45 results on '"Issler O"'
Search Results
2. List of Contributors
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Aguilera, G., primary, Allen, A.M., additional, Anacker, C., additional, Antoni, F.A., additional, Bader, M., additional, Baltatu, O.C., additional, Bartlang, M.S., additional, Bassi, J.K., additional, Bauer, C.M., additional, Beck, K., additional, Berridge, C.W., additional, Boari, B., additional, Borniger, J.C., additional, Bowers, M.E., additional, Bowman, R., additional, Buckingham, J.C., additional, Campos, L.A., additional, Carvalho, L.A., additional, Chen, A., additional, Cisse, Y.M., additional, Connelly, A.A., additional, de Bruijn, R., additional, de Jong, F.H., additional, de Kloet, E.R., additional, den Boon, F.S., additional, Fink, G., additional, Flory, J.D., additional, Flower, R.J., additional, Fong, A.Y., additional, Funder, J.W., additional, Gomez, J., additional, Gong, H., additional, Goonan, K., additional, Grigoriadis, D.E., additional, Handa, R.J., additional, Hassell Jr., J.E., additional, Hodges, T.E., additional, Hofland, J., additional, Holschbach, M.A., additional, Issler, O., additional, Jiang, C.-L., additional, Joëls, M., additional, Johnson, P.L., additional, Johnson, S.B., additional, Karst, H., additional, Khan, A.M., additional, Korosi, A., additional, Krugers, H.J., additional, Kyrou, I., additional, Lattin, C.R., additional, Lightman, S.L., additional, Liu, L., additional, Lovejoy, D.A., additional, Lowry, C.A., additional, Lucassen, P.J., additional, Luine, V., additional, Lundkvist, G.B., additional, Manfredini, F., additional, Manfredini, R., additional, Martin, L.B., additional, McCormick, C.M., additional, Meijer, O.C., additional, Menuet, C., additional, Michalec, O.M., additional, Mishra, N., additional, Nelson, R.J., additional, Nikkheslat, N., additional, Oomen, C.A., additional, Ortiz Zacarias, N.V., additional, Pariante, C.M., additional, Paul, E.D., additional, Pooley, J., additional, Price, L.H., additional, Pruessner, J.C., additional, Radley, J.J., additional, Randeva, H.S., additional, Rhodes, M.E., additional, Ridout, K.K., additional, Ridout, S.J., additional, Romero, L.M., additional, Roy, A., additional, Roy, R.N., additional, Russell, G., additional, Salmi, R., additional, Sarabdjitsingh, R.A., additional, Sarkar, D.K., additional, Sawchenko, P.E., additional, Schaaf, M.J.M., additional, Seckl, J.R., additional, Sevigny, C.P., additional, Shekhar, A., additional, Soreq, H., additional, Spencer, R.C., additional, Spiga, F., additional, Stoney, C.M., additional, Tiseo, R., additional, Tsigos, C., additional, Tyrka, A.R., additional, Walker, E.M., additional, Watts, A.G., additional, Wolf, O.T., additional, Yamashita, P.S.M., additional, Yehuda, R., additional, Zangrossi Jr., H., additional, Zorrilla, E.P., additional, and Zunszain, P.A., additional
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- 2017
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3. Sex-Specific Role for SLIT1 in Regulating Stress
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van der Zee, Y.Y., Lardner, C.K., Parise, E.M., Mews, P., Ramakrishnan, A., Patel, V., Teague, C.D., Salery, M., Walker, D.M., Browne, C.J., Labonte, B., Parise, L.F., Kronman, H., Pena, C.J., Torres-Berrio, A., Duffy, J.E., de Nijs, L., Eijssen, L.M.T., Shen, L., Rutten, B., Issler, O., Nestler, E.J., RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, and MUMC+: MA Psychiatrie (3)
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AXON GUIDANCE ,EXPRESSION ,GENDER-DIFFERENCES ,CORTEX ,SYNAPTIC PLASTICITY ,SLIT ,PYRAMIDAL NEURONS ,DEPRESSION ,DENDRITIC MORPHOLOGY ,CYCLIN D1 - Abstract
BACKGROUND: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. METHODS: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. RESULTS: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex specific increase in anxiety-and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. CONCLUSIONS: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
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- 2022
4. Perifornical Urocortin 3 Mediates the Link between Stress-Induced Mood and Energy Homeostasis.
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Kuperman, Y, primary, Issler, O, additional, Regev, L, additional, Musseri, I, additional, Neufeld-Cohen, A, additional, and Chen, A, additional
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- 2010
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5. Chapter 11 - The Role of MicroRNAs in Stress-Induced Psychopathologies
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Issler, O. and Chen, A.
