Current Research Interests:
Research in the Akil laboratory is focused on understanding the neurobiology of emotions, including pain, anxiety, depression and substance abuse. Early on, our research focused on the role of the endorphins and their receptors in pain and stress responsiveness. We provided the first physiological evidence for a role of endogenous opioids in the brain; and showed that endorphins are activated by stress and cause pain inhibition, a phenomenon we termed Stress-Induced Analgesia. We defined how the posttranslational processing of opioid precursors is modulated by stress, and demonstrated the coordinate actions of the neuropeptide products on behavior.
We collaborated with Dr. Stanley Watson in a series of studies characterizing the anatomy of the opioid peptides and their receptors. The Akil & Watson research groups collaboratively cloned two types of opioid receptors and conducted structure-function analyses defining the molecular basis of high affinity and selectivity towards the endogenous ligands.
Our laboratory investigated the molecular and neural mechanisms underlying stress reactivity and their relation to anxiety and depression. We have focused on the role of the steroid stress hormone receptors in emotionality, demonstrating the involvement of the mineralocorticoid receptor in human depression. Our research group has created a transgenic mouse that overexpresses the glucocorticoid receptor selectively in forebrain and exhibits increased emotional lability and responsiveness to antidepressants, two features of bipolar illness.
A major focus of our current research program is to develop animal models to understand the genetic and developmental basis of differences in temperament and the implications of these inborn differences for vulnerability to anxiety, depression and substance abuse.
Our research group is one of six nodes in the Pritzker Neuropsychiatric Research Consortium, an integrated collaborative effort using genomic tools to uncover the neural phenotypes associated with major depression and bipolar illness in human postmortem brains. In this context, we have implicated, for the first time, the FGF (Fribroblast Growth Factor) system in major depression. Other Pritzker Consortium efforts include the search for the genes responsible for Bipolar Disorder, genome-wide characterization of epigenetic changes in normal and psychiatric brains, and the identification of biomarkers for psychiatric disorders.
Research tools in our laboratory include the use of a range of molecular, genetic, anatomical, behavioral and clinical approaches in a highly interdisciplinary environment. The goal is to use a convergence of strategies to understand the biology of emotions.
"The Scientific Method is doing your damnedest, no holds barred!"
Percy Bridgeman, High Pressure Physicist.
Selected Publications:
Kabbaj, M., Devine, D.P., Savage, V. and Akil, H.: Neurobiological correlates of individual differences in novelty seeking behavior in the rat: Differential expression of stress-related molecules. J. Neuroscience, 20(18): 6983-6988, 2000 PMID: 10995843
Young, E.A., Lopez, J.F., Murphy-Weinberg, V., Watson, S.J. and Akil, H.: Mineralocorticoid receptor function in major depression. Arch. Gen. Psychiatry, 60:24-28, 2003 PMID: 12511169
Wei, Q., Lu, X.-Y., Liu, L., Schafer, G., Shieh, K.-R., Burke, S., Robinson, T.E., Watson, S.J., Seasholtz, A.F. & Akil, H.: Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability. Proc. Natl. Acad. Sci. U.S.A., 101(32): 11851-11856, 2004 PMCID: 511063
