Application of a pharmacological transcriptome filter identifies a shortlist of mouse glucocorticoid receptor target genes associated with memory consolidation

Glucocorticoids regulate memory consolidation, facilitating long-term storage of relevant information to adequately respond to future stressors in similar conditions. This effect of glucocorticoids is well-established and is observed in multiple types of behaviour that depend on various brain regions. By and large, higher glucocorticoid levels strengthen event-related memory, while inhibition of glucocorticoid signalling impairs consolidation. The mechanism underlying this glucocorticoid effect remains unclear, but it likely involves the transcriptional effects of the glucocorticoid receptor (GR). We here used a powerful paradigm to investigate the transcriptional effects of GR in the dorsal hippocampus of mice after training in an auditory fear conditioning task, aiming to identify a shortlist of GR target genes associated to memory consolidation. Therefore, we utilized in an explorative study the properties of selective GR modulators (CORT108297 and CORT118335), alongside the endogenous agonist corticosterone and the classical GR antagonist RU486, to pinpoint GR-dependent transcriptional changes. First, we confirmed that glucocorticoids can modulate memory strength via GR activation. Subsequently, by assessing the specific effects of the available GR-ligands on memory strength, we established a pharmacological filter which we imposed on the hippocampal transcriptome data. This identified a manageable shortlist of eight genes by which glucocorticoids may modulate memory consolidation, warranting in-depth follow-up. Overall, we showcase the strength of the concept of pharmacological transcriptome filtering, which can be readily applied to other research topics with an established role of glucocorticoids

An emerging role for microglia in stress-effects on memory

Stressful experiences evoke, among others, a rapid increase in brain (nor)epinephrine (NE) levels and a slower increase in glucocorticoid hormones (GCs) in the brain. Microglia are key regulators of neuronal function and contain receptors for NE and GCs. These brain cells may therefore potentially be involved in modulating stress effects on neuronal function and learning and memory. In this review, we discuss that stress induces (1) an increase in microglial numbers as well as (2) a shift toward a pro-inflammatory profile. These microglia have (3) impaired crosstalk with neurons and (4) disrupted glutamate signaling. Moreover, microglial immune responses after stress (5) alter the kynurenine pathway through metabolites that impair glutamatergic transmission. All these effects could be involved in the impairments in memory and in synaptic plasticity caused by (prolonged) stress, implicating microglia as a potential novel target in stress-related memory impairments

Late glucocorticoid receptor antagonism normalizes the programming effects of brief and repeated periods of social isolation stress in adolescent rats

Social isolation stress (SIS) is one of the most commonly used stress paradigms to reproduce psychiatric-like disorders in rodents and it is generally conducted for several weeks from weaning to adulthood. However, the long-term effects of briefer periods of SIS only during early-adolescence, a critical phase for brain development, are less explored. The present study aims at investigating the programming effects induced by brief and repeated SIS at early-adolescence and the potential effectiveness of late glucocorticoid receptor (GR) antagonism in counteracting such SIS-induced alterations. Further, the neurobiological mechanisms underlying these effects were evaluated as well. Male Sprague-Dawley rats were subjected to two hours of SIS per day during early-adolescence from postnatal day (PND) 28 to PND 34. Adult animals stressed in early-adolescence and their relative control groups were intraperitoneally treated with the GR antagonist RU486 (30 mg/kg) or vehicle at PND 83, 85 and 87. Potential reversal of programming effects on behavioral reactivity was evaluated starting 1 week after treatment (PND 90). To investigate the neurobiological mechanisms underlying such effects, transcriptome analysis was performed within ventral and dorsal hippocampus. Our results demonstrated that brief and repeated periods of SIS during early-adolescence induced a reduction of time spent in the open arms, number of entries in the open arms and frequency of head-dippings in the elevated plus maze task, and an enhanced emotional reactivity in the acoustic startle response task, suggesting the development of anxious-like profile later in life. Strikingly, we found that treatment with RU486 at adulthood normalized such SIS-induced programming effects in rats tested 1 week after treatment. However, transcriptome analysis did not reveal significant alterations within ventral and dorsal hippocampus, indicating that gene expression in these two brain areas is not involved in the behavioral effects of SIS and treatment. Our data reveal that glucocorticoid stress hormones due to SIS exposure during early-adolescence induced effects on emotional reactivity which persist later in life and which are counteracted by late GR antagonism. These findings have a groundbreaking potential of introducing a promising therapeutic approach to treat and counteract the development of stress-related disorders long-after trauma. However, additional studies are needed to understand the neurobiological underpinnings of this process

Corticosteroid Action in the Brain: The Potential of Selective Receptor Modulation

Glucocorticoid hormones have important effects on brain function in the context of acute and chronic stress. Many of these are mediated by the glucocorticoid receptor (GR). GR has transcriptional activity which is highly context-specific and differs between tissues and even between cell types. The outcome of GR-mediated transcription depends on the interactome of associated coregulators. Selective GR modulators (SGRMs) are a class of GR ligands that can be used to activate only a subset of GR-coregulator interactions, thereby giving the possibility to induce a unique combination of agonistic and antagonistic GR properties. We describe SGRM action in animal models of brain function and pathology, and argue for their utility as molecular filters, to characterize context-specific GR interactome and transcriptional activity that are responsible for particular glucocorticoid-driven effects in cognitive processes such as memory consolidation. The ultimate objective of this approach is to identify molecular processes that are responsible for adaptive and maladaptive effects of glucocorticoids in the brain.</p