Circadian patterns of gene expression in the human brain and disruption in major depressive disorder
Li J, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, Evans SJ, Choudary PV, Cartagena P, Barchas JD, Schatzberg AF, Jones EG, Myers RM, Watson SJ, Akil H, Bunney WE
A cardinal symptom of Major Depressive Disorder (MDD) is the disruption of circadian patterns. Yet, to date, there is no direct evidence of circadian clock dysregulation in the brains of MDD patients. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain was difficult to characterize. Here we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-hour cyclic patterns in six cortical and limbic regions. Cyclic patterns were much weaker in MDD brains, due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This is the first transcriptome-wide analysis of cyclic patterns in the human brain and demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggest novel molecular targets for treatment of mood disorders.
Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals
Turner CA, Clinton SM, Thompson RC, Watson SJ Jr, Akil H
PNAS. 2011 May 10; 108(19):8021-5
The fibroblast growth factor system has been previously implicated by the Pritzker Consortium to be altered in the human post-mortem brain of individuals with Major Depressive Disorder (MDD). We have also shown that one of the members of this family, FGF2, has antidepressant and anxiolytic properties in rodents. These effects are thought to be due to an increase in the survival of cells in a region of the brain known to undergo new cell birth, the hippocampus. Recently, we decreased expression of FGF2 in this brain region, as illustrated at right. This manipulation resulted in increased anxiety in an animal model used to screen anti-anxiety agents. Taken together, these results suggest that levels of FGF2 in the brain not only modulate anxiety but can also produce anxiety.
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Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior
Eren-Koçak E, Turner CA, Watson SJ, Akil H
Biol Psychiatry. 2011 Mar 15; 69(6):534-40
In continuing with this line of research, we found that FGF2 levels early in life can have dramatic and lifelong consequences on brain and behavior. In normal animals, FGF2 increased cell survival and permanently altered the structure and function of the hippocampus. Specifically, animals with high levels of FGF2 early in life had more neurons in adulthood. This is important given that the volume of this region is known to be correlated with the likelihood to develop certain mood disorders. Perhaps most interestingly, high levels of FGF2 early in life decreased anxiety, but only in animals predisposed to develop anxiety. Finally, this manipulation altered the expression of genes in the hippocampus, a region known to respond to anxiolytics, providing novel targets for the treatment of anxiety.
Read the abstract at PubMed »