Recapitulation and Reversal of a Persistent Depression‐like Syndrome in Rodents

Abstract

Alterations in multiple biological functions, such as transcription factor activity, are implicated in the neurobiology of depression based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that capture the protracted feelings of anhedonia and helplessness that typify depression. In order to address this issue, the authors developed protocols in rats and mice calling for chronic oral exposure to the stress-associated adrenal hormone, corticosterone (CORT), resulting in anhedonic-and helplessness-like behaviors that are persistent yet reversible by chronic antidepressant treatment. Prior CORT exposure also chronically influences molecular targets hypothesized to contribute to negative mood: One example is phosphorylation of cAMP Response Element Binding protein in the hippocampus and nucleus accumbens. Prior chronic CORT exposure provides an alternative method to chronic mild stress models of depression that is easily replicable and persists well beyond the CORT exposure period, thereby modeling the persistent depressive-like state in man. Keywordsstress; corticosterone; anhedonia; helplessness; CREB; hippocampus; nucleus accumbens; antidepressant Depression is a debilitating and chronic illness characterized by feelings of helplessness, anhedonia, and loss of motivation to perform even everyday tasks. Although the relationship between stress and Major Depressive Disorder (MDD) is incompletely understood, stressinduced cortisol release from the adrenal glands and subsequent activation of glucocorticoid receptors in brain (c.f., de Kloet, 2004) likely plays a crucial role, as stressful life events are potent factors that trigger, induce, or exacerbate major depressive episodes. While no stressinduced depression-like syndrome in rodents can fully recapitulate the human condition, a model that produces a persistent, varied behavioral sequela (including helplessness, anhedonia, and loss of sensitivity to reward) sensitive to chronic antidepressant treatment would be a major advance for understanding the neurobiology of depression (c.f., Willner et al., 1987Willner et al., , 2005.Correspondence: Jane Taylor, PhD, CT Mental Health Center, Ribicoff Labs, 34 Park St., New Haven, CT 06508, jane.taylor@yale.edu;. NOTE: All protocols using live animals must first be reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) or conform to governmental regulations regarding the care and use of laboratory animals.The authors declare they have no competing financial interests. NIH Public Access Author ManuscriptCurr Protoc Neurosci. Author manuscript; available in PMC 2010 October 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThis unit presents a depression model based on oral exposure to the stress hormone corticosterone (CORT) in its hemisuccinate form in rodents (also see Gourley et al., 2008; in press). The use of CORT hemisuccinate for oral administration provides an alternative to dissolving CORT in small amount...

Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

“…However, this is the first study to show decreased mGluR5 expression in the nucleus accumbens following CORT exposure, and this finding adds to the growing literature identifying neuroadaptations within this brain region as a consequence of CORT or repeated stressor exposure (Campioni et al, 2009;Gourley and Taylor, 2009;Lemos et al, 2012;Morales-Medina et al, 2009;Perrotti et al, 2004;Shoji and Mizoguchi, 2010;Tidey and Miczek, 1997). Importantly, the presence of CORT-induced neuroadaptations in mGluR5, as we show here, potentially has broad implications and may be relevant to better understanding some mental health disorders (ie, depression, post-traumatic stress disorder), specifically as chronic CORT exposure is commonly used to induce various behavioral aspects of these disorders (Ardayfio and Kim, 2006;Gourley and Taylor, 2009;Hache et al, 2012;Rainer et al, 2011). Further, this is especially relevant given that pharmacological manipulation of mGluR5 and other mGluRs is of interest as potential therapeutics for the treatment of neuropsychiatric disorders (Krystal et al, 2010;Witkin et al, 2007).…”

“…Corticosterone hemisuccinate (4-pregnen-11b, 21-DIOL-3, 20-DIONE 21-hemisuccinate; Steraloids, Newport, RI) was dissolved in tap water by addition of NaOH and neutralized with HCl, to a final pH of 7.0-7.4 (Besheer et al, 2012b;Besheer et al, 2013;Gourley and Taylor, 2009). 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB; Tocris) dose and pretreatment interval were chosen based on the literature (Clifton et al, 2013;Fowler et al, 2011;Gass and Olive, 2009;Stefani and Moghaddam, 2010).…”

Transient Downregulation of Dab1 Protein Levels during Development Leads to Behavioral and Structural Deficits: Relevance for Psychiatric Disorders

“…Adult mice (two to three months of age) were given corticosterone (Sigma) in their drinking water (25 mg/l) for 3 weeks, as previously described (Gourley and Taylor, 2009;Teixeira et al, 2011). Mice were tested 1 week after the end of treatment.…”

Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term Treatment with Fluoxetine in a Mouse Model of Anxiety/Depression Based on Repeated Corticosterone Administration

“…Alterations in multiple biological markers are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naive rodents (Gourley and Taylor, 2009). However, it seems more appropriate to perform pharmacological studies in animal models that exhibit hallmark characteristics of anxiety/depression.…”

“…Although UCMS has been efficiently used to assess antidepressant activity (Surget et al, 2009;Farley et al, 2010), it is notoriously difficult to reproduce consistently in rodents. An intriguing alternative may be to supply mice with exogenous corticosterone (David et al, 2009;Gourley and Taylor, 2009), a hormone produced in the adrenal glands in response to stress and found to be elevated in several animal models of depression and in depressed humans (Sterner and Kalynchuk, 2010). We have recently reported, in mice administered with corticosterone, some behavioral abnormalities that are indicative of anhedonia and hopelessness (David et al, 2009) and that mimic depressive symptoms observed in humans (Holsboer, 2000;Nemeroff and Vale, 2005).…”