Biomedical subjects

David R Riddle

Publications and source records attributed to David R Riddle.

6 recordsLinked to original sources

PubMed2006

Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis.

Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.

Analysis of Variance↗

PubMed2005

Dendritic stability in a model of adult-onset IGF-I deficiency.

OBJECTIVE: A significant decrease in plasma levels of insulin-like growth factor-I (IGF-I) is one of the most robust hallmarks of aging and may contribute to functional changes associated with senescence. This study examined the role of IGF-I in the maintenance of adult dendritic morphology. DESIGN: We utilized a model of the aging-related decrease in plasma IGF-I to examine whether such a decrease, in itself, leads to dendritic changes in the cerebral cortex. The dw/dw rat, originally of the Lewis strain, suffers from a spontaneous mutation in which growth hormone (GH) production is severely decreased. Since GH is responsible for the production of circulating IGF-I by the liver, these animals are deficient in plasma IGF-I. Homozygous dw/dw rats were administered porcine GH to sustain IGF-I levels during development and then GH injections were stopped as adults in order to examine the effects of adult-onset GH and IGF-I deficiency. Animals sacrificed after two or eight weeks of GH and IGF-I deficiency were compared to age-matched dw/dw animals that received GH both developmentally and throughout adulthood (GH/IGF-I replete). The dendritic arbors of pyramidal neurons in cingulate cortex were labeled by intracellular injection and reconstructed in three dimensions. RESULTS: Comparing GH/IGF-I replete and deficient dw/dw rats, we found no differences in the apical or basal arbors of either layer two or layer five pyramidal neurons. CONCLUSIONS: These findings indicate that a decrease in plasma levels of IGF-I is not sufficient in itself to produce dendritic changes like those seen in aging animals.

Aging↗

PubMed2005

Caloric restriction does not reverse aging-related changes in hippocampal BDNF.

Caloric restriction (CR) can attenuate the aging-related decline in learning and memory in rats. Understanding the mechanisms underlying this effect could lead to therapies for human memory impairment. We tested the hypotheses that aging is associated with a decline in hippocampal brain-derived neurotrophic factor (BDNF), a growth factor that enhances learning and memory, and that CR increases hippocampal BDNF. We compared BDNF protein levels in hippocampal subregions of young, middle-aged and old rats fed CR or ad libitum (AL) diets. Mean BDNF levels in the dentate gyrus and CA3 did not differ with diet but increased with age. In CA1, BDNF levels were slightly higher in CR than AL rats at middle and old age but did not change across lifespan. These data suggest that mnemonic impairments with age do not reflect a decrease in hippocampal BDNF. Furthermore, if CRs attenuation of aging-related memory changes is mediated by BDNF, then it must be through a small, CA1-specific increase and does not involve reversal of an aging-related decline in BDNF.

Age Factors↗

PubMed2003

Nonhuman primate parthenogenetic stem cells.

Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.

Animals↗

PubMed2003

Microvascular plasticity in aging.

Understanding the bases of aging-related cognitive decline remains a central challenge in neurobiology. Quantitative studies reveal little change in the number of neurons or synapses in most of the brain but their ongoing replacement is reduced, resulting in a significant loss of neuronal plasticity with senescence. Aging also may alter neuronal function and plasticity in ways that are not evident from anatomical studies of neurons and their connections. Since the nervous system is dependent upon a consistent blood supply, any aging-related changes in the microvasculature could affect neuronal function. Several studies suggest that, as the nervous system ages, there is a rarefaction of the microvasculature in some regions of the brain, as well as changes in the structure of the remaining vessels. These changes contribute to a decline in cerebral blood flow (CBF) that reduces metabolic support for neural signaling, particularly when levels of neuronal activity are high. In addition to direct effects on the microvasculature, aging reduces microvascular plasticity and the ability of the vessels to respond appropriately to changes in metabolic demand. This loss of microvascular plasticity has significance beyond metabolic support for neuronal signaling, since neurogenesis in the adult brain is regulated coordinately with capillary growth.

Aging↗

PubMed2002

Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat.

Early hypotheses that normal brain aging involves widespread loss of neurons have been revised in light of accumulating evidence that, in most regions of the brain, the number of neurons is stable throughout adulthood and senescence. It is not clear, however, that all aspects of neuronal structure are similarly maintained, and anatomical changes are likely to contribute to age-related declines in cognitive function. The extent and pattern of dendritic branches is one likely target for age-dependent regulation since dendrites remain plastic into adulthood and since dendrites, as the site of most synapses, critically regulate neuronal function. This study quantified the dendritic extent and geometry of superficial and deep pyramidal neurons in the medial frontal cortex of Brown Norway rats from young adulthood through senescence. This region of cortex is of specific interest given its involvement in a variety of cognitive functions that change with age. In the present study, age-related changes in dendritic extent were found to occur with remarkable specificity. Superficial, but not deep, pyramidal neurons exhibited ongoing dendritic growth after 2 months-of-age and then dendritic regression after 18 months-of-age. Apical and basal dendrites were similarly regulated; in each arbor adult growth and regression were limited to terminal dendritic segments. The focal specificity of age-related changes suggests several possible regulatory mechanisms, including regional changes in trophic support and in neuronal activity. Although restricted to specific neuronal populations, dendritic regression in aged animals is likely to contribute to cognitive changes associated with senescence.

Aging↗