The objective of this grant is to contribute to a better understanding of the regulation of mood under normal circumstances as well as the mechanisms underlying depression and antidepressant treatment. For the first 14 years of the grant, our focus was quite broad. We contributed to an appreciation of the role of several classes of signaling proteins in these phenomena. Over the past 4 years, we have greatly focused the grant on one of these signaling proteins, namely, the transcription factor DFosB. DFosB, a member of the Fos family, is induced in a region- and cell type-specific manner in brain by many types of chronic stimuli, including chronic consumption of natural rewards, chronic stress, or chronic antidepressant treatments. Unlike all other Fos family proteins, which exhibit a very short half-life, DFosB is a highly stable protein. As a result, once it accumulates in brain it can persist for weeks or months and thereby mediate relatively long-lived plasticity to the original chronic stimulus. This grant focuses on the consequences of DFosB induction in the nucleus accumbens (NAc) and certain other brain areas. In the NAc, chronic exposure to stress or antidepressants induces DFosB in both dynorphin+ and enkephalin+ neurons, while natural rewards do so selectively in dynorphin+ neurons. Using a combination of inducible bitransgenic mice and viral-mediated gene transfer to overexpress DFosB or a dominant negative antagonist, we have evidence that DFosB induction in this brain region mediates an "antidepressant-like" response in the social defeat, forced swim, and learned helplessness tests. DFosB mediates a similar antidepressant-like effect in other brain areas of interest. Work is currently underway to better understand the behavioral phenotype mediated by DFosB in these regions in models of natural rewards, stress, and antidepressant responses. As a transcription factor, DFosB presumably produces these behavioral effects through the regulation of other genes. Accordingly, a related major goal of this grant is to identify putative target genes for DFosB in these brain regions, including the use of chromatin remodeling assays to help identify DFosB targets as well as to provide detailed insight into the underlying molecular mechanisms involved. Our work to date thus suggests that induction of DFosB in the NAc and other brain areas may represent a positive adaptation to stress, which enhances motivation for natural rewards and contributes to an individual's ability to actively cope with adverse circumstances. In some of these regions, where DFosB is also induced by antidepressants, the protein may contribute to the therapeutic mechanism of action of these treatments. The proposed studies will further evaluate these hypotheses and improve our understanding of stress and antidepressant responses.

Public Health Relevance

The objective of this grant is to contribute to a better understanding of the regulation of mood under normal circumstances as well as the mechanisms underlying depression and antidepressant treatment. The grant focuses on the role of the transcription factor, DFosB, in depression models and in antidepressant action. Given that only half of all depressed individuals are fully treated with available medications, the improved knowledge of depression and antidepressant mechanisms derived from this project promises to lead to the development of more effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH051399-21
Application #
8265899
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1994-09-30
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
21
Fiscal Year
2012
Total Cost
$413,789
Indirect Cost
$166,289
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel et al. (2016) Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles. Biol Psychiatry :
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Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel et al. (2016) Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility. Neuron 90:969-83
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Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100
Vialou, Vincent; Thibault, Mackenzie; Kaska, Sophia et al. (2015) Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress. Neuropharmacology 99:28-37

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