Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders

Abstract

This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescents. Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood. In adolescents with alcohol use disorders (AUDs), the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered. This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently among the age groups. Finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an AUD.

Figure 1

This figure is a cartoon representation of when two of the most commonly used cell cycle markers, Bromo-deoxy-Uridine (BrdU) and Ki-67, are observed with regard to the different stages of the cell cycle. Ki-67 is an endogenous marker of proliferation that is expressed throughout the active phases of cell division, specifically G₁, S, G₂ and M phases (Scholzen and Gerdes, 2000). BrdU, however, is only incorporated during synthesis phase (S-phase) of the cycle and therefore indicates that a cell is either in or has passed through the S-phase. Morris et al., 2009b proposes that in an adolescent model of an alcohol use disorder, that alcohol is arresting cells in the G₁ phase of the cycle. A cell arrested at G₁, would therefore be positive for Ki-67 but negative for BrdU, which would explain why a decrease in BrdU-positive cells, but no change in Ki-67 positive cells, were observed during alcohol intoxication. Notably, this difference in expression for BrdU versus Ki-67 is not observed in adult models. This difference may suggest a different mechanism of alcohol inhibition of proliferation in adults versus adolescents.

Figure 2

Representative photomicrographs of various neurogenesis-related markers (via immunohistochemistry) are shown and contrasted for adolescent versus adult rats. All images above are taken at the intersection of the superior and inferior blades of the dentate gyrus of the hippocampus. The images highlight that proliferation markers, BrdU and Ki-67, are increased in the adolescent brain compared the adult, which supports the higher rates of neural stem cell proliferation observed in the adolescent (He and Crews, 2007). The arrows in the BrdU and Ki-67 panels point towards clusters of dividing cells. In the doublecortin images, a thinner band of doublecortin-positive cell bodies is easily visualized in the adult panel. Further, the density immature granule cell neurons is also evident by more dendrites (arrows) projecting through the granule cell layer in the adolescent versus a single dendrite in the adult.