Index

Adult neurogenesis

Regulation of adult neurogenesis

Several factors are known to regulate neurogenesis in the adult mammalian brain.  Exercise increases the number of new neurons, while stress and age decrease the number of newly-born cells.  Demonstration of the regulation of neurogenesis in the adult hippocampus by environmental, physiological, and pharmacological manipulations has become a priority.  I have already identified opiates as a factor that decreases the number of new neurons in the adult rat brain (Eisch et al., 2000).  Opiates share many characteristics with other drugs of abuse, such as cocaine, amphetamine, THC and ethanol.  All of these drugs have addictive potential, and many studies suggest that long-term use of many of these drugs results in deficits in learning and memory.  It is intriguing to consider whether a decrease in adult neurogenesis is a general effect of drugs of abuse, or whether it is specific to opiates. 

Therefore, one of the avenues of research in my laboratory is explore the regulation of adult neurogenesis by drugs of abuse.  We have made significant progress in characterizing the inhibition of adult neurogenesis by opiate and stimulants, and we are collaborating with others to find out is ethanol and THC have similar effects.  We are also extremely interested in HOW these factors alter adult neurogenesis.  Do they kill progenitor cells, or just stop them from entering S phase? (For a basic introduction to the cell cycle, click here)  Do they act directly on progenitor cells, or via alterations in blood flow, growth factors, cytokines, etc?  How permanent are the alterations in adult neurogenesis?  And, importantly, what functional impact does altered neurogenesis have on the adult brain?  Recent research suggests that addiction is itself a form of learning, albeit one that might utilize non-hippocampal brain structures.  We are excited about teasing apart brain structures involved in different types of learning, and examining the role that adult neurogenesis plays in these different brain regions.  All of these questions are actively being explored by my group. 

Addiction is one of the most straightforward psychiatric disorders to model in laboratory animals.  However, there are several other psychiatric disorders that we are interested in studying in regards to adult neurogenesis.   For example, in collaboration with Dwight German's laboratory, we are examining adult neurogenesis in a transgenic mouse model of Alzheimer's Disease.  In old age, these mice have cognitive deficits and decreased hippocampal volume.  We are addressing the role of altered progenitor cell proliferation in the cognitive and pathological profiles of these mice. 

Characterizing newly-born cells via immunohistochemical and transgenic approaches

In addition to studies exploring the potential link between psychiatric disorders and adult neurogenesis, we are extremely interested in answering basic questions about the newly-born cells in the adult mammalian hippocampus.  Cells in the hippocampal subgranular zone, or SGZ, are born in clusters.  We have an active research team using exogenous as well as endogenous cell cycle markers to characterize these clusters (for pictures of staining with endogenous cell cycle markers, click here).  Do all cells in a cluster move through the cell cycle together?  Do they all have the same fate?  Do they all express the same cell surface receptors, and use the same second messenger signaling pathways?  To ask these questions, we take several approaches.  First, we do multiple immunostaining of clusters, analyze them on a confocal microscope and analyze them with a three-dimensional reconstruction program (to see a sample image or movie of the 3D reconstruction, click here).  These tools allow us to ask important, but basic, questions about the essential characteristics of the clusters of progenitor cells in the mammalian hippocampus.  Another approach we use is transgenic mouse technology.  In collaboration with the DiLeone Laboratory, we are making a transgenic mouse that is designed to inducibly label or cut out genes in the progenitor cells.  In collaboration with Bob Beech of the Picciotto Laboratory at Yale University, we are involved in characterizing another line of mice which inducibly over-express a certain gene in the progenitor cells.  Finally, in collaboration with Masahiro Yamaguchi's laboratory at the University of Tokyo we are studying the effects of drugs of abuse and antidepressants on mice that express a fluorescent protein in their progenitor cells.

Growth Factors

Involvement of the ventral midbrain in a depressive-like phenotype

Involvement of the growth factors in regulation of adult neurogenesis