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- 2017
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6. Cocaine-induced chromatin modifications are associated with increased gene expression and DNA-DNA interactions of autism-candidate 2
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Engmann, O., primary, Labonte, B., additional, Mitchell, A., additional, Bashtrykov, P., additional, Calipari, E., additional, Rosenbluh, C., additional, Loh, Y., additional, Walker, D., additional, Burek, D., additional, Hamilton, P., additional, Issler, O., additional, Neve, R., additional, Turecki, G., additional, Hurd, Y., additional, Chess, A., additional, Shen, L., additional, Jeltsch, A., additional, Akbarian, S., additional, and Nestler, E., additional
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- 2017
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7. mGlu2 as a novel target underling sex-differences in a ventral dentate gyrus (vDG)-medial amygdala (MeA) circuit controlling social behaviour: importance of early life experiences
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Nasca, C., primary, Bigio, B., additional, Cates, H., additional, Zelli, D., additional, Lau, T., additional, Liston, C., additional, De Angelis, P., additional, Hall, B., additional, Issler, O., additional, Lee, F., additional, Nestler, E., additional, and McEwen, B., additional
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- 2017
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8. microRNA as Repressors of Stress-Induced Anxiety: The Case of Amygdalar miR-34
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Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R, Horenstein E and Chen A.
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- 2011
9. P.1.c.008 - mGlu2 as a novel target underling sex-differences in a ventral dentate gyrus (vDG)-medial amygdala (MeA) circuit controlling social behaviour: importance of early life experiences
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Nasca, C., Bigio, B., Cates, H., Zelli, D., Lau, T., Liston, C., De Angelis, P., Hall, B., Issler, O., Lee, F., Nestler, E., and McEwen, B.
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- 2017
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10. S.06.02 - Cocaine-induced chromatin modifications are associated with increased gene expression and DNA-DNA interactions of autism-candidate 2
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Engmann, O., Labonte, B., Mitchell, A., Bashtrykov, P., Calipari, E., Rosenbluh, C., Loh, Y., Walker, D., Burek, D., Hamilton, P., Issler, O., Neve, R., Turecki, G., Hurd, Y., Chess, A., Shen, L., Jeltsch, A., Akbarian, S., and Nestler, E.
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- 2017
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11. The 43rd Annual Meeting of the Canadian College of Neuropsychopharmacology, November 4, 2021
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Torres-Berrío A, Ramakrishnan A, Minier-Toribio A, Parise E, Martínez-Rivera F, Browne C, Issler O, van der Zee Y, Sial O, García B, Helin K, and Salmaso N
12. Sex differences in change-of-mind neuroeconomic decision-making is modulated by LINC00473 in medial prefrontal cortex.
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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.
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- 2024
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13. Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.
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Torres-Berrío A, Estill M, Patel V, Ramakrishnan A, Kronman H, Minier-Toribio A, Issler O, Browne CJ, Parise EM, van der Zee YY, Walker DM, Martínez-Rivera FJ, Lardner CK, Durand-de Cuttoli R, 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 susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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14. Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1 .
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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.
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- 2024
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15. Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny.
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Morel C, Parise LF, Van der Zee Y, Issler O, Cai M, Browne C, Blando A, Leclair K, Haynes S, Williams RW, Mulligan MK, Russo SJ, Nestler EJ, and Han MH
- Abstract
Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions-specifically gene x chronic stress -here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J. Utilizing the chronic social defeat stress (CSDS) and chronic variable stress (CVS) paradigms, we first showed sexual dimorphism in the behavioral stress response between the mouse strains. Further, we observed an interaction between genetic background and vulnerability to prolonged exposure to non-social stressors. Finally, we found that DBA/2J and C57BL/6J mice pre-exposed to stress displayed differences in morphine sensitivity. Our results support the hypothesis that genetic variation in predisposition to stress responses influences morphine sensitivity and is likely to modulate the development of drug addiction.
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- 2024
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16. Monomethylation of Lysine 27 at Histone 3 Confers Lifelong Susceptibility to Stress.
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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.
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- 2023
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17. The long noncoding RNA FEDORA is a cell type- and sex-specific regulator of depression.
