This lecture will summarize our research aimed at understanding the biology of mood disorders, including efforts at identifying genetic vulnerability factors and at characterizing the consequences of these illnesses on the brain. It will describe a combination of genome-wide association and candidate genetic studies, post-mortem gene expression profiling and downstream analyses in animal models. It will offer examples of how these “discovery approaches” can lead to unexpected insights into the molecular neurobiology of mood and emotions.

This lecture will also discuss the limitations of the strategies used to date given the unique challenges intrinsic to complex brain diseases, particularly mood disorders. It will end by proposing an integrated approach, termed “Circuit Neuromics”—a framework for meeting these challenges, and for discovering both the antecedents of dysregulated moods and the consequences of these disorders on brain function.

The research to be presented reflects collaborative work in the laboratories of H. Akil and S. J. Watson, as well as a broader team effort by members of an NIMH Conte Center and the Prizker Neuropsychiatric Research Consortium. Collaborators include Drs. J.D. Barchas, W.E. Bunney, E.G. Jones, R. M. Myers, A.F. Schatzberg, S.J. Watson and their colleagues.

Huda Akil is the Gardner Quarton Distinguished University Professor of Neuroscience and Psychiatry at the University of Michigan, and the co-Director of the Molecular and Behavioral Neuroscience Institute (MBNI). Dr. Akil has made seminal contributions to the understanding of the neurobiology of emotions, including pain, anxiety, depression and substance abuse. Early on, she focused on the role of the endorphins and their receptors in pain and stress responsiveness. She and her colleagues provided the first physiological evidence for a role of endorphins in the brain; and showed that endorphins are activated by stress and cause pain inhibition, a phenomenon they termed Stress-Induced Analgesia. She defined how the postranslational processing of opioid precursors is modulated by stress, and demonstrated the coordinate actions of the neuropeptide products on behavior. Her research group, in collaboration with Dr. Stanley Watson, characterized the anatomy of the opioid peptides and their receptors, cloned two types of opioid receptors and conducted structure-function analyses defining the molecular basis of high affinity and selectivity towards the endogenous ligands.

Dr. Akil has investigated the molecular and neural mechanisms underlying stress reactivity and their relation to anxiety and depression. She demonstrated that social defeat in rodents activates unique neural pathways that resemble those altered in human depression. She and her colleagues have focused on the role of the steroid stress hormone receptors in emotionality, demonstrating the involvement of the mineralocorticoid receptor in human depression. She and her collaborators have created transgenic mouse models that overexpresses either the mineralocorticoid receptor or the glucocorticoid receptor selectively in forebrain and studied the impact on anxiety and stress responses. They have shown that the glucocorticoid receptor over-expressor exhibits increased emotional lability and enhanced responsiveness to antidepressants, two features of bipolar (manic-depressive) illness.

Dr. Akil is one of the key investigators in a major research consortium using genomic tools to uncover the pattern of gene expression associated with major depression and bipolar illness in human postmortem brains. This team is currently conducting a genome-wide search for the allelic genetic variants involved in bipolar illness.

Dr. Akil’s scientific contributions have been recognized with numerous honors and awards. These include the Pacesetter Award from the National Institute on Drug Abuse (NIDA) in 1993, and with Dr. Stanley Watson, the Pasarow Award for Neuroscience Research in 1994. In 1998, she received the Sachar Award from Columbia University and the Bristol Myers Squibb Unrestricted Research Funds Award. Dr. Akil is the past President of the American College of Neuropsychopharmacology (1998) and the past President of the Society for Neuroscience (2004). She was elected as a Fellow of the American Association for the Advancement of Science in 2000 and to the American Academy of Arts and Sciences in 2004. In 1994, she was elected to the membership of the Institute of Medicine (IOM) of the National Academy of Science and currently serves on its Council.

More information available at
http://www.mbni.med.umich.edu/mbni/faculty/akil/akil.html

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomed