subgranule zone (SGZ), is an area of active proliferation within the adult hippocampus known to generate new neurons throughout adult life. Although the neuronal fate of many dividing cells is well documented, little information is available about the phenotypes of cells in S-phase or how the dividing cells might interact with neighboring cells in the process of neurogenesis. Here, we make the unexpected observation that dividing cells are found in dense clusters associated with the vasculature and roughly 37% of all dividing cells are immunoreactive for endothelial markers. Most of the newborn endothelial cells disappear over several weeks, suggesting that neurogenesis is intimately associated with a process of active vascular recruitment and subsequent remodeling. The present data provide the first evidence that adult neurogenesis occurs within an angiogenic niche. This environment may provide a novel interface where mesenchyme-derived cells and circulating factors influence plasticity in the adult central nervous system.

Aging↗
PubMed2000

Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord.

The existence of multipotent progenitor populations in the adult forebrain has been widely studied. To extend this knowledge to the adult spinal cord we have examined the proliferation, distribution, and phenotypic fate of dividing cells in the adult rat spinal cord. Bromodeoxyuridine (BrdU) was used to label dividing cells in 13- to 14-week-old, intact Fischer rats. Single daily injections of BrdU were administered over a 12 d period. Animals were killed either 1 d or 4 weeks after the last injection of BrdU. We observed frequent cell division throughout the adult rodent spinal cord, particularly in white matter tracts (5-7% of all nuclei). The majority of BrdU-labeled cells colocalized with markers of immature glial cells. At 4 weeks, 10% of dividing cells expressed mature astrocyte and oligodendroglial markers. These data predict that 0.75% of all astrocytes and 0.82% of all oligodendrocytes are derived from a dividing population over a 4 week period. To determine the migratory nature of dividing cells, a single BrdU injection was given to animals that were killed 1 hr after the injection. In these tissues, the distribution and incidence of BrdU labeling matched those of the 4 week post injection (pi) groups, suggesting that proliferating cells divide in situ rather than migrate from the ependymal zone. These data suggest a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes.

Age Factors↗
PubMed2000

Mammalian neural stem cells.

Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved, although the number of viable locations is limited in the adult. The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

Animals↗
PubMed2000

Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain.

Expanded polyglutamine (polyQ) tracts have been linked to a new class of human disease characterized by psychiatric/motor syndromes associated with specific patterns of neurodegeneration. We have used a direct viral approach to locally express expanded polyglutamine tracts fused to the green fluorescent protein (97Q-GFP) in the adult rat brain. We show that intrastriatal expression of 97Q-GFP causes the rapid formation of fibrillar, cytoplasmic, and ubiquitinated nuclear aggregates in neurons. 97Q-GFP expression also results in a specific temporal pattern of cell death in the striatum. Co-infection studies suggest that high level 97Q-GFP-expressing cells die during the first month, whereas low level 97Q-GFP-expressing neurons persist for up to 6 months after infection. These data indicate that cumulative expression of polyQ repeats throughout the life of the animal is not required to induce neuronal death, but rather acute overexpression of polyQ is toxic to adult neurons in vivo.

Adenoviridae↗
PubMed2000

Neuronal differentiation and morphological integration of hippocampal progenitor cells transplanted to the retina of immature and mature dystrophic rats.

Attempts to repopulate the retina with grafted neurons have been unsuccessful, in large part because donor cells prefer not to integrate with those of the host. Here we describe the first use of neural progenitor cells in the diseased adult retina. Adult rat hippocampal progenitor cells were injected into the eyes of rats with a genetic retinal degeneration. After survival times up to 16 weeks, the retinae of 1-, 4-, and 10-week-old recipients exhibited widespread incorporation of green fluorescent protein-expressing (GFP+) donor cells into the host retina. The 18-week-old recipients showed a similar pattern, but with fewer cells. Grafted cells expressed the mature neuronal markers NF-200, MAP-5, and calbindin. GFP+ cells extended numerous neurites into the host plexiform layers and these processes were intimately associated with synaptophysin+ profiles. GFP+ neurites also extended into the host optic nerve head. These results demonstrate the differentiation of substantial numbers of new neurons within the mature dystrophic retina.

Aging↗
PubMed2000

Lentiviral vectors: regulated gene expression.