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Issler O, van der Zee YY, Ramakrishnan A, Xia S, Zinsmaier AK, Tan C, Li W, Browne CJ, Walker DM, Salery M, Torres-Berrío A, Futamura R, Duffy JE, Labonte B, Girgenti MJ, Tamminga CA, Dupree JL, Dong Y, Murrough JW, Shen L, and Nestler EJ
- Abstract
Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.
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- 2022
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18. Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females.
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Walker DM, Zhou X, Cunningham AM, Ramakrishnan A, Cates HM, Lardner CK, Peña CJ, Bagot RC, Issler O, Van der Zee Y, Lipschultz AP, Godino A, Browne CJ, Hodes GE, Parise EM, Torres-Berrio A, Kennedy PJ, Shen L, Zhang B, and Nestler EJ
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- Animals, Male, Female, Mice, mu-Crystallins, Reward, Neurons metabolism, Amygdala metabolism, Cocaine pharmacology, Cocaine metabolism
- Abstract
Background: Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse., Methods: We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward., Results: We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI., Conclusions: These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2022
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19. Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression.
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van der Zee YY, Eijssen LMT, Mews P, Ramakrishnan A, Alvarez K, Lardner CK, Cates HM, Walker DM, Torres-Berrío A, Browne CJ, Cunningham A, Cathomas F, Kronman H, Parise EM, de Nijs L, Shen L, Murrough JW, Rutten BPF, Nestler EJ, and Issler O
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- Mice, Animals, Biomarkers, Epigenesis, Genetic, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Depressive Disorder, Major diagnosis, Depressive Disorder, Major drug therapy, Depressive Disorder, Major genetics, MicroRNAs metabolism, Ketamine pharmacology, Ketamine therapeutic use
- Abstract
Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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20. Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility.
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van der Zee YY, Lardner CK, Parise EM, Mews P, Ramakrishnan A, Patel V, Teague CD, Salery M, Walker DM, Browne CJ, Labonté B, Parise LF, Kronman H, Penã CJ, Torres-Berrío A, Duffy JE, de Nijs L, Eijssen LMT, Shen L, Rutten B, Issler O, and Nestler EJ
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- Anhedonia, Animals, Anxiety, Female, Male, Mice, Prefrontal Cortex, Sex Characteristics, Depressive Disorder, Major
- Abstract
Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility., Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice., Results: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature., Conclusions: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2022
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21. Sperm Transcriptional State Associated with Paternal Transmission of Stress Phenotypes.
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Cunningham AM, Walker DM, Ramakrishnan A, Doyle MA, Bagot RC, Cates HM, Peña CJ, Issler O, Lardner CK, Browne C, Russo SJ, Shen L, and Nestler EJ
- Abstract
Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend on paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination (AI) reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing (RNA-seq), we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible versus resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes (DEGs) in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience. SIGNIFICANCE STATEMENT This manuscript contributes to the complex factors that influence the paternal transmission of stress phenotypes. By leveraging the segregation of males exposed to chronic social defeat stress (CSDS) into either resilient or susceptible categories we were able to identify the phenotypic differences in the paternal transmission of stress phenotypes across generations between the two lineages. Importantly, this work also alludes to the significance of both long noncoding RNAs (lncRNAs) and protein coding genes (PCGs) mediating the paternal transmission of stress. The knowledge gained from these data are of particular interest in understanding the risk for the development of psychiatric disorders such as anxiety and depression., (Copyright © 2021 the authors.)
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- 2021
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22. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.
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Kronman H, Torres-Berrío A, Sidoli S, Issler O, Godino A, Ramakrishnan A, Mews P, Lardner CK, Parise EM, Walker DM, van der Zee YY, Browne CJ, Boyce BF, Neve R, Garcia BA, Shen L, Peña CJ, and Nestler EJ
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- Animals, F-Box Proteins metabolism, Gene Expression Regulation, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Male, Mice, Histone Demethylases metabolism, Neurons metabolism, Nucleus Accumbens metabolism, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism, Stress, Psychological metabolism
- Abstract
Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.
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- 2021
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23. Author Correction: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.
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Kronman H, Torres-Berrío A, Sidoli S, Issler O, Godino A, Ramakrishnan A, Mews P, Lardner CK, Parise EM, Walker DM, van der Zee YY, Browne CJ, Boyce BF, Neve R, Garcia BA, Shen L, Peña CJ, and Nestler EJ
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- 2021
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24. Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression.
