Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

Bagot, Rosemary C.; Cates, Hannah M.; Purushothaman, Immanuel; Vialou, Vincent; Heller, Elizabeth A.; Yieh, Lynn; Labonté, Benoit; Peña, Catherine J.; Shen, Li; Wittenberg, Gayle M.; Nestler, Eric J.

doi:10.1016/j.biopsych.2016.06.012

Cited by 128 publications

(127 citation statements)

References 51 publications

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“…Bagot et al (71) have used a model based on a social-interaction paradigm, subjecting the mice to a chronic social defeat stress to induce a depression-like state. This is likely to induce transcriptional responses that differ from our mice, because we used an experimental paradigm that does not include chronic stress (72).…”

Section: Discussionmentioning

confidence: 99%

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

Orozco-Solís

Montellier

Aguilar-Arnal

et al. 2017

Biological Psychiatry

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BACKGROUND Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD. METHODS We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice. RESULTS We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice. CONCLUSIONS We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.

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Section: Discussionmentioning

confidence: 99%

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

Orozco-Solís

Montellier

Aguilar-Arnal

et al. 2017

Biological Psychiatry

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“…For gene expression studies involving chronic imipramine treatments in behaviorally susceptible animals, NAc RNA was obtained from behavioral "responders," as determined in a recently published study (13). For ChIP-seq experiments, control and susceptible mice (determined in SI test 48 h postdefeat) were killed 28 d following the final defeat episode.…”

Section: Methodsmentioning

confidence: 99%

Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

Lepack

Bagot

Peña

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type-and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc)-a key limbic brain reward regionin the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stressassociated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.H3.3 | nucleus accumbens | depression | chronic social defeat stress | histone dynamics M ajor depressive disorder (MDD) affects ∼17% of the population, making it the most prominent and debilitating psychiatric disease worldwide (1). Current antidepressants (ADs) can take weeks to months to produce an effective therapeutic response, with about one-third of patients remaining nonresponsive to existing treatment strategies. Although the prevalence of MDD and a lack of sufficient treatment options highlight the importance of identifying new drug targets, progress has been hindered by a general lack of understanding of the precise molecular mechanisms underlying this disorder.The nucleus accumbens (NAc), a critical component of the brain's limbic reward circuitry, has become increasingly implicated in depression, as well as in mechanisms of antidepressant action (2, 3). In recent years, numerous studies in both human MDD and in animal models of depression have identified changes in gene expression, along with related alterations in chromatin structure and function, that contribute to aberrant forms of transcriptional and behavioral plasticity associated with depressive-like phenotypes (4-9). Although multiple studies have successfully linked alterations in histone posttranslational modifications (PTMs) or chromatinremodeling events to chron...

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“…Future investigations will require the inclusion of both sexes in animal testing (Hodes et al, 2017), but it is interesting to note that in a mouse model of depression during menopause, Miyata et al (2016b) also found that the gene expression alterations induced by ovariectomy were mainly associated with ribosomal and mitochondrial functions in both the medial prefrontal cortex and the blood, strengthening the results we discussed above. We also only addressed the response to antidepressant treatment with a single drug, fluoxetine, while other drugs with different selectivity for neurotransmitters other than serotonin are frequently used in the clinic (Bagot et al, 2017). Other modalities such as repeated transcranial magnetic stimulation have been increasingly proposed, especially to patients resistant to first and second-line antidepressant drug treatments.…”

Section: Discussionmentioning

confidence: 99%

Translational identification of transcriptional signatures of major depression and antidepressant response

Hervé¹,

Bergon²,

Guisquet³

et al. 2017

European Neuropsychopharmacology

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Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD.

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Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles

Cited by 128 publications

References 51 publications

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior

Translational identification of transcriptional signatures of major depression and antidepressant response

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