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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    059—Mood Disorders: Animal Models I

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    59.03: β-catenin mediates the development of behavioral resilience

    Location: Halls B-H

    *C. M. DIAS1, J. FENG1, H. SUN1, M. MAZEI-ROBISON1, D. DAMEZ-WERNO1, K. SCOBIE1, N.-Y. SHAO1, P. KENNEDY1, V. VIALOU1, R. BAGOT1, M. CAHILL1, D. FERGUSON1, S. GHOSE2, C. TAMMINGA2, R. NEVE3, L. SHEN1, E. J. NESTLER1;
    1Neurosci., Mount Sinai Sch. of Med., New York, NY; 2UT Southwestern, Dallas, TX; 3McGovern Brain Inst. at MIT, Cambridge, MA

    Abstract Body: β-catenin is a multi-functional protein that plays an important role in the mature central nervous system, and has been implicated in several neurological and psychiatric diseases. However, to date there has been a lack of evidence directly demonstrating the transcriptional role of β-catenin in the context of psychiatric illness. Here we show that chronic social defeat stress, a mouse model of depression, regulates the transcriptional activity of β-catenin in the nucleus accumbens (NAc), a key brain reward region. There is a relative reduction in β-catenin transcriptional activity in D2 medium spiny neurons (MSNs) but not D1 MSNs, in susceptible versus resilient mice after defeat stress, suggesting cell-type specific regulation of this signaling pathway. Furthermore, over-expression of β-catenin in the NAc promotes the development of resilience after defeat stress, an effect mimicked by specifically over-expressing β-catenin in D2 but not D1 MSNs. β-catenin over-expression in NAc also mediates baseline antidepressant and anxiolytic responses, while blocking β-catenin signaling in this brain region promotes susceptibility to stress. We performed ChIP-Seq for β-catenin from NAc of susceptible and resilient mice who had undergone chronic social defeat stress and demonstrated global genome-wide regulation of β-catenin-DNA interactions. We identified Dicer as a novel target gene from this dataset and found that the ability of β-catenin to induce behavioral resilience is attenuated in the absence of Dicer from the NAc. We posit that global alterations in miRNA biogenesis via Dicer are critical to the antidepressant effects of β-catenin. Overall, we show that β-catenin is a critical regulator of the development of behavioral resilience, likely acting primarily in D2 MSNs. This work presents a foundation for the development of novel, more precise therapeutic targets for the treatment of depression.

    Lay Language Summary: Depression is a chronic, debilitating disorder that poses an enormous socio-economic burden on the US and the world. Despite decades of research in the field, the complexity of the human brain has impeded attempts to derive a comprehensive understanding of the pathophysiology of this disorder. One important aspect in understanding depression is to determine what makes some people ‘resilient’ to the development of depression in the face of serious life stressors and trauma. For example, it is known that individuals who are resilient often exhibit characteristic traits, such as a positive outlook, an ability to overcome challenging situations, and cognitive flexibility to reframe negative experiences in a more constructive light. However, what makes some individuals able to do this, while others remain vulnerable to stressful life events?
    Our lab uses a psychosocial, chronic model of depression in mice, chronic social defeat stress (CSDS) to study the molecular biology of this precise question. Our research has demonstrated that changes in molecular signaling within a key brain reward region, the nucleus accumbens (NAc), appear to be critical in the development of behavioral resilience. Specifically, we study the multi-functional protein β- catenin, which, among other roles, is an important transcription factor, i.e. a molecule that turns on a host of other genes in response to certain stimuli. We have found that there is suppression of the activity of this protein in the NAc in human post-mortem depressed patients, as well as in the NAc of mice who were susceptible to stress in our CSDS model of depression. Conversely, resilient mice had upregulation of the activity of this protein in this brain region. The nucleus accumbens is composed primarily of two distinct neuronal subtypes named D1 and D2 medium spiny neurons that have opposing yet synergistic functioning. We found that the regulation of β-catenin was primarily occurring in the D2 subtype, whose role in the NAc has been specifically implicated in behavioral flexibility. We found further that the prefrontal cortex, a brain region important in executive function, was specifically critical in the modulation of the activity of β-catenin in the NAc. When we over-expressed β-catenin in the NAc of mice using viral vectors, we found baseline antidepressant and anxiolytic effects in a variety of behavioral assays. β-catenin overexpression also mediated pro-resilient effects in our social defeat model. Blocking β-catenin function in the NAc either with viral vectors or with transgenic tools promoted susceptibility to stress, indicating that this molecule is both necessary and sufficient for the development of behavioral resilience. We further found that overexpressing β-catenin only in the D2 subtype, but not the D1 neuronal subtype, mimicked the anti-depressant effects seen earlier, suggesting that restoring the decreased activity of β-catenin in D2 neurons mediated the anti-depressant behavioral effects. We then studied potential targets of β-catenin on the genome-wide level and uncovered a novel connection between β-catenin and Dicer. Dicer is a protein that is critical in miRNA biogenesis; miRNA’s are small RNA’s that inhibit gene expression. We demonstrate novel molecular and behavioral connections between β-catenin and Dicer and hypothesize that Dicer is a critical component of the transcriptional arsenal that β-catenin activates in the NAc to mediate adaptive, pro-resilient behavioral responses.
    Our work represents an in-depth characterization of a molecule critical to the etiology of behavioral resilience and furthermore presents opportunities for more precise pharmaco-therapeutic development in the battle against depression.