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Issler O, van der Zee YY, Ramakrishnan A, Wang J, Tan C, Loh YE, Purushothaman I, Walker DM, Lorsch ZS, Hamilton PJ, Peña CJ, Flaherty E, Hartley BJ, Torres-Berrío A, Parise EM, Kronman H, Duffy JE, Estill MS, Calipari ES, Labonté B, Neve RL, Tamminga CA, Brennand KJ, Dong Y, Shen L, and Nestler EJ
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Behavior, Animal, Depression genetics, Depression metabolism, Depressive Disorder, Major metabolism, Down-Regulation, Female, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Neurons metabolism, RNA, Long Noncoding metabolism, RNA-Seq, Sex Factors, Stress, Psychological metabolism, Young Adult, Depressive Disorder, Major genetics, Prefrontal Cortex metabolism, RNA, Long Noncoding genetics, Resilience, Psychological, Stress, Psychological genetics
- Abstract
Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression., Competing Interests: Declaration of Interests The authors declare no competing interests, (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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25. Unraveling the epigenetic landscape of depression: focus on early life stress .
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Torres-Berrío A, Issler O, Parise EM, and Nestler EJ
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- Animals, DNA Methylation genetics, Depression drug therapy, Depressive Disorder drug therapy, Epigenomics methods, Humans, Depression genetics, Depressive Disorder genetics, Genetic Predisposition to Disease genetics, Stress, Psychological genetics
- Abstract
Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. Early life stress (ELS) in particular is known to "scar" the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. Epigenetic processes lead to changes in gene expression that are not due to changes in DNA sequence, but achieved via modulation of chromatin modifications, DNA methylation, and noncoding RNAs. Here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. We then describe recent developments in understanding how ELS leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. We conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to ELS for the development of much-needed novel therapeutic strategies and biomarker discovery. ., (© 2019, AICH Servier GroupCopyright © 2019 AICH Servier Group. All rights reserved.)
- Published
- 2019
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26. Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
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Lorsch ZS, Hamilton PJ, Ramakrishnan A, Parise EM, Salery M, Wright WJ, Lepack AE, Mews P, Issler O, McKenzie A, Zhou X, Parise LF, Pirpinias ST, Ortiz Torres I, Kronman HG, Montgomery SE, Loh YE, Labonté B, Conkey A, Symonds AE, Neve RL, Turecki G, Maze I, Dong Y, Zhang B, Shen L, Bagot RC, and Nestler EJ
- Subjects
- Animals, Gene Regulatory Networks genetics, Mice, Mice, Inbred C57BL, Prefrontal Cortex metabolism, Transcription, Genetic, Adaptation, Psychological physiology, Stress, Psychological genetics, Zinc Fingers genetics
- Abstract
Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.
- Published
- 2019
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27. Gadd45b mediates depressive-like role through DNA demethylation.
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Labonté B, Jeong YH, Parise E, Issler O, Fatma M, Engmann O, Cho KA, Neve R, Nestler EJ, and Koo JW
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- Animals, Brain-Derived Neurotrophic Factor metabolism, DNA metabolism, Dopamine metabolism, Male, Mice, Mice, Inbred C57BL, Neural Pathways physiology, Nucleus Accumbens metabolism, Social Behavior, Stress, Psychological physiopathology, Ventral Tegmental Area metabolism, Antigens, Differentiation metabolism, DNA Demethylation drug effects, Depression metabolism
- Abstract
Animal studies using chronic social defeat stress (CSDS) in mice showed that brain-derived neurotrophic factor (BDNF) signaling in the mesolimbic dopamine (DA) circuit is important for the development of social aversion. However, the downstream molecular targets after BDNF release from ventral tegmental area (VTA) DA terminals are unknown. Here, we show that depressive-like behaviors induced by CSDS are mediated in part by Gadd45b downstream of BDNF signaling in the nucleus accumbens (NAc). We show that Gadd45b mRNA levels are increased in susceptible but not resilient mice. Intra-NAc infusion of BDNF or optical stimulation of VTA DA terminals in NAc enhanced Gadd45b expression levels in the NAc. Importantly, Gadd45b downregulation reversed social avoidance in susceptible mice. Together, these data suggest that Gadd45b in NAc contributes to susceptibility to social stress. In addition, we investigated the function of Gadd45b in demethylating CpG islands of representative gene targets, which have been associated with a depressive phenotype in humans and animal models. We found that Gadd45b downregulation changes DNA methylation levels in a phenotype-, gene-, and locus-specific fashion. Together, these results highlight the contribution of Gadd45b and changes in DNA methylation in mediating the effects of social stress in the mesolimbic DA circuit.
