Recent research from my laboratory, in collaboration with European colleagues, has shown that neurogenesis in the hippocampus is selectively affected by alcohol. Scientists have known that chronic alcoholism results in brain cells loss in different areas of the brain. The best studied of these areas are the cerebellum and the thalamus. Interestingly, cognitive functions such as short-term memory and spatial orientation are largely regulated by the hippocampus, a structure that did not appear to show consistent pathological changes in alcoholism, yet neuropsychological and neuroimaging studies indicated that it was clearly affected. The assumption was that only neuronal loss could explain such selective impairment of the hippocampus. My work resolved that problem and showed that neurogenesis in the hippocampus can be dramatically impaired by blood alcohol levels similar to those seen in moderately intoxicated individuals. Therefore, it is the impairment of adult neurogenesis rather than loss of mature neurons that seems to underlie the effects of alcohol. In addition, we have shown how to prevent such effects of alcohol. Interestingly, extensive research indicates that there is a significant co-morbidity between alcoholism and mood disorders, and a common biological mechanism has been suggested but not identified. These findings opened up new possibilities in the treatment of neuropsychiatry disorders. That work has been published in the Proceedings of the National Academy of Sciences.
My laboratory has shown that ethanol-induced cell death of newly born neurons in the adult dentate gyrus can be prevented by antioxidants. Interestingly, the type of cell death induced in immature neurons during early stages of development in fetal alcohol syndrome is very similar to work done in my laboratory on the adult dentate gyrus of rats exposed chronically to alcohol. Research in the last few years has demonstrated that alcohol exposure during brain development induces neuronal cell death through apoptosis. Ethanol induces neuronal death at specific developmental stages, particularly during the ?brain growth spurt?. This period occurs shortly after the period of cell proliferation and migration, when young neurons are establishing functional contacts, and is reached at different time points in different brain areas. The brain growth period in humans corresponds to the third trimester of gestation; in rodents, however, this period occurs early postnatally. Ethanol triggers cell death through the activation of a ?suicide program? or apoptosis and my laboratory has demonstrated that certain drugs can inhibit apoptosis in young neurons even after exposure to ethanol. We went on to characterize the effects of one of these agents, nicotinamide (an amide of vitamin B3), and showed that this substance could not only block the apoptotic process in the brain of postnatal day seven (P7) mice, but could also prevent the decrease in the number of neurons counted in the thalamus, cingulate cortex and hippocampus after ethanol exposure. Furthermore, the behavioral impairments seen in these same animals at the age of 3 months were reverted and comparable to normal animals. There are no therapies, pharmacological or otherwise, to ameliorate the cognitive deficits triggered by exposure to ethanol of immature neurons in the developing brain. These finding were published in PloS Medicine.

More recently, we have shown, in collaboration with Dr. Niko Schiff, that electrical stimulation of the central thalamus facilitates cognition and induces specific patterns of gene expression in the neocortex. These studies are aimed at achieving an amelioration of cognitive symptoms in non-progressive encephalopathies. Our findings, in non-lesioned rats, showed that an increase in arousal led to the aforementioned cognitive facilitation and these results were published in the Proceedings of the National Academy of Sciences. I am now collaborating with Dr. Donald Pfaff at Rockefeller University, Niko Schiff and Keith Purpura from the Department of Neurology and Neuroscience at Cornell. Interestingly, in work done in Dr. Alvarez-Buylla?s and in my own laboratories, we discovered that neural stem cells are more widespread in the brain than previously thought. We called the region where these cells are found the subcallosal zone (SCZ). Further research showed that new oligodendrocytes probably originate from the SCZ. New neurons seem to be limited to two restricted areas of the adult brain: the dentate gyrus and the subventricular zone (SVZ). Neurogenesis in the neocortex has been a highly controversial topic. There is evidence that there is neurogenesis in the neocortex of adult primates, but there is also similar evidence that shows NO cortical neurogenesis in primates. In rodents, the issue is no less controversial. A very specific lesion might be able to induce neuronal replacement, data that has not been repeated by none other than the original laboratory that reported it. Strokes can induce the migration of young neurons to the lesioned area of the brain but there are no signs that these new neurons would establish new contacts and become functional. Neuronal recruitment is a critical step in brain repair; simply having neural stem cells does not guarantee new functional neurons. In work done with Dr. Alvarez-Buylla, we showed that grafts of SVZ-derived cells would originate new olfactory neurons when transplanted to the olfactory bulb. Grafting the SVZ-derived cells into the striatum gave rise to new, young neurons that would eventually die off. We are now combining many of the above techniques to a) detect neural stem cells in vivo; b) establish the recruitment of neural stem cells though electrophysiological manipulation; c) allow for the survival of newly born neurons, particularly preventing or antagonizing oxidative stress; d) demonstrate the anatomical and pharmacological recovery from a non-progressive encephalopathy.