Evans SJ, Choudary PV, Neal CR, Li JZ, Vawter MP, Tomita H, Lopez JF, Thompson RC, Meng F, Stead JD, Walsh DM, Meyers RM, Bunney WE, Watson SJ, Jones EG and Akil H. Dysregulation of the Fibroblast Growth Factor (FGF) system in Major Depression. Proc. Natl. Acad. Sci. U.S.A., 101 (43) 15506-11, 2004 PMCID: 523463
Akil, H: Stressed and depressed. Nature Medicine, 11, 116-118, 2005 PMID: 15692589
Stead JD, Neal C, Meng F, Wang Y, Evans S, Vazquez DM, Watson SJ, Akil H. Transcriptional profiling of the developing rat brain reveals that the most dramatic regional differentiation in gene expression occurs postpartum. J Neurosci. 2006 Jan 4;26(1):345-53 PMID: 16399705
Wei Q, Hebda-Bauer EK, Pletsch A, Luo J, Hoversten MT, Osetek AJ, Evans SJ, Watson SJ, Seasholtz AF, Akil H. Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction. J Neurosci. 2007 Aug 15;27(33):8836-44. PMID: 17699665
Scott, L.J., Pierandrea, M., Upmanyu, R., Guan, W., Flickinger, M., Kong, X., Tozzi, F., Li, J., Burmeister, M., Absher, D., Thompson, R.C., Francks, C., Meng, F., Antoniades, A., Southwick, A., Schatzberg, A., Bunney, W., Barchas, J., Jones, E., Day, R., Matthews, K., McGuffin, P., Kennedy, J.L., Farmer, A., Vincent, J., Watson, S.J., Middleton, L., Myers, R.M., Roses, A., Akil, H., Burns, D., Boehnke, M.: Genome-wide association and meta-analysis of bipolar disorder in European ancestry samples. Proc. Natl. Acad. Sci. U.S.A. 106:18, 7501-7506, 2009. PMID: 19416921
Perez, J.A., Clinton, S.M., Turner, C.A., Watson, S.J., Akil, H.: A new role for FGF2 as an endogenous inhibitor of anxiety, J. Neuroscience. 2009 May 13;29(19):6379-87. PMID 19439615
Akil, H., Brenner, S., Kandel, E., Kendler, K. , King M-C, Scolnick, E., Watson, J.D., Zoghbi, H.Y. The Future of Psychiatric Research: Genomes and Neural Circuits. Science, (327) 26 March, 2010
Eren-Koçak E, Turner CA, Watson SJ, Akil H. Short Hairpin RNA Silencing of Endogenous Fibroblast Growth Factor 2 in Rat Hippocampus Increases Anxiety Behavior. Biol Psychiatry. 2011 Mar 15;69(6):534-40. PMID: 21215386
Flagel, S.B*, Clark, J.J* Robinson, T.E., Mayo,L, Czuj, A, Wilhuln I, Akers, C.A., Clinton, S.M., Phillips, P.E.M., Akil, H., A Selective Role for Dopamine in Stimulus-Reward Learning, Nature, 469(7328):53-7, 2011 PMID: 21150898
Akil H, Martone ME, Van Essen DC. Challenges and Opportunities in Mining Neuroscience Data, Science, 2011, Feb: 11:331 (6018): 708-12. PMID: 21311009
Turner CA, Clinton SM, Thompson RC, Watson SJ Jr, Akil H. Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulvulnerable animals. Proc Natl Acad Sci U S A. 2011 May 10;108(19):8021-5. Epub 2011 Apr 25.
Turner CA, Watson SJ, Akil H. The fibroblast growth factor family: Neuromodulation of affective behavior. Neuron, 2012. Oct 4;76(1):160-74 PMCID:PMC3476848.
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 Jr, Akil H, Bunney WE. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9950-5.
Chaudhury S, Aurbach EL, Sharma V, Blandino Jr. P, Turner CA, Watson SJ, Akil H. FGF2 is a Target and a Trigger of Epigenetic Mechanisms Associated with Differences in Emotionality: Partnership with H3K9me3, Proc. Natl. Acad. Sci. U.S.A. 2014,12;111(32):11834-9
Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat Neurosci. 2015 Feb;18(2):199-209.
Aurbach EL, Inui EG, Turner CA, Hagenauer MH, Prater KE, Li JZ, Absher D, Shah N, Blandino P Jr, Bunney WE, Myers RM, Barchas JD, Schatzberg AF, Watson SJ Jr, Akil H. Fibroblast growth factor 9 is a novel modulator of negative affect.Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11953-8. PMID:26351673
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