- Published
- 2019
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28. Corrigendum: Sex-specific transcriptional signatures in human depression.
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Labonté B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, Scarpa JR, Moy G, Loh YE, Cahill M, Lorsch ZS, Hamilton PJ, Calipari ES, Hodes GE, Issler O, Kronman H, Pfau M, Obradovic ALJ, Dong Y, Neve RL, Russo S, Kasarskis A, Tamminga C, Mechawar N, Turecki G, Zhang B, Shen L, and Nestler EJ
- Abstract
This corrects the article DOI: 10.1038/nm.4386.
- Published
- 2018
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29. Estrogen receptor α drives pro-resilient transcription in mouse models of depression.
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Lorsch ZS, Loh YE, Purushothaman I, Walker DM, Parise EM, Salery M, Cahill ME, Hodes GE, Pfau ML, Kronman H, Hamilton PJ, Issler O, Labonté B, Symonds AE, Zucker M, Zhang TY, Meaney MJ, Russo SJ, Shen L, Bagot RC, and Nestler EJ
- Subjects
- Animals, Estrogen Receptor alpha genetics, Female, Gene Expression Profiling, Male, Mice, Mice, Inbred C57BL, Models, Animal, Sex Factors, Transcriptome genetics, Adaptation, Psychological physiology, Behavior, Animal physiology, Depression physiopathology, Estrogen Receptor alpha metabolism, Nucleus Accumbens metabolism, Stress, Psychological physiopathology
- Abstract
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
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- 2018
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30. Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2.
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Engmann O, Labonté B, Mitchell A, Bashtrykov P, Calipari ES, Rosenbluh C, Loh YE, Walker DM, Burek D, Hamilton PJ, Issler O, Neve RL, Turecki G, Hurd Y, Chess A, Shen L, Mansuy I, Jeltsch A, Akbarian S, and Nestler EJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Cell Line, Tumor, Cohort Studies, Conditioning, Operant drug effects, Cytoskeletal Proteins, DNA Methylation drug effects, Gene Expression Regulation genetics, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Models, Molecular, Molecular Conformation, Neuroblastoma pathology, Nuclear Proteins genetics, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1 genetics, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 genetics, Receptors, Dopamine D2 metabolism, Transcription Factors, Young Adult, Chromatin drug effects, Cocaine administration & dosage, Dopamine Uptake Inhibitors administration & dosage, Gene Expression Regulation drug effects, Nuclear Proteins metabolism
- Abstract
Background: Exposure to drugs of abuse alters the epigenetic landscape of the brain's reward regions, such as the nucleus accumbens. We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on Auts2, a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region., Methods: We combined chromosome conformation capture, circularized chromosome conformation capture, and related approaches with behavioral paradigms relevant to cocaine phenotypes. Cell type-specific functions were assessed by fluorescence-activated cell sorting and viral-mediated overexpression in Cre-dependent mouse lines., Results: We observed that Auts2 gene expression is increased by repeated cocaine administration specifically in D
2 -type medium spiny neurons in the nucleus accumbens, an effect seen in male but not female mice. Auts2 messenger RNA expression was also upregulated postmortem in the nucleus accumbens of male human cocaine addicts. We obtained evidence that chromosomal looping, bypassing 1524 kb of linear genome, connects Auts2 to the Caln1 gene locus under baseline conditions. This looping was disrupted after repeated cocaine exposure, resulting in increased expression of both genes in D2 -type medium spiny neurons. Cocaine exposure reduces binding of CCCTC-binding factor, a chromosomal scaffolding protein, and increases histone and DNA methylation at the Auts-Caln1 loop base in the nucleus accumbens. Cell type-specific overexpression of Auts2 or Caln1 in D2 -type medium spiny neurons demonstrated that both genes promote cocaine reward., Conclusions: These findings suggest that cocaine-induced alterations of neuronal three-dimensional genome organization destabilize higher order chromatin at specific loci that regulate responses to the drug., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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31. Sex-specific transcriptional signatures in human depression.
