Insights into neurogenesis and aging: potential therapy for degenerative disease?

Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age.

Even neural stem cells get the blues: evidence for a molecular link between modulation of adult neurogenesis and depression.

An emerging hypothesis, linking modulation of neurogenesis with the onset and subsequent treatment of depression, has received much attention recently as an attractive explanation for successful behavioral changes induced by antidepressant medication in both humans and animals. However, evidence for such a link remains elusive and inconsistent. This review discusses evidence for modulation of neurogenesis as a neurobiological substrate for depression within the context of heterogeneous animal models of depression. Examining the evidence currently available linking neurogenesis and depression is problematic for at least four reasons: 1) approaches to document ongoing neurogenesis and neuronal lineage commitment are varied, making cross-study comparison difficult; 2) as the functional contribution of adult neurogenesis has yet to be completely determined, it is speculative to state a functional significance to changes in neurogenesis; 3) there is diversity in animal models of depression with variable degrees of correlation with human depression; and 4) there remains insufficient knowledge of molecular factors and changes in gene expression that conclusively link neurogenesis modulation and depression. This review examines the current state of evidence regarding the following: 1) consistent data collection delineating the existence of neurogenesis, its stages of progression, and stage modulation; 2) the functional contribution of adult hippocampal neurogenesis and the use of stress-based animal models for its modulation, 3) possible molecular links between antidepressant medication and neurogenesis, specifically neurotrophins and trophic factors; and finally 4) specific suggestions for further investigations necessary to warrant full acceptance of a link between modulation of neurogenesis and depression.

Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation.

Factors modulating neurogenesis may contribute to the pathophysiology of affective disorders such as major depression. Environmental stressors in animal models have been proposed to alter neurogenesis, suggesting a mechanism for this contribution. The effect of an acute psychosocial stressor on either proliferation or survival (immediate, short term, and long term) was examined along with subsequent neuronal differentiation in the hippocampus of adult male Sprague Dawley rats. Subjects were exposed to a widely used social dominance paradigm that elicits behavioral and physiological responses to an acute psychosocial stressor. This social dominance paradigm may mimic human relational stress more realistically than laboratory stressors and provides a socially relevant model. We found that exposure to an acute psychosocial stressor at the time of cell generation resulted in a decreased number of newly generated cells in the hippocampus. By using sequential thymidine analog administration to provide temporal discrimination of DNA replication, we showed that short-term survival but not initial proliferation or immediate survival was altered in response to stress. Furthermore, we determined that stress experienced subsequent to proliferation also diminished long-term survival of cells. Thus, an acute episode of a social stress produces long-lasting effects on the incorporation of new hippocampal neurons by reducing their survival.

Acute exposure to predator odor elicits a robust increase in corticosterone and a decrease in activity without altering proliferation in the adult rat hippocampus.

Stress has long been implicated as a major cause of depression in humans and more recently has been suggested to decrease neurogenesis, which may be a contributing factor to depression development. Animal models of stress may be a relevant tool for investigating links between neurogenesis and depression. This has largely been investigated using chronic stress models in rodents. However, stress may be chronic or experienced in discrete episodes. Acute stress may be particularly relevant to humans experiencing unexpected societal pressures and obligations. Our study examined the effect of acute stress on the proliferative phase of adult hippocampal neurogenesis. Young adult rats were exposed for 20 min to the predator odor TMT, a natural stressor for rodents with significant ethological relevance. BrdU IP injections were concurrent with TMT exposure to assess proliferation effects with animal sacrifice 2 h after BrdU injection. Robust stress responses were evident following TMT exposure as detected by elevated corticosterone (CORT) levels and a significant reduction in exploratory behavior. Exposure to TMT did not alter the number of BrdU-positive cells in the hippocampus despite physiological and behavioral evidence of stress. CORT level elevation has long been accepted as a marker of stress; however, this study indicates that increases in CORT level may not always correlate with diminished neurogenic proliferation. This study further suggests that various stressors may not operate through the same biological substrates resulting in a differential ability to modulate neurogenesis.

Influence of asparaginase on a combination chemotherapy protocol for canine multicentric lymphoma.

Combination chemotherapy is superior to single-agent chemotherapy for treating canine lymphoma, but the effect of each drug on efficacy remains unknown. By comparing 34 dogs treated with a modified cyclophosphamide, vincristine, prednisone (COP) chemotherapy protocol and 42 dogs given asparaginase in the induction phase of the same protocol, the effect of asparaginase on the chemotherapeutic protocol was determined. Both groups were compared based on clinical response at 2 weeks and 6 weeks, and on the progression-free interval. Asparaginase did not significantly increase the likelihood of a clinical remission or prolong the initial progression-free interval in the dogs studied.

A neurogenic theory of depression gains momentum.

The rate of adult neurogenesis fluctuates in response to several environmental factors. Chronic stress, which can lead to neuronal apoptosis and dendritic atrophy, certainly affects the overall rate of neurogenesis in the adult brain. Depression, which arises from several causes, including chronically stressful situations, is known to correlate with altered hippocampal morphology. But is the link between depression and neuronal regeneration merely coincidental? Recent studies indicate that ingestion of antidepressants leads to increased neurogenesis in the hippocampus. However, the hippocampus is generally thought important for learning and memory-not for "mood" state-thus, there is much more to the story that requires clarification. Also, caveats abound in the interpretation of neurogenesis in the amelioration of depression; nonetheless, these results are quite intriguing and might point to better design and prediction of new-generation antidepressants.