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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    ABSTRACT: Expression or introduction the neuropeptide substance-P (SP; encoded by the TAC1 gene in humans and Tac1 in rodents) in the amygdala induces anxiety related behaviour in rodents. In addition, pharmacological antagonism of the main receptor of SP in humans; NK1, is anxiolytic. In the current study we show that the Tac1 locus is up-regulated in primary rat amygdala neurones in response to activation of the glucocorticoid receptor (GR); a classic component of the stress response. Using a combination of bioinformatics, electrophoretic mobility shift assays (EMSA) and reporter plasmid magnetofection into rat primary amygdala neurones we identified a highly conserved GR response sequence (2GR) in the human TAC1 promoter that binds GR in response to dexamethasone (Dex) or forskolin. We also identified a second GR binding site in the human promoter that was polymorphic and whose T-allele is only found in Japanese and Chinese populations. We present evidence that the T-allele of SNPGR increases the activity of the TAC1 promoter through de-sequestration or de-repression of 2GR. The identification of Dex/forskolin response elements in the TAC1 promoter in amygdala neurones suggests a possible link in the chain of molecular events connecting GR activation and anxiety. In addition, the discovery of a SNP which can alter this response may have implications for our understanding of the role of regulatory variation in susceptibility to stress in specific populations.
    Psychoneuroendocrinology 09/2014; 47(100). DOI:10.1016/j.psyneuen.2014.04.017 · 4.94 Impact Factor
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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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    ABSTRACT: Obesity markedly increases the odds of developing depression. Depressed mood not only impairs motivation, quality of life and overall functioning but also increases the risks of obesity complications. Abdominal obesity is a better predictor of depression and anxiety risk than overall adipose mass. A growing amount of research suggests that metabolic abnormalities stemming from central obesity that lead to metabolic disease may also be responsible for the increased incidence of depression in obesity. As reviewed here, a higher mass of dysfunctional adipose tissue is associated with several metabolic disturbances that are either directly or indirectly implicated in the control of emotions and mood. To better comprehend the development of depression in obesity, this review pulls together select findings addressing the link between adiposity, diet and negative emotional states and discusses the evidence that alterations in glucocorticoids, adipose-derived hormones, insulin and inflammatory signaling that are characteristic of central obesity may be involved.
    Frontiers in Neuroscience 10/2013; 7(7):177. DOI:10.3389/fnins.2013.00177 · 3.66 Impact Factor
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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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