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Labonté B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C, Scarpa JR, Moy G, Loh YE, Cahill M, Lorsch ZS, Hamilton PJ, Calipari ES, Hodes GE, Issler O, Kronman H, Pfau M, Obradovic ALJ, Dong Y, Neve RL, Russo S, Kazarskis A, Tamminga C, Mechawar N, Turecki G, Zhang B, Shen L, and Nestler EJ
- Subjects
- Adult, Aged, Animals, Blotting, Western, Case-Control Studies, Cerebral Cortex metabolism, Disease Models, Animal, Down-Regulation, Female, Hippocampus metabolism, Humans, Immunohistochemistry, Male, Mice, Middle Aged, Nucleus Accumbens metabolism, Patch-Clamp Techniques, Prefrontal Cortex metabolism, Pyramidal Cells metabolism, Sequence Analysis, RNA, Sex Characteristics, Sex Factors, Brain metabolism, Depressive Disorder, Major genetics, Stress, Psychological genetics, Transcriptome
- 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.
- Published
- 2017
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32. Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors.
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Feng J, Pena CJ, Purushothaman I, Engmann O, Walker D, Brown AN, Issler O, Doyle M, Harrigan E, Mouzon E, Vialou V, Shen L, Dawlaty MM, Jaenisch R, and Nestler EJ
- Subjects
- Animals, Anxiety genetics, Behavior, Animal, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins genetics, Depression genetics, Disease Models, Animal, Gene Expression genetics, Male, Mice, Mice, Knockout, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins genetics, Up-Regulation, Anxiety physiopathology, DNA-Binding Proteins physiology, Depression physiopathology, Nucleus Accumbens metabolism, Proto-Oncogene Proteins physiology, Stress, Psychological physiopathology
- Abstract
Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts.
- Published
- 2017
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33. Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.
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Peña CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, Issler O, Loh YE, Leong T, Kiraly DD, Goodman E, Neve RL, Shen L, and Nestler EJ
- Subjects
- Age Factors, Animals, Depression physiopathology, Female, Gene Knockdown Techniques, Male, Mice, Mice, Inbred C57BL, Protein Binding, Depression genetics, Gene Expression Regulation, Otx Transcription Factors genetics, Stress, Physiological genetics, Ventral Tegmental Area physiopathology
- Abstract
Early life stress increases risk for depression. Here we establish a "two-hit" stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)-a brain reward region-to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 ( Otx2 ) as an upstream mediator of these enduring effects. Transient juvenile-but not adult-knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2 ., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
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34. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior.
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Lepack AE, Bagot RC, Peña CJ, Loh YE, Farrelly LA, Lu Y, Powell SK, Lorsch ZS, Issler O, Cates HM, Tamminga CA, Molina H, Shen L, Nestler EJ, Allis CD, and Maze I
- Subjects
- Adult, Aged, Animals, Depressive Disorder genetics, Depressive Disorder metabolism, Female, Gene Expression Regulation, Gene Knockdown Techniques, Histones genetics, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Nucleus Accumbens metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, Stress, Psychological genetics, Depressive Disorder physiopathology, Histones metabolism, Nucleus Accumbens physiopathology, Stress, Psychological physiopathology
- Abstract
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 region-in 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 stress-associated 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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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35. Alterations of the Host Microbiome Affect Behavioral Responses to Cocaine.
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Kiraly DD, Walker DM, Calipari ES, Labonte B, Issler O, Pena CJ, Ribeiro EA, Russo SJ, and Nestler EJ
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Cocaine metabolism, Corticosterone blood, Corticosterone metabolism, Dopamine metabolism, Gastrointestinal Microbiome drug effects, Gene Expression Profiling, Gene Expression Regulation drug effects, Glutamic Acid metabolism, Male, Mice, Transcriptome, Behavior, Animal drug effects, Cocaine pharmacology, Microbiota drug effects
- Abstract
Addiction to cocaine and other psychostimulants represents a major public health crisis. The development and persistence of addictive behaviors comes from a complex interaction of genes and environment - the precise mechanisms of which remain elusive. In recent years a surge of evidence has suggested that the gut microbiome can have tremendous impact on behavioral via the microbiota-gut-brain axis. In this study we characterized the influence of the gut microbiota on cocaine-mediated behaviors. Groups of mice were treated with a prolonged course of non-absorbable antibiotics via the drinking water, which resulted in a substantial reduction of gut bacteria. Animals with reduced gut bacteria showed an enhanced sensitivity to cocaine reward and enhanced sensitivity to the locomotor-sensitizing effects of repeated cocaine administration. These behavioral changes were correlated with adaptations in multiple transcripts encoding important synaptic proteins in the brain's reward circuitry. This study represents the first evidence that alterations in the gut microbiota affect behavioral response to drugs of abuse.
- Published
- 2016
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36. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.
