Challis, Collin
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Publication HDAC6 Regulates Glucocorticoid Receptor Signaling in Serotonin Pathways with Critical Impact on Stress Resilience(2012-03-28) Teegarden, Sarah L; Challis, Collin; Jochems, Jeanine; Espallergues, Julie; Veerakumar, Avin; Boulden, Janette; Hahn, Chang-Gyu; Lucki, Irwin; Chan, Michael; Beck, Sheryl G; Petersen, Tess; Deneris, Evan; Matthias, Patrick; Berton, OlivierGenetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90–GR protein–protein interactions, as well as hormone- and stress-induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre-driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open-field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for proresilience and antidepressant interventions through regulation of the Hsp90–GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones.Publication Top-Down Control of Serotonergic Systems in Socioaffective Choices and Depression-Like Behaviors(2014-01-01) Challis, CollinRegulation of social behaviors is necessary to achieve social inclusion, establish relationships and sustain those relationships through adversity. Impairments in socio-emotional function and competence are prominent and debilitating features of major depression, yet are not traditionally recognized as cardinal symptoms of the disease. However, these deficits often persist in patients whose other mood symptoms have remitted and can predict risk of relapse, indicating an important role as a vulnerability factor. Understanding the neurobiology of socioaffective dysfunction in depression is thus important for determining the pathology of the disorder and developing effective treatments. Human imaging studies of depressive patients have consistently reported abnormal activity in the ventromedial prefrontal cortex (vmPFC), an area important for emotional processing and social cognition. Tracing studies in animals and tractography in humans have shown that the dorsal raphe nucleus (DRN) is a major projection target of the vmPFC. The DRN contains the most serotonin (5-HT) producing neurons in the brain and its output has been shown to regulate behaviors along an affiliative-agonistic axis, however it is neuronally heterogeneous. This thesis investigated the cytoarchitecture of the vmPFC-DRN microcircuit and its relevance to socioaffective behaviors using genetic mapping, whole cell electrophysiology and optogenetics. I showed that GABAergic neurons, which are the primary non-serotonergic neuronal population in the DRN, mediated top-down projections from the vmPFC onto mood-regulating 5-HT neurons and demonstrated the relevance of this pathway in mediating socioaffective decisions using the chronic social defeat stress (CSDS) paradigm. In addition, I used deep brain stimulation of the vmPFC as an antidepressant model to show that therapeutic response may rely on restoring the excitatory/inhibitory balance of inputs to 5-HT neurons. Together, these results will provide a better understanding of socioaffective circuitry and could lead to the development of more effective and efficient strategies to treat mood disorders.