Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes

Meijer, Onno C.; Buurstede, Jacobus C; Viho, Eva M.G.; Amaya, Jorge Miguel; Koning, Anne‐Sophie C. A. M.; Meulen, Matty Van der; Weert, Lisa T. C. M. van; Paul, Susana N.; Kroon, Jan; Koorneef, Lisa L

doi:10.1111/jne.13213

Cited by 20 publications

(10 citation statements)

References 135 publications

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“…The widespread molecular changes induced in the brain by an acute stress exposure (Stankiewicz et al 2015; von Ziegler et al 2022; Floriou-Servou et al 2018; Mifsud et al 2021) are part of a healthy stress response, and their dysregulation is often a hallmark of neuropsychiatric disorders (Girgenti, Pothula, and Newton 2021; Rubin, Gray, and McEwen 2014). To date, the contribution of corticosteroid signaling to stress-induced transcriptional changes has been well characterized (Mifsud et al 2021; Gray et al 2013; Meijer et al 2022), yet the contribution of other stress-mediators remains unexplored. Here, we extensively characterize the contribution of noradrenergic signaling to the transcriptomic response in the hippocampus during stress.…”

Section: Discussionmentioning

confidence: 99%

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Privitera

Ziegler

Floriou-Servou

et al. 2023

Preprint

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Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here we combine RNA-sequencing with selective pharmacological, chemogenetic and optogenetic manipulations to isolate the contribution of the locus coeruleus - noradrenaline (LN-NA) system to the acute stress response. We reveal that NA-release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC mediated hippocampal function, and offer new molecular targets for understanding LC function in health and disease.

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Section: Discussionmentioning

confidence: 99%

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Privitera

Ziegler

Floriou-Servou

et al. 2023

Preprint

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“…TF target analysis showed several active TFs in FS-stressed animals immediately after stress; therefore, we tested the protein expression of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), which are directly activated by corticosterone—the main stress hormone [ 28 ]. We observed no changes in GR ( Figure 4 I) and MR ( Figure 4 K) protein levels, while pGR significantly increased after FS (Welch’s t -test p < 0.001; Figure 4 J)—suggesting its activation by phosphorylation, which is in line with the TF target gene set analysis.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

Martini

Mingardi

Carini

et al. 2023

Genes

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Stress is a primary risk factor for psychiatric disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD). The response to stress involves the regulation of transcriptional programs, which is supposed to play a role in coping with stress. To evaluate transcriptional processes implemented after exposure to unavoidable traumatic stress, we applied microarray expression analysis to the PFC of rats exposed to acute footshock (FS) stress that were sacrificed immediately after the 40 min session or 2 h or 24 h after. While no substantial changes were observed at the single gene level immediately after the stress session, gene set enrichment analysis showed alterations in neuronal pathways associated with glia development, glia–neuron networking, and synaptic function. Furthermore, we found alterations in the expression of gene sets regulated by specific transcription factors that could represent master regulators of the acute stress response. Of note, these pathways and transcriptional programs are activated during the early stress response (immediately after FS) and are already turned off after 2 h—while at 24 h, the transcriptional profile is largely unaffected. Overall, our analysis provided a transcriptional landscape of the early changes triggered by acute unavoidable FS stress in the PFC of rats, suggesting that the transcriptional wave is fast and mild, but probably enough to activate a cellular response to acute stress.

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“…In turn, ACTH, delivered via the systemic circulation to the adrenal cortex, induces the synthesis and release of glucocorticoid steroid hormones (GCs), i.e., cortisol in humans and corticosterone in rodents [ 78 , 79 , 82 ]. GCs insert their slow gene transcription and rapid nongenomic effects through activation of the high-affinity mineralocorticoid receptors (MRs) and low-affinity glucocorticoid receptors (GRs) distributed throughout the body, including the brain [ 80 , 81 , 82 , 85 , 86 , 87 , 88 , 89 ]. In comparison with GRs, MRs have about a 10 times higher affinity for GCs [ 80 , 81 , 82 , 85 , 86 , 87 , 88 , 89 ].…”

Section: Pathogenesis Of Pndmentioning

confidence: 99%

Intergenerational Perioperative Neurocognitive Disorder

Morey

Seubert

et al. 2023

Biology

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Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors’ own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

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Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes

Cited by 20 publications

References 135 publications

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Transcriptional Profiling of Rat Prefrontal Cortex after Acute Inescapable Footshock Stress

Intergenerational Perioperative Neurocognitive Disorder

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