- Author
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Bagot RC, Cates HM, Purushothaman I, Lorsch ZS, Walker DM, Wang J, Huang X, Schlüter OM, Maze I, Peña CJ, Heller EA, Issler O, Wang M, Song WM, Stein JL, Liu X, Doyle MA, Scobie KN, Sun HS, Neve RL, Geschwind D, Dong Y, Shen L, Zhang B, and Nestler EJ
- Subjects
- Animals, Depression metabolism, Excitatory Postsynaptic Potentials physiology, Hippocampus physiology, Mice, Social Behavior, Brain metabolism, Depression genetics, Gene Regulatory Networks, Genetic Predisposition to Disease genetics, Neural Pathways metabolism, Transcriptome
- Abstract
Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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37. Determining the role of microRNAs in psychiatric disorders.
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Issler O and Chen A
- Subjects
- Animals, Humans, Mental Disorders metabolism, Behavior physiology, Brain metabolism, Mental Disorders genetics, MicroRNAs genetics
- Abstract
Recent studies have revealed that patients with psychiatric disorders have altered microRNA (miRNA) expression profiles in the circulation and brain. Furthermore, animal studies have shown that manipulating the levels of particular miRNAs in the brain can alter behaviour. Here, we review recent studies in humans, animal models, cellular systems and bioinformatics that have advanced our understanding of the contribution of brain miRNAs to the regulation of behaviour in the context of psychiatric conditions. These studies highlight the potential of miRNA levels to be used in the diagnosis of psychiatric disorders and suggest that brain miRNAs could become novel treatment targets for psychiatric disorders.
- Published
- 2015
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38. MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity.
- Author
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Issler O, Haramati S, Paul ED, Maeno H, Navon I, Zwang R, Gil S, Mayberg HS, Dunlop BW, Menke A, Awatramani R, Binder EB, Deneris ES, Lowry CA, and Chen A
- Subjects
- Animals, Antidepressive Agents pharmacology, Anxiety genetics, Anxiety metabolism, Behavior, Animal drug effects, Behavior, Animal physiology, Brain metabolism, Depression genetics, Depression metabolism, Mice, Mice, Transgenic, MicroRNAs metabolism, Receptor, Serotonin, 5-HT1A genetics, Receptor, Serotonin, 5-HT1A metabolism, Serotonergic Neurons drug effects, Serotonergic Neurons metabolism, Serotonin Plasma Membrane Transport Proteins genetics, Serotonin Plasma Membrane Transport Proteins metabolism, Social Behavior, Stress, Psychological metabolism, Antidepressive Agents therapeutic use, Brain drug effects, Depression drug therapy, MicroRNAs genetics, Resilience, Psychological, Serotonin metabolism, Stress, Psychological genetics
- Abstract
The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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39. 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
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Issler O, Carter RN, Paul ED, Kelly PA, Olverman HJ, Neufeld-Cohen A, Kuperman Y, Lowry CA, Seckl JR, Chen A, and Jamieson PM
- 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
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40. Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear.
- Author
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Elharrar E, Warhaftig G, Issler O, Sztainberg Y, Dikshtein Y, Zahut R, Redlus L, Chen A, and Yadid G
- Subjects
- Amygdala metabolism, Animals, Behavioral Symptoms psychology, Behavioral Symptoms therapy, Disease Models, Animal, Male, Rats, Rats, Sprague-Dawley, Receptors, Corticotropin-Releasing Hormone genetics, Stress Disorders, Post-Traumatic psychology, Fear physiology, Receptors, Corticotropin-Releasing Hormone metabolism, Septal Nuclei metabolism, Stress Disorders, Post-Traumatic therapy
- Abstract
Background: Posttraumatic stress disorder (PTSD) is a severe, persistent psychiatric disorder in response to a traumatic event, causing intense anxiety and fear. These responses may increase over time upon conditioning with fear-associated cues, a phenomenon termed fear incubation. Corticotropin-releasing factor receptor type 1 (CRFR1) is involved in activation of the central stress response, while corticotropin-releasing factor receptor type 2 (CRFR2) has been suggested to mediate termination of this response. Corticotropin-releasing factor (CRF) receptors are found in stress-related regions, including the bed nucleus of stria terminalis (BNST), which is implicated in sustained fear., Methods: Fear-related behaviors were analyzed in rats exposed to predator-associated cues, a model of psychological trauma, over 10 weeks. Rats were classified as susceptible (PTSD-like) or resilient. Expression levels of CRF receptors were measured in the amygdala nuclei and BNST of the two groups. In addition, lentiviruses overexpressing CRFR2 were injected into the medial division, posterointermediate part of the BNST (BSTMPI) of susceptible and resilient rats and response to stress cues was measured., Results: We found that exposure to stress and stress-associated cues induced a progressive increase in fear response of susceptible rats. The behavioral manifestations of these rats were correlated both with sustained elevation in CRFR1 expression and long-term downregulation in CRFR2 expression in the BSTMPI. Intra-BSTMPI injection of CRFR2 overexpressing lentiviruses attenuated behavioral impairments of susceptible rats., Conclusions: These results implicate the BNST CRF receptors in the mechanism of coping with stress. Our findings suggest increase of CRFR2 levels as a new approach for understanding stress-related atypical psychiatric syndromes such as PTSD., (© 2013 Society of Biological Psychiatry.)
