Highlighted Publications

Fibroblast growth factor 9 is a novel modulator of negative affect

Aurbach EL, Inui EG, Turner CA, Hagenauer MH, Prater KE, Li JZ, Absher DM, Shah N, Blandino P Jr, Bunney WE, Myers RM, Barchas JD, Schatzberg AF, Watson SJ Jr, Akil H
PNAS. Epub 2015 Sep 2.

FGF9 Neurons
The green cells show where an injected virus was used to block production of FGF9 in rat brains.
Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

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Circadian patterns of gene expression in the human brain and disruption in major depressive disorder

Li JZ, 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
PNAS. 2013 Jun 11;110(24):9950-5

Image of human brain made up of gearsA 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.

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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

Diagram of Short Hairpin RNA Silencing of Fibroblast Growth Factor 2 Gene Expression in Rat Hippocampus 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

Diagram showing that FGF2 levels early in life can have lifelong effects on brain and behavior 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 »