Reference 3
NUTRITIONAL MEDICINE RESEARCH
UK

Nature Neuroscience
October 1999 Volume 2 Number 10 pp 894 - 897
 

Reference 3
Selected sections from
Restoring production of hippocampal neurons in old age
Heather A. Cameron & Ronald D. G. McKay
Laboratory of Molecular Biology, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA

The production of hippocampal granule neurons continues throughout adulthood but dramatically decreases in old age. Here we show that reducing corticosteroid levels in aged rats restored the rate of cell proliferation, resulting in increased numbers of new granule neurons. This result indicates that the neuronal precursor population in the dentate gyrus remains stable into old age, but that neurogenesis is normally slowed by high levels of corticosteroids. The findings further suggest that decreased neurogenesis may contribute to age-related memory deficits associated with high corticosteroids, and that these deficits may be reversible.
The hippocampus has an important role in specific types of learning and memory, those related to personal experience ('episodic memory) that are impaired in a large percentage of the elderly population. Aging in both rats and humans is characterized by increased exposure to corticosteroids, adrenal stress hormones, both from prolonged stress-induced secretion and from increased basal levels. These high levels of corticosteroids are believed to cause or accelerate hippocampal damage, leading to memory impairment associated with 'normal' aging. Consistent with this, a subpopulation of elderly humans with normal corticosteroid levels (that is, levels standard for young adults) shows no evidence of structural or functional changes in the hippocampus.
Neurons in one portion of the hippocampal region, the dentate gyrus, are unusual in that they continue to be replaced in adults of many species, including humans. However, the rate of production of these granule neurons is dramatically decreased in aged animals. Stress and corticosteroids inhibit production of hippocampal granule cells in developing and young adult mammals, from rodents to primates, suggesting that a corticosteroid-induced decrease in neurogenesis may contribute to memory deficits in old age. High levels of corticosteroids in old age could damage or kill precursor cells, permanently decreasing the size of the dividing population. Alternatively, corticosteroids may inhibit proliferation of cells in the aged dentate gyrus without damaging the progenitors, resulting in a reversible decline in neurogenesis.
To determine if neurogenesis in the aged dentate gyrus can be restored by removing corticosteroids, we adrenalectomized young adult and aged rats and examined dividing cells labeled with bromodeoxyuridine (BrdU), a thymidine analog incorporated into cells during DNA synthesis. We then used cell-specific markers to identify newly born neurons after longer survival times.

DISCUSSION
These results show that the capacity for granule cell progenitor proliferation in the dentate gyrus of aged rats is the same as that in young rats and that the inhibition of neurogenesis in aged animals is the result of high corticosteroid levels. They also demonstrate that new cells born in the aged rat dentate gyrus after adrenalectomy can survive and differentiate into granule cells with characteristic dendritic trees and normal marker expression.
The granule neuron precursor population seems to be robust; that is, the size of the population does not diminish with age. The precursor cells in this population can apparently stop dividing for long periods of time, but still proliferate rapidly when prompted by the right signal, such as removal of corticosteroids. In this study, adrenal steroids were completely removed to ensure equivalent corticosteroid levels in young and old rats. However, smaller decreases in corticosteroids, such as those produced by inhibitors of steroid synthesis, would likely increase proliferation in the aged dentate gyrus as well, because neurogenesis in the dentate gyrus is inversely proportional to a wide range of corticosteroid levels.
Although the death of neurons in the adult brain is generally thought of as pathological, granule cell death normally occurs throughout life in the dentate gyrus. The 'turnover' in this population suggests that cell death may be required to create space for new neurons.

NEXT ARTICLE
PREVIOUS ARTICLE
RESEARCH SUBJECTS