- Published
- 2013
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41. Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge.
- Author
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Neufeld-Cohen A, Kelly PA, Paul ED, Carter RN, Skinner E, Olverman HJ, Vaughan JM, Issler O, Kuperman Y, Lowry CA, Vale WW, Seckl JR, Chen A, and Jamieson PM
- Subjects
- Analysis of Variance, Animals, Anxiety genetics, Brain metabolism, Chromatography, Liquid, Corticosterone metabolism, Hydroxyindoleacetic Acid analysis, In Situ Hybridization, Mice, Mice, Transgenic, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Receptor, Serotonin, 5-HT1A genetics, Receptors, Corticotropin-Releasing Hormone genetics, Serotonin analysis, Stress, Physiological, Stress, Psychological, Urocortins metabolism, Anxiety metabolism, Hypothalamo-Hypophyseal System metabolism, Pituitary-Adrenal System metabolism, Receptor, Serotonin, 5-HT1A metabolism, Receptors, Corticotropin-Releasing Hormone metabolism, Serotonin 5-HT1 Receptor Agonists metabolism, Urocortins genetics
- Abstract
Background: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation., Methods: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions., Results: Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei., Conclusions: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
42. ACTH-dependent regulation of microRNA as endogenous modulators of glucocorticoid receptor expression in the adrenal gland.
- Author
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Riester A, Issler O, Spyroglou A, Rodrig SH, Chen A, and Beuschlein F
- Subjects
- 3' Untranslated Regions, Adrenal Glands drug effects, Adrenocorticotropic Hormone administration & dosage, Animals, Female, Gene Expression Regulation drug effects, Mice, Mice, Inbred C3H, Oligonucleotide Array Sequence Analysis, Adrenal Glands metabolism, Adrenocorticotropic Hormone metabolism, MicroRNAs genetics, MicroRNAs metabolism, Receptors, Glucocorticoid genetics
- Abstract
MicroRNA (miR) are a subset of small RNA molecules, which posttranscriptionally modulate target gene expression. Although miR have been demonstrated to impact a number of processes during development and tumorigenesis, little is known about the expression and the role of miR in the adrenal gland. Because tight regulation of steroid synthesis is crucial for maintaining homeostasis upon stressful stimuli, here, we determined the miR expression pattern in mouse adrenal glands under baseline conditions, as well as 10, 30, and 60 min upon ACTH stimulation, using miR microarray. Changes in miR expression levels detected by array analysis were confirmed by real-time PCR and further analyzed by bioinformatic tools to identify miR that putatively target genes involved in adrenal function. After selecting miR, with a significant change in their expression level upon ACTH stimulation, four of the predefined miR (miR-96, miR-101a, miR-142-3p, and miR-433) were found to putatively target the glucocorticoid receptor [nuclear receptor subfamily 3, group C, member 1 (Nr3c1)]. Nr3c1 expression levels were elevated 10 min after ACTH stimulation but decreased after 60 min in comparison with baseline conditions. Modified Nr3c1-3'-untranslated region constructs were further tested by in vitro luciferase assays. Thereby, we could confirm that miR96, miR101a, miR142-3p, and miR433 target the Nr3c1-3'-untranslated region and result in a 20-40% repression of it. Taken together, ACTH stimulation could be demonstrated to acutely influence adrenal miR expression pattern in vivo; thus, potentially modulating adrenal response to acute stressors.
- Published
- 2012
- Full Text
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43. Expression and regulation of corticotropin-releasing factor receptor type 2β in developing and mature mouse skeletal muscle.
- Author
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Kuperman Y, Issler O, Vaughan J