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3. Sex-specific transcriptional signatures in human depression

Author

Labonté, Benoit, Engmann, Olivia, Purushothaman, Immanuel, Menard, Caroline, Wang, Junshi, Tan, Chunfeng, Scarpa, Joseph R, Moy, Gregory, Loh, Yong-Hwee E, Cahill, Michael, Lorsch, Zachary S, Hamilton, Peter J, Calipari, Erin S, Hodes, Georgia E, Issler, Orna, Kronman, Hope, Pfau, Madeline, Obradovic, Aleksandar L J, Dong, Yan, Neve, Rachael L, Russo, Scott, Kazarskis, Andrew, Tamminga, Carol, Mechawar, Naguib, Turecki, Gustavo, Zhang, Bin, Shen, Li, and Nestler, Eric J

Subjects
Depression (Mood disorder) -- Models -- Genetic aspects -- Physiological aspects -- Analysis -- Research, Transcription (Genetics) -- Analysis -- Models -- Physiological aspects -- Research, Biological sciences, Health
Abstract

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder., Author(s): Benoit Labonté [1]; Olivia Engmann [1]; Immanuel Purushothaman [1]; Caroline Menard [1]; Junshi Wang [2]; Chunfeng Tan [3]; Joseph R Scarpa [1, 4]; Gregory Moy [1]; Yong-Hwee E Loh [...]

Published
2017
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4. The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression

Author

Issler, Orna, primary, van der Zee, Yentl Y., additional, Ramakrishnan, Aarthi, additional, Xia, Sunhui, additional, Zinsmaier, Alexander K., additional, Tan, Chunfeng, additional, Li, Wei, additional, Browne, Caleb J., additional, Walker, Deena M., additional, Salery, Marine, additional, Torres-Berrío, Angélica, additional, Futamura, Rita, additional, Duffy, Julia E., additional, Labonte, Benoit, additional, Girgenti, Matthew J., additional, Tamminga, Carol A., additional, Dupree, Jeffrey L., additional, Dong, Yan, additional, Murrough, James W., additional, Shen, Li, additional, and Nestler, Eric J., additional

Published
2022
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6. Sperm Transcriptional State Associated with Paternal Transmission of Stress Phenotypes

Author

Cunningham, Ashley M., primary, Walker, Deena M., additional, Ramakrishnan, Aarthi, additional, Doyle, Marie A., additional, Bagot, Rosemary C., additional, Cates, Hannah M., additional, Peña, Catherine J., additional, Issler, Orna, additional, Lardner, Casey K., additional, Browne, Caleb, additional, Russo, Scott J., additional, Shen, Li, additional, and Nestler, Eric J., additional

Published
2021
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7. The 43rd Annual Meeting of the Canadian College of Neuropsychopharmacology, November 4, 2021.

Author

Torres-Berrío, Angélica, Ramakrishnan, Aarthi, Minier-Toribio, Angélica, Parise, Eric M., Martínez-Rivera, Freddyson J., Browne, Caleb J., Issler, Orna, van der Zee, Yentl Y., Sial, Omar, García, Benjamin, Helin, Kristian, Sidoli, Simone, Shen, Li, Nestler, Eric J., Yap, Sidney, Luki, Jessica, Hanstock, Christopher C., Seres, Peter, Shandro, Tami, and Hanstock, Sarah

Subjects
ABSTRACTING, CONFERENCES & conventions, PROFESSIONAL associations, PSYCHOPHARMACOLOGY
Published
2022
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10. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

Author

Issler, Orna, primary, van der Zee, Yentl Y., additional, Ramakrishnan, Aarthi, additional, Wang, Junshi, additional, Tan, Chunfeng, additional, Loh, Yong-Hwee E., additional, Purushothaman, Immanuel, additional, Walker, Deena M., additional, Lorsch, Zachary S., additional, Hamilton, Peter J., additional, Peña, Catherine J., additional, Flaherty, Erin, additional, Hartley, Brigham J., additional, Torres-Berrío, Angélica, additional, Parise, Eric M., additional, Kronman, Hope, additional, Duffy, Julia E., additional, Estill, Molly S., additional, Calipari, Erin S., additional, Labonté, Benoit, additional, Neve, Rachael L., additional, Tamminga, Carol A., additional, Brennand, Kristen J., additional, Dong, Yan, additional, Shen, Li, additional, and Nestler, Eric J., additional

Published
2020
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12. Corrigendum: Sex-specific transcriptional signatures in human depression

Author

Labonté, Benoit, Engmann, Olivia, Purushothaman, Immanuel, Menard, Caroline, Wang, Junshi, Tan, Chunfeng, Scarpa, Joseph R, Moy, Gregory, Loh, Yong-Hwee E, Cahill, Michael, Lorsch, Zachary S, Hamilton, Peter J, Calipari, Erin S, Hodes, Georgia E, Issler, Orna, Kronman, Hope, Pfau, Madeline, Obradovic, Aleksandar L J, Dong, Yan, Neve, Rachael L, Russo, Scott, Kasarskis, Andrew, Tamminga, Carol, Mechawar, Naguib, Turecki, Gustavo, Zhang, Bin, Shen, Li, and Nestler, Eric J

