Earlier versions of this R01 grant focused on the role of transcription factors in mediating depression-related behavioral abnormalities in animal models. We were the first to implicate CREB in stress models and antidepressant responses. More recently, over the past 10 years, we have similarly defined the actions of delta-FosB in determining an animal's susceptibility vs. resilience to chronic stress. We have also used a range of genome-wide assays to define the target genes of these transcription factors. These evolving datasets suggest the central involvement of glutamatergic neurotransmission within the nucleus accumbens (NAc), a key brain reward region, in governing these distinct responses to stress. Thus, for this competitive renewal application, we propose to utilize this novel insight to define how altered glutamatergic signaling in NAc controls stress susceptibility vs. resilience. We use state-of-the-art optogenetic tools to activate or suppress specific glutamatergic inputs to NAc and investigate the effect of these manipulations on both the development of stress-related behavioral abnormalities as well as their expression .We present robust preliminary evidence that different glutamatergic inputs alter stress vulnerability in very different ways. For example, acute optogenetic activation of the prelimbic prefrontal cortex (PFC) promotes resilience, while acute activation of the ventral subiculum (vSUB) or medial thalamus promotes susceptibility. As another example, induction of long-term depression (LTD) specifically at vSUB synapses dramatically enhances resilience, while LTD at infralimbic PFC synapses may enhance susceptibility. These data set the stage for a uniquely comprehensive analysis of how different glutamatergic inputs to NAc differentially control stress responses. The second part of this R01 investigates the role of several prominent target genes, arising from our genome-wide assays and not previously implicated in stress responses, in mediating post- and presynaptic forms of glutamatergic plasticity in NAc. Together, the proposed studies will shed fundamental light on circuit-level mechanisms in stress susceptibility and resilience, and validate a series of new targets for the development of better treatments for depression and other stress-related disorders.
We believe that the best way to ultimately develop improved diagnostic tests and treatments for depression and other stress-related illnesses is through a better understanding of the basic biological mechanisms involved. This R01 grant renewal will contribute importantly to this goal by defining novel circuit mechanisms, and their molecular underpinnings, involved in depression-related phenomena.
| 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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