Abstract
Stress elicits the release of glucocorticoids (GCs) that regulate energy metabolism and play a role in emotional memory. Astrocytes express glucocorticoid receptors (GR), but their contribution to cognitive effects of GC’s action in the brain is unknown. To address this question, we studied how astrocyte-specific elimination of GR affects animal behavior known to be regulated by stress. Mice with astrocyte-specific ablation of GR presented impaired aversive memory expression in two different paradigms of Pavlovian learning: contextual fear conditioning and conditioned place aversion. These mice also displayed compromised regulation of genes encoding key elements of the glucose metabolism pathway upon GR stimulation. In particular, we identified that the glial, but not the neuronal isoform of a crucial stress-response molecule, Sgk1, undergoes GR-dependent regulation in vivo and demonstrated the involvement of SGK1 in regulation of glucose uptake in astrocytes. Together, our results reveal astrocytes as a central element in GC-dependent formation of aversive memory and suggest their relevance for stress-induced alteration of brain glucose metabolism. Consequently, astrocytes should be considered as a cellular target of therapies of stress-induced brain diseases.
Highlights
Stressful events leave emotional memory traces that enable adaptation of the animal to novel conditions[1,2]
glucocorticoid hormones (GCs) exert their action through their glucocorticoid receptors (GR)[6,7,8,9], which are uniformly distributed across cell types and regions of the central nervous system (CNS) and which regulate gene transcription[10,11]
In our previous work[26] we showed that GR activation in astrocytes leads to upregulation of two protein kinases known to regulate metabolism, namely the pyruvate dehydrogenase kinase-4 (PDK4) that controls entering of glucose into the citric acid cycle and serum and glucocorticoid-regulated kinase[1] (SGK1), a protein associated with post-traumatic stress disorder (PTSD) and depression[31]
Summary
Stressful events leave emotional memory traces that enable adaptation of the animal to novel conditions[1,2]. Emotional memories persist longer than memories of neutral events and rely on the interaction between several brain regions, including hippocampus and amygdala[3]. The exposure to stress may turn into disease, for example post-traumatic stress disorder (PTSD) or depression[1,2,3]. GCs exert their action through their glucocorticoid receptors (GR)[6,7,8,9], which are uniformly distributed across cell types and regions of the central nervous system (CNS) and which regulate gene transcription[10,11]. Detailed understanding of how GR contributes to stress-induced brain dysfunction may lead to more successful therapeutic strategies for stress-induced disorders
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