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: 4.24). 11/2010; 336(1-2):2-5. DOI: 10.1016/j.mce.2010.11.011
Source: PubMed

ABSTRACT 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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    • "Whilemanystudieshaveexaminedwhetherchangesin circulatingGCsalterBDNFexpression,relativelyafew reportshaveexploredthecontributionoftheGC receptorsMRandGRtotheregulationofBDNF(Chao andMcEwen,1994;Hanssonetal.,2000;Kinoetal., 2010).Pharmacologicalandgeneticstrategies(reviewed inKolberetal.,2008;Arnettetal.,2011)targetingtheGC receptors,providepowerfultoolstoaddressthecontributionofGCreceptorstoBDNFregulation .Invitro pharmacologicalstudiesdemonstratedthataldosterone whichhasahigheraffinityfortheMRreceptorincreased BdnfmRNAandproteinlevelsinculturedcortical neurons,whereasdexamethasonewhichhasahigher affinityforGRevokedadeclineinBdnfmRNAand protein(Kinoetal.,2010).TheroleofGRsandMRsin theregulationofBDNFhasalsobeenexaminedina studywhereADXanimalsreceivedcorticosterone, aldosteroneorRU28362,thesyntheticGRagonist(Chao andMcEwen,1994).Thesestudies(ChaoandMcEwen, 1994;Hanssonetal.,2000;Kinoetal.,2010)indicate thatligandsforbothMRandGRregulatehippocampal BDNFexpression.However,treatmentwiththeMR antagonistsspironolactone(McCullersandHerman, 1998)oreplerenone(Hlavacovaetal.,2010)doesnot "
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    • "This CRF-NE loop between CeA and LC may contribute to sensitization of stress responses following multiple stress exposures (Koob, 1999) and is likely dysregulated during the transition to alcohol dependence (Funk et al., 2006; Gilpin and Koob, 2010; Walker et al., 2008). Furthermore, glucocorticoids act at receptors in the CeA to regulate CRF synthesis following fear conditioning (Arnett et al., 2011), and glucocorticoids in BLA positively modulate β-adrenoceptor-mediated consolidation of fear memories via seemingly direct interactions with CRF 1 Rs and α 1 -adrenoceptors on the post-synaptic terminal (Roozendaal et al., 2008). "
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    ABSTRACT: The central amygdala (CeA) is uniquely situated to function as an interface between stress- and addiction-related processes. This brain region has long been attributed an important role in aversive (e.g., fear) conditioning, as well as the negative emotional states that define alcohol dependence and withdrawal. The CeA is the major output region of the amygdala and receives complex inputs from other amygdaloid nuclei as well as regions that integrate sensory information from the external environment (e.g., thalamus, cortex). The CeA is functionally and anatomically divided into lateral and medial subdivisions that themselves are interconnected and populated by inhibitory interneurons and projections neurons. Neuropeptides are highly expressed in the CeA, particularly in the lateral subdivision, and the role of many of these peptides in regulating anxiety- and alcohol-related behaviors has been localized to the CeA. This review focuses on two of these peptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY), that exhibit a high degree of neuroanatomical overlap (e.g., in CeA) and largely opposite behavioral profiles (e.g., in regulating anxiety- and alcohol-related behavior). CRF and NPY systems in the CeA appear to be recruited and/or up-regulated during the transition to alcohol dependence. These and other neuropeptides may converge on GABA synapses in CeA to control projection neurons and downstream effector regions, thereby translating negative affective states into anxiety-like behavior and excessive alcohol consumption.
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    • "Preclinical research has shown that the response of basolateral amygdala neurons to corticosterone is mediated by GR (Karst et al., 2010; Arnett et al., 2011; Groeneweg et al., 2011). Whether GR number in PBMCs is a reliable reflection of GR number in the brain has not been studied extensively. "
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    ABSTRACT: Individuals who are exposed to a traumatic event are at increased risk of developing psychiatric disorders such as posttraumatic stress disorder (PTSD). Studies have shown that increased amygdala activity is frequently found in patients with PTSD. In addition, pre-trauma glucocorticoid receptor (GR) number in peripheral blood mononuclear cells (PBMCs) has been found to be a significant predictor for the development of PTSD symptoms. Research in rodents has shown that the response of basolateral amygdala neurons to corticosterone is mediated by GR. However, to the best of our knowledge, no previous study has investigated GR number in PBMCs and amygdala function in humans. To investigate whether peripheral GR number is related to amygdala functioning, we assessed GR number in PBMCs of healthy soldiers before their deployment to Afghanistan. Amygdala functioning was assessed with fMRI before and after deployment. We found that pre-deployment GR number was significantly negatively correlated to pre-deployment amygdala activity. More importantly, pre-deployment GR number predicted the increase in amygdala activity by deployment. Our results demonstrate that peripheral GR number is associated with amygdala functioning and predicts the increase in amygdala activity following military deployment in healthy individuals who did not develop PTSD. It is uncertain how this relationship is mediated mechanistically, but future studies should examine the relation of GR and amygdala activity to determine whether this is part of a common pathway leading to increased vulnerability to stress-related disorders.
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