Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, Clark D, Rose H, Fu G, Clarke J, McKercher S, Meerloo J, Muller FJ, Park KI, Butters TD, Dwek RA, Schwartz P, Tong G, Wenger D, Lipton SA, Seyfried TN, Platt FM, Snyder EY. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007 Mar 11; PubMed.
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Baylor College of Medicine
The new study by Thomas et al. provides surprising data that even acute bouts of psychosocial stress can have dramatic, long-lasting effects on hippocampal neurogenesis. Using a social dominance paradigm in which young adult male intruders are briefly placed into an older resident colony, they show that a single 20-minute stressor can significantly lower the survival of newborn neurons in the hippocampus. Given this (at least to me) unexpected outcome, the study raises a number of follow-up questions that will be of interest to the Alzheimer community. Perhaps most obvious among them is, what effect does such acute stress, with its resultant decline in hippocampal neurogenesis, have on cognitive behavior? Given the complex nature of the stress response in rodents, it may be hard to relate any changes in behavior directly to a decrease in survival of newborn neurons, but it would nonetheless be an important question to pursue.
What impact acute stress (or hippocampal neurogenesis, for that matter) has on AD is a bit of a stretch from the data at hand. However, if the high rate of cell death among newborn hippocampal progenitor cells (roughly 80 percent die within 4 weeks of mitosis) reflects a population of cells that are teetering on the brink between life and death, and this study shows that acute stress can push them over the edge in even greater numbers than normal, perhaps cells struggling to stay alive in the face of high levels of Aβ might also succumb in greater-than-normal numbers following episodes of acute stress (arguments with caregivers, agitation following a change in routine, etc.). Admittedly, this is an enormous extrapolation from their results, but one that would be interesting to test in mouse models of the disease.
In reading the results, I wonder if the Thomas study might have revealed an even greater impact of stress on neurogenesis than the authors state. Specifically, they find 60 percent more CldU-labeled newborn cells in the hippocampi of stressed animals than in non-stressed controls. The difference in means is just short of statistical significance (p = 0.068), but this experiment used only four animals in each condition. Would they have also observed a significant difference in proliferation as well as survival had they counted more animals? Further, Thomas et al. show that an increased percentage of the newborn cells in stressed rats express a marker of immature neurons (DCX) shortly after cell division (41.9 percent vs. 26.3 percent). Could this suggest that recent stress increases the production of new neurons, but that these cells later die in greater numbers, ultimately resulting in a normal number of surviving mature neurons after the two effects cancel each other out?
Finally, because I have been stumped by this in my own work, I wonder whether the effect of stress on hippocampal neurogenesis is influenced by gender. The paradigm they have used, a form of resident-intruder aggression testing, is most often used with male animals. Females are more accepting of outsiders, and might not reach the same stress levels as males under the same conditions. But if corticosterone were directly administered at the same doses to male and female rats, would they show the same decrement in neurogenesis? And how does neurogenesis in each gender respond to chronic stress? Thomas et al. have shown an almost frightening consequence of a single acute stressor—I hate to think how many new neurons I have lost sweating over deadlines even in my brief academic career.
View all comments by Joanna JankowskyLife Technologies Corporation
This study by Lee et al. is an extension of several previous studies showing that enzymatic replacement, even at relatively low levels, can provide significant benefit to animals. The effects are quantifiable by biochemical, anatomical, and functional endpoints, though no full or lasting cure has been demonstrated.
In this study the authors make several important points. They suggest that mouse neuronal stem cells (NSCs) may be a useful model of human NSCs, something others in the field have argued may not be true. They also suggest a synergy between therapies and indicate that enzymatic replacement is more important and leads to reduced inflammation and prolonged survival of endogenous neurons. The authors do show some neurogenesis but agree that this cannot account for the global changes seen.
While these studies are encouraging, it is clear that much additional work needs to be done. Longer-term studies, absence of tumorigenesis as was shown to occur with embryonic stem cell transplants in other studies, the potential for longer-term rejection, and the effects of any immune suppressives that may be required need to be evaluated.
No doubt the authors have begun such studies and I look forward to future reports.
View all comments by Mahendra RaoUniversity of Illinois at Chicago
The carefully designed study by Thomas et al. is aimed at deepening our understanding of the effect of acute stress on hippocampal neurogenesis by investigating its temporal stage, potentially susceptible to alteration by acute psychosocial stress. Thomas and colleagues show that an acute episode of stress induced by a social dominance paradigm diminishes short-term survival of proliferating cells and long-term survival of newly differentiated neurons in the dentate gyrus. The mechanism underlying acute stress-induced alterations in progenitor cell survival in the hippocampus is largely unknown. In this study, an increase in levels of corticosterone was observed in the serum of animals
exposed to psychosocial stress, but these levels did not correlate with BrdU cell number and measures of aggression (number of bites).
The differential effect of acute stress on proliferation and survival of progenitor cells raises the important question of whether these processes are innate properties of the progenitors, or processes regulated by the neurogenic microenvironment.
In addition, it would be interesting to examine alterations in other measures of hippocampal plasticity following stress. Examination of the effect of acute stress on neurogenesis in the subventricular zone may help us identify whether stress exerts a general effect on neurogenic processes or if these effects are hippocampus-specific. During the last decade, an increasing number of studies demonstrate that stress induces alterations in expression of several neurotrophic factors, such as BDNF, VEGF and FGF-2, in limbic brain regions that play a role in the regulation of cognition. Stress can further lead to depressed synaptic physiology, neuronal atrophy and cell loss in specific brain areas such as the hippocampus and amygdala. Although the physiological response to stress is not fully understood, it becomes increasingly clear that the effects of environmental factors on homeostasis, metabolic pathways, and cellular processes are far reaching. Whether impaired neurogenesis leads to compromised cognitive function in AD and whether a cross-talk exists between Alzheimer pathology and hippocampal neurogenesis are highly relevant questions that have yet to be explored.
View all comments by Orly LazarovMake a Comment
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