Subjects
Biological sciences, Health
Abstract

Author(s): Benoit Labonté; Olivia Engmann; Immanuel Purushothaman; Caroline Menard; Junshi Wang; Chunfeng Tan; Joseph R Scarpa; Gregory Moy; Yong-Hwee E Loh; Michael Cahill; Zachary S Lorsch; Peter J Hamilton; Erin [...]

Published
2018
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13. Erratum: Corrigendum: Sex-specific transcriptional signatures in human depression

Author

Labonté, Benoit, primary, Engmann, Olivia, additional, Purushothaman, Immanuel, additional, Menard, Caroline, additional, Wang, Junshi, additional, Tan, Chunfeng, additional, Scarpa, Joseph R, additional, Moy, Gregory, additional, Loh, Yong-Hwee E, additional, Cahill, Michael, additional, Lorsch, Zachary S, additional, Hamilton, Peter J, additional, Calipari, Erin S, additional, Hodes, Georgia E, additional, Issler, Orna, additional, Kronman, Hope, additional, Pfau, Madeline, additional, Obradovic, Aleksandar L J, additional, Dong, Yan, additional, Neve, Rachael L, additional, Russo, Scott, additional, Kasarskis, Andrew, additional, Tamminga, Carol, additional, Mechawar, Naguib, additional, Turecki, Gustavo, additional, Zhang, Bin, additional, Shen, Li, additional, and Nestler, Eric J, additional

Published
2018
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14. Estrogen receptor α drives pro-resilient transcription in mouse models of depression

Author

Lorsch, Zachary S., primary, Loh, Yong-Hwee Eddie, additional, Purushothaman, Immanuel, additional, Walker, Deena M., additional, Parise, Eric M., additional, Salery, Marine, additional, Cahill, Michael E., additional, Hodes, Georgia E., additional, Pfau, Madeline L., additional, Kronman, Hope, additional, Hamilton, Peter J., additional, Issler, Orna, additional, Labonté, Benoit, additional, Symonds, Ann E., additional, Zucker, Matthew, additional, Zhang, Tie Yuan, additional, Meaney, Michael J., additional, Russo, Scott J., additional, Shen, Li, additional, Bagot, Rosemary C., additional, and Nestler, Eric J., additional

Published
2018
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15. Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors

Author

Feng, Jian, primary, Pena, Catherine J, additional, Purushothaman, Immanuel, additional, Engmann, Olivia, additional, Walker, Deena, additional, Brown, Amber N, additional, Issler, Orna, additional, Doyle, Marie, additional, Harrigan, Eileen, additional, Mouzon, Ezekiell, additional, Vialou, Vincent, additional, Shen, Li, additional, Dawlaty, Meelad M, additional, Jaenisch, Rudolf, additional, and Nestler, Eric J, additional

Published
2017
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17. Unraveling the epigenetic landscape of depression: focus onearly life stress

Author

Torres-Berrío, Angélica, Issler, Orna, Parise, Eric M., and Nestler, Eric J.

Abstract

Depression is a devastating psychiatric disorder caused by a combination of geneticpredisposition and life events, mainly exposure to stress. Early life stress (ELS) inparticular is known to “scar” the brain, leading to an increased susceptibility todeveloping depression later in life via epigenetic mechanisms. Epigenetic processeslead to changes in gene expression that are not due to changes in DNA sequence, butachieved via modulation of chromatin modifications, DNA methylation, and noncodingRNAs. Here we review common epigenetic mechanisms including the enzymes that takepart in reading, writing, and erasing specific epigenetic marks. We then describerecent developments in understanding how ELS leads to changes in the epigenome thatare manifested in increased susceptibility to depression-like abnormalities in animalmodels. We conclude with highlighting the need for future studies that willpotentially enable the utilisation of the understanding of epigenetic changes linkedto ELS for the development of much-needed novel therapeutic strategies and biomarkerdiscovery.

Published
2019
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18. Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas

Author

Issler, Orna, Carter, Roderick N, Paul, Evan D, Kelly, Paul AT, Olverman, Henry J, Neufeld-Cohen, Adi, Kuperman, Yael, Lowry, Christopher A, Seckl, Jonathan R, Chen, Alon, and Jamieson, Pauline M

Subjects
nervous system
Abstract

BACKGROUND: Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice. RESULTS: CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact. CONCLUSIONS: These results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.

