Behavioral insights from mouse models of forebrain- and amygdala-specific glucocorticoid receptor genetic disruption

Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, United States.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 11/2010; 336(1-2):2-5. DOI: 10.1016/j.mce.2010.11.011
Source: PubMed


Genetic modulation of glucocorticoid receptor (GR) function in the brain using transgenic and gene knockout mice has yielded important insights into many aspects of GR effects on behavior and neuroendocrine responses, but significant limitations regarding interpretation of region-specific and temporal requirements remain. Here, we summarize the behavioral phenotype associated with two knockout mouse models to define the role of GRs specifically within the forebrain and amygdala. We report that forebrain-specific GR knockout mice exhibit impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased despair- and anxiety-like behaviors. In addition, mice with a disruption of GR specifically within the central nucleus of the amygdala (CeA) are deficient in conditioned fear behavior. Overall, these models serve as beneficial tools to better understand the biology of GR signaling in the normal stress response and in mood disorders.

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Available from: Melinda Arnett, Sep 26, 2014
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    • "Interestingly, previous studies on adrenalectomised rats demonstrated a significant up-regulation in Tac1 gene expression in the amygdala of animals treated with corticosterone (Pompei et al., 1995). Glucocorticoids influence gene expression within the brain by acting as ligands to the GR and mineralocorticoid receptors (MR) that subsequently bind DNA to modulate gene expression (Arnett et al., 2010). GR is expressed in the central amygdala but has also been reported in lateral amygdala (Johnson et al., 2005; Prager et al., 2011; Reul and de Kloet, 1985). "
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    • "GCs not only act peripherally to maintain energy homeostasis but also feedback to the CNS to modulate HPA activity and the emotional and behavioral effects of stress (Herman et al., 2003). GCs are known to target GC receptors [including mineralocorticoid (MC) receptors] in midbrain and limbic circuits that regulate reward and emotional processes (Arnett et al., 2011; Solomon et al., 2012; Wang et al., 2013). Repeated administration of corticosterone to rodents is reported to produce depressive-like behavior (Kalynchuk et al., 2004; Gregus et al., 2005) whereas GC receptor overexpression in the forebrain increases depressive-like behavior in the forced swim test and anxiety-like behavior in the elevated plus maze task (Wei et al., 2004). "
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    • "Based on our microarray data, such homeostatic cues may include glucocorticoid signaling, a stress-response system altered in mood disorders [41], [42] and previously implicated in chromatin-mediated neuroplasticity changes underlying mood-related behaviors [43]. Lead examples for this model based on the most significant Cpd-60-induced expression changes include Sgk1 and Sult1a1, both induced by glucocorticoid signaling [44], [45]. "
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    ABSTRACT: Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary - albeit often ineffective - treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.
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