Viral vector-mediated blockade of the endocrine stress–response modulates non-spatial memory

Abstract

Stress results in the release of glucocorticoids (GCs) which, at high levels, impair hippocampusdependent tasks. Estrogen is neurotrophic and can rescue stress-induced memory impairments. Here we report the use of a viral-vector to overexpress a chimeric gene (ER/GR) that converts the deleterious effects of glucocorticoids into beneficial estrogenic effects. A short immobilization stress regimen was sufficient to impair non-spatial memory. In contrast, viral vector-mediated overexpression of ER/GR in the dentate gyrus of the hippocampus protected against stress-induced impairments of non-spatial memory. These data add to the growing evidence that increasing estrogenic signaling can protect against the impairing effects of stress on non-spatial memory.Hippocampal memory is sensitive to glucocorticoids (GCs, the adrenal steroids secreted during stress) in an inverted-U manner, such that low to moderate GC concentrations enhance hippocampal function, whereas abnormally low or the high levels associated with major stressors impair function [1,7]. In contrast to these detrimental effects of GCs, systemic and intrahippocampal estradiol administration can enhance performance in males and females in spatial and non-spatial memory tasks [8,9,[43][44][45]. Moreover, estrogen rescues both spatial and non-spatial memory from stress-induced learning impairments [20,21].Here we report a viral vector gene delivery strategy to express a chimeric receptor (ER/GR) that converts the deleterious effects of GCs into protective estrogenic effects. ER/GR is a modular chimeric gene that consists of the C-terminal hormone-binding domain of the glucocorticoid receptor and the N-terminal DNA-binding domain of the primary human estrogen receptor ERα [6,2]. ER/GR, when expressed, has the dual effects of competing with endogenous GR for GCs and converting GR-mediated signaling into neurotrophic ER responses [6]. In this study, we assessed if expression of ER/GR in the dentate gyrus could block the disruptive effects of stress on non-spatial memory. The construction of the ER/GR amplicon vector has been previously described [6]. Briefly, for stereotaxic infusion of vector, rats were anesthetized with 1ml/kg of a mixture consisting of 100 mg/kg ketamine, 10 mg/kg acepromazine, and 100 mg/kg xylazine. ER/GR or a control vector, expressing only a reporter gene GFP, were infused using a Hamilton syringe (Hamilton Company, Reno, NV) with a 28-gauge needle (1 ul over a 5 min period with a titer of 1× l0^6) dorsal to the apex of the dentate gyrus (DG) (coordinates: anteroposterior, 4 mm from bregma; mediolateral, 3.00 from midline;

Enhancement of Stress Resilience Through Histone Deacetylase 6–Mediated Regulation of Glucocorticoid Receptor Chaperone Dynamics

“…The glucocorticoid receptor (GR) and several components of its multiprotein chaperone complex have been implicated as a point of convergence for genetic, epigenetic and environmental factors shaping stress vulnerability (5–9). Converging data from psychiatric genetics and animal studies indicate that mechanisms affecting the stoichiometry and interactions of proteins within the GR chaperone heterocomplex profoundly influence the physiology of the hypothalamic-pituitary-adrenal (HPA) axis (10–12) as well as stress coping (13–18). However, how molecular regulation of GR chaperone dynamics translates into emergent neurobehavioral traits defining vulnerability or resilience is not well understood.…”

Suppression of sex behavior by kappa opiates and stress steroids occurs via independent neuroendocrine pathways

“…While glucocorticoids (stress-steroids) are instrumental in the chronic disease states developed after experiencing prolonged stress, they also initiate rapid behavioral responses to direct threats or acutely stressful situations (Breuner et al, 1998;Coddington et al, 2007;Moore and Miller, 1984). A majority of the neuroendocrine research into stress-steroid effects has focused on long-term genomic effects (Akama and McEwen, 2005;Carrasco and Van de Kar, 2003;Ferguson et al, 2008;Ferguson and Sapolsky, 2007;Kaufer et al, 2004;Sapolsky, 2000). However, the neuroendocrine regulation of rapid behavioral/neuronal responses to immediate threats is not yet well understood.…”

Estrogen and Environmental Enrichment Differentially Affect Neurogenesis, Dendritic Spine Immunolabeling and Synaptogenesis in the Hippocampus of Young and Reproductively Senescent Female Rats

“…As mentioned above, approximately one-quarter of the people with Alzheimer disease have cardiovascular disease, and another quarter have diabetes [2]. Therefore, while the positive effects of certain steroid hormones on memory may be due to their direct effects on the nervous system, the increase in activity [36], along with the cardiovascular protective effects of steroids [7,36], may also play a role in sustaining improvements in memory function by maintaining blood flow to the brain, and enhancing the metabolic activity of cells in the brain, which makes them less sensitive to the activation of pathways involved in apoptosis and necrosis [37][38][39]. Previous studies have demonstrated that when there is a reduction in glucose availability to the central nervous system, any challenge (i.e., metabolic, disease related, stress-induced etc.)…”

“…Previous studies have demonstrated that when there is a reduction in glucose availability to the central nervous system, any challenge (i.e., metabolic, disease related, stress-induced etc.) is exacerbated [37][38][39][40]. Studies have demonstrated that E2 treatment reduces the damage that occurs as a result of a stroke [6,40,41].…”

“…Studies have demonstrated that E2 treatment reduces the damage that occurs as a result of a stroke [6,40,41]. The effects of E2 treatment may be due to the maintenance of neurons in the hippocampus, improved blood flow and vascularization in the presence of E2, the maintained supply of glucose to the affected brain region, and the fact that E2 provides protection against a number of neural insults [6,[38][39][40][41]. The current study examined the effects E2, after an acute exposure (24-72 h).…”