Published
2014

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

Author

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

Published
2016
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21. MicroRNA 135 Is Essential for Chronic Stress Resiliency, Antidepressant Efficacy, and Intact Serotonergic Activity

Author

Issler, Orna, primary, Haramati, Sharon, additional, Paul, Evan D., additional, Maeno, Hiroshi, additional, Navon, Inbal, additional, Zwang, Rayya, additional, Gil, Shosh, additional, Mayberg, Helen S., additional, Dunlop, Boadie W., additional, Menke, Andreas, additional, Awatramani, Rajeshwar, additional, Binder, Elisabeth B., additional, Deneris, Evan S., additional, Lowry, Christopher A., additional, and Chen, Alon, additional

Published
2014
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22. Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas

Author

Issler, Orna, primary, Carter, Roderick N, additional, Paul, Evan D, additional, Kelly, Paul AT, additional, Olverman, Henry J, additional, Neufeld-Cohen, Adi, additional, Kuperman, Yael, additional, Lowry, Christopher A, additional, Seckl, Jonathan R, additional, Chen, Alon, additional, and Jamieson, Pauline M, additional

Published
2014
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24. Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis.

Author

YaeIKuperman, Issler, Orna, Regev, Limor, Musseri, Ifat, Navon, Inbal, Neufeld-Cohen, Adi, Gil, Shosh, and Chen, Alon

Subjects
*PSYCHOLOGICAL stress, *ANXIETY, *HOMEOSTASIS, *NEUROENDOCRINE cells, *GENETIC regulation, *HYPOTHALAMIC hormones, *LABORATORY mice
Abstract

In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological re- sponses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic neuropeptide Urocortin-3, a specific ligand for the type-2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a neuro-modulator linking stress-induced anxiety and energy homeostasis and pave the way toward better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders. [ABSTRACT FROM AUTHOR]

Published
2010
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25. Sex differences in change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex.

Author

Cuttoli RD, Issler O, Yakubov B, Jahan N, Abid A, Kasparov S, Granizo K, Ahmed S, Russo SJ, Nestler EJ, and Sweis BM

Abstract

Changing one's mind is a complex cognitive phenomenon involving a continuous re-appraisal of the trade-off between past costs and future value. Recent work modeling this behavior across species has established associations between aspects of this choice process and their contributions to altered decision-making in psychopathology. Here, we investigated the actions in medial prefrontal cortex (mPFC) neurons of long intergenic non-coding RNA, LINC00473, known to induce stress resilience in a striking sex-dependent manner, but whose role in cognitive function is unknown. We characterized complex decision-making behavior in male and female mice longitudinally in our neuroeconomic foraging paradigm, Restaurant Row, following virus-mediated LINC00473 expression in mPFC neurons. On this task, mice foraged for their primary source of food among varying costs (delays) and subjective value (flavors) while on a limited time-budget during which decisions to accept and wait for rewards were separated into discrete stages of primary commitments and secondary re-evaluations. We discovered important differences in decision-making behavior between female and male mice. LINC00473 expression selectively influenced multiple features of re-evaluative choices, without affecting primary decisions, in female mice only. These behavioral effects included changing how mice (i) cached the value of the passage of time and (ii) weighed their history of economically disadvantageous choices. Both processes were uniquely linked to change-of-mind decisions and underlie the computational bases of distinct aspects of counterfactual thinking. These findings reveal a key bridge between a molecular driver of stress resilience and psychological mechanisms underlying sex-specific decision-making proclivities.

Published
2024
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26. Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1 .

Author

Parise EM, Gyles TM, Godino A, Sial OK, Browne CJ, Parise LF, Torres-Berrío A, Salery M, Durand-de Cuttoli R, Rivera MT, Cardona-Acosta AM, Holt L, Markovic T, van der Zee YY, Lorsch ZS, Cathomas F, Garon JB, Teague C, Issler O, Hamilton PJ, Bolaños-Guzmán CA, Russo SJ, and Nestler EJ

Abstract

Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1 , which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1 manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brain's ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.

Published
2024
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27. Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress.

Author

Torres-Berrío A, Estill M, Ramakrishnan A, Kronman H, Patel V, Minier-Toribio A, Issler O, Browne CJ, Parise EM, van der Zee Y, Walker D, Martínez-Rivera FJ, Lardner CK, Cuttoli RD, Russo SJ, Shen L, Sidoli S, and Nestler EJ

Abstract

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling, and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice exposed to early life stress (ELS) or to chronic social defeat stress (CSDS) in adulthood displayed increased enrichment of H3K27me1, and transient decreases in H3K27me2, in the nucleus accumbens (NAc), a key brain-reward region. Stress induction of H3K27me1 was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which is induced by chronic stress and controls H3K27 methylation patterns. Overexpression of the VEFS domain led to social, emotional, and cognitive abnormalities, and altered excitability of NAc D1 mediums spiny neurons. Together, we describe a novel function of H3K27me1 in brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.

Published
2023
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