Lentiviral vectors can deliver and express genes in a wide variety of dividing and nondividing cells. These include terminally differentiated neurons, myotubes, hepatocytes, and hematopoietic stem cells. We now describe the generation of lentiviral vectors in which the expression of the transgene can be regulated. We have developed an inducible lentiviral vector system that contains the entire tetracycline (Tet)-regulated system developed by H. Bujard and colleagues. The novel vector expresses the GFP reporter gene and the tetracycline transactivator under the control of the tetracycline-inducible promoter and the human CMV promoter, respectively. In vitro transduction of human 293 cells resulted in a very low basal expression of GFP in the presence of the effector substance doxycyline. Withdrawal of doxycyline induced a more than 500-fold increase in transgene expression. Switching transgene expression "off and on" did not change either the kinetics or the magnitude of induction. Maximal suppression of GFP mRNA transcription was achieved within 24 h of addition of the drug; however, due to the slow turnover rate of GFP, green fluorescent cells could be detected up to 10 days following doxycyline treatment. Following transduction of rat brain with recombinant lentiviruses, doxycyline-regulated GFP expression could be observed in terminally differentiated neurons. Specifically, by adding or withdrawing doxycyline from the rats' drinking water, induction and suppression of GFP expression could be regulated in vivo. These studies show that an inducible lentiviral vector can deliver and regulate transgene expression in vivo. We believe that regulated gene expression is an essential tool for successful gene therapy approaches.

Animals↗
PubMed2000

Activity-dependent regulation of neuronal plasticity and self repair.

Plasticity is an essential characteristic of the brain: it is part of how the brain functions and is continuous while the brain interacts with the outer world. The state of activation and the level of activity of the entire organism affect the brain's plastic response. Brain plasticity has many substrates, ranging from synapses to neurites and entire cells. The production of new neurons is part of plasticity even in the adult and old brain, but under normal conditions neurogenesis only occurs in two privileged regions of the adult brain: hippocampus and olfactory system. At least in the hippocampus, physical activity stimulates neurogenesis by acting on the proliferation of neuronal stem cells. More specific functions such as learning may be able to recruit new neurons from the pool of cells with neurogenic potential. In a broader context neuronal stem cells can likely be found throughout the brain. Therefore, novel approaches to neuroregeneration will, when most effective, make use of the activity-related effects on neuronal stem cells in the adult brain to activate these stem cells in a targeted manner to enhance brain function.

Animals↗
PubMed2000

FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor.

We have purified and characterized a factor, from the conditioned medium of neural stem cell cultures, which is required for fibroblast growth factor 2's (FGF-2) mitogenic activity on neural stem cells. This autocrine/paracrine cofactor is a glycosylated form of cystatin C (CCg), whose N-glycosylation is required for its activity. We further demonstrated that, both in vitro and in vivo, neural stem cells undergoing cell division are immunopositive for cystatin C. Finally, we showed in vivo functional activity of CCg by demonstrating that the combined delivery of FGF-2 and CCg to the adult dentate gyrus stimulated neurogenesis. We propose that the process of neurogenesis is controlled by the cooperation between trophic factors and autocrine/paracrine cofactors, of which CCg is a prototype.

Animals↗
PubMed2000

Neurobiology of disease.

Advances in technology and basic sciences this past decade have transformed neurobiological research. Practitioners looking prospectively in 1990 could hardly have hoped for the diagnostics and rational therapeutics that have become part of regular practice today. Here, we discuss three areas that have had great impact: genetics, cell death, and stem cell/gene therapy research.

Animals↗
PubMed2000

Neural consequences of environmental enrichment.

Neuronal plasticity is a central theme of modern neurobiology, from cellular and molecular mechanisms of synapse formation in Drosophila to behavioural recovery from strokes in elderly humans. Although the methods used to measure plastic responses differ, the stimuli required to elicit plasticity are thought to be activity-dependent. In this article, we focus on the neuronal changes that occur in response to complex stimulation by an enriched environment. We emphasize the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.

Animals↗
PubMed2000

Adult brain neurogenesis and psychiatry: a novel theory of depression.

Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release. Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression. Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.

Adult↗
PubMed2000

Neurogenesis in the adult hippocampus.

The surprising finding that the adult hippocampus produces new neurons throughout life has challenged many old views about the brain, because the brain appears to be plastic enough to integrate new neurons. Research on adult hippocampal neurogenesis also allows one to study neuronal stem or progenitor cells in the mature and working brain. It therefore will provide key information necessary for any attempt to use neuronal stem cells in situ to treat neurological disease. Although this new strategy holds great promise, a large number of questions, some of which are discussed herein, remain to be addressed.

Adult↗
PubMed1999

Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

BRCA2 mutations predispose carriers mainly to breast cancer. The vast majority of BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function. A series of green fluorescent protein (GFP)-tagged BRCA2 deletion mutants revealed that nuclear localization depends on two nuclear localization signals that reside within the final 156 residues of BRCA2. Consistent with this observation, an endogenous truncated BRCA2 mutant (6174delT) was found to be cytoplasmic. Together, these studies provide a simple explanation for why the vast majority of BRCA2 mutants are nonfunctional: they do not translocate into the nucleus.

BRCA2 Protein↗
PubMed1999

Running enhances neurogenesis, learning, and long-term potentiation in mice.

Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.

Animals↗