The objective of this grant is to contribute to a better understanding of the regulation of mood and the mechanisms underlying depression and antidepressant treatments. For the first nine 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 year, we have greatly focused the grant on one of these signaling proteins, namely, the transcription factor DeltaFosB. DeltaFosB, a member of the Fos family, is induced in a region- and cell type-specific manner in brain by many types of chronic perturbations, including chronic stress and chronic antidepressant treatments. Unlike all other Fos family proteins, which exhibit a very short half-life, DeltaFosB 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 perturbation. This grant focuses on the consequences of DeltaFosB induction in four brain areas, the nucleus accumbens (NAc), ventral periaqueductal gray (vPAG), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA). In NAc, chronic stress induces DeltaFosB selectively in dynorphin+ neurons. Using a combination of inducible transgenic mice and viral mediated gene transfer to overexpress DeltaFosB or a dominant negative antagonist, we have evidence that stress induction of DeltaFosB in this brain region mediates an """"""""antidepressant-like"""""""" response to stress in the forced swim and learned helplessness tests. In the vPAG, chronic stress as well as chronic antidepressant treatments induce DeltaFosB primarily in substance P+ neurons, which also appears to mediate an antidepressant-like response. Work is currently underway to better understand the behavioral phenotype mediated by DeltaFosB in these two regions, as well as to establish the cellular localization and functional significance of DeltaFosB induction by stress or antidepressant treatments in the mPFC and BLA. As a transcription factor, DeltaFosB presumably produces these behavioral effects through the regulation of other genes. Accordingly, a related goal of this grant is to identify putative target genes for DeltaFosB in each of these brain regions. Our work to date thus suggests that induction of DeltaFosB, at least in the NAc and vPAG, may represent a positive adaptation to stress, which contributes to an individual's ability to actively cope with adverse circumstances. In the vPAG, where DeltaFosB is also induced by antidepressants, the protein may contribute to the mechanism of action of these treatments. The proposed studies will further evaluate these hypotheses, and explore the behavioral consequences of DeltaFosB induction in the mPFC and BLA. Together, the proposed research will improve our understanding of the ways in which the brain adapts to chronic stress and antidepressant treatments.
| Monteggia, Lisa M; Heimer, Hakon; Nestler, Eric J (2018) Meeting Report: Can We Make Animal Models of Human Mental Illness? Biol Psychiatry 84:542-545 |
| Muir, Jessie; Lorsch, Zachary S; Ramakrishnan, Charu et al. (2018) In Vivo Fiber Photometry Reveals Signature of Future Stress Susceptibility in Nucleus Accumbens. Neuropsychopharmacology 43:255-263 |
| Hamilton, Peter J; Burek, Dominika J; Lombroso, Sonia I et al. (2018) Cell-Type-Specific Epigenetic Editing at the Fosb Gene Controls Susceptibility to Social Defeat Stress. Neuropsychopharmacology 43:272-284 |
| Lorsch, Zachary S; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel et al. (2018) Estrogen receptor ? drives pro-resilient transcription in mouse models of depression. Nat Commun 9:1116 |
| Hultman, Rainbo; Ulrich, Kyle; Sachs, Benjamin D et al. (2018) Brain-wide Electrical Spatiotemporal Dynamics Encode Depression Vulnerability. Cell 173:166-180.e14 |
| Tan, Aaron; Costi, Sara; Morris, Laurel S et al. (2018) Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. Mol Psychiatry : |
| Kaufman, Joan; Wymbs, Nicholas F; Montalvo-Ortiz, Janitza L et al. (2018) Methylation in OTX2 and related genes, maltreatment, and depression in children. Neuropsychopharmacology 43:2204-2211 |
| Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Viral Expression of Epigenome Editing Tools in Rodent Brain Using Stereotaxic Surgery Techniques. Methods Mol Biol 1767:205-214 |
| Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Neuroepigenetic Editing. Methods Mol Biol 1767:113-136 |
| Akil, Huda; Gordon, Joshua; Hen, Rene et al. (2018) Treatment resistant depression: A multi-scale, systems biology approach. Neurosci Biobehav Rev 84:272-288 |
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