Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Bagot, Rosemary C.; Cates, Hannah M.; Purushothaman, Immanuel; Lorsch, Zachary S.; Walker, Deena M.; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M.; Maze, Ian; Peña, Catherine J.; Heller, Elizabeth A.; Issler, Orna; Wang, Minghui; Song, Won Min; Stein, Jason L.; Liu, Xiaochuan; Doyle, Marie; Scobie, Kimberly N.; Sun, HaoSheng; Neve, Rachael L.; Geschwind, Daniel H.; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J.

doi:10.1016/j.neuron.2016.04.015

Cited by 306 publications

(368 citation statements)

References 69 publications

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“…In vivo, one of the members of this family of proteins, NeuroD2, was found at MR-, but not at GR-exclusive binding sites (van Weert et al 2017). The NeuroD2 proteins have a role in neuronal differentiation and studies with NeuroD2 mutants revealed their role in stress susceptibility (Bagot et al 2016).…”

Section: Molecular Studiesmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

Joëls

Kloet

2017

Journal of Endocrinology

119

109

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In 1968, Bruce McEwen discovered that 3 H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era dominated by the conundrum of two types of corticosterone-binding receptors in the brain, which led to the identification of the high-affinity corticosterone receptor as the 'promiscuous' MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the function of the brain MR from that of the closely related GR on different levels of biological complexity. Finally, the synthesis section that highlights the two faces of brain MR: Salt and Stress. 'Salt' refers to the regulation of salt appetite, and reciprocal arousal, motivation and reward, by a network of aldosterone-selective MR-expressing neurons projecting from nucleus tractus solitarii (NTS) and circumventricular organs. 'Stress' is about the limbic-forebrain nuclear and membrane MRs, which act as a switch in the selection of the best response to cope with a stressor. For this purpose, activation of the limbic MR promotes selective attention, memory retrieval and the appraisal process, while driving emotional expressions of fear and aggression. Subsequently, rising glucocorticoid concentrations activate GRs in limbic-forebrain circuitry underlying executive functions and memory storage, which contribute in balance with MR-mediated actions to homeostasis, excitability and behavioural adaptation.

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Section: Molecular Studiesmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

Joëls

Kloet

2017

Journal of Endocrinology

119

109

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“…Dysregulation of biological pathways and functional gene sets contribute to manifestation of depression-related behaviors 26 In contrast to GO, classification by Gene Set Enrichment Analysis (GSEA) is designed to detect changes in groups of functionallyrelated genes whose expression is coordinately regulated 30,31 . GSEA analysis revealed that low-dose ketamine alters the expression of diverse gene sets involved in GPCR signaling, neuronal metabolism, vascularization, and structural plasticity ( Figure 3B).…”

Section: Profiling the Translatome After Antidepressant Ketaminementioning

confidence: 99%

Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

Miller

Grabole

Wells

et al. 2018

Preprint

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Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major Depression Disorder patients receiving a single infusion report elevated mood within two hours, and ketamine's antidepressant effects have been observed as long as seven days post-treatment. In light of this remarkable observation, efforts have been undertaken to "reverse-translate" ketamine's effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit level changes that are initiated by lowdose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncover a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice and Gene Set Enrichment Analysis points to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine's effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in cortex and identified as a potential novel target for antidepressant action.

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“…Given such predictions, we sought to examine the precise relationship between H3.3 differential enrichment and alterations in gene expression that may influence the activation or inhibition of these functional biological processes. To do so, odds ratio analyses were performed comparing H3.3 ChIP-seq analyses with corresponding published mRNA expression data (21). We found that, although acute stress leads to roughly as many changes in H3.…”

mentioning

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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Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility

Cited by 306 publications

References 69 publications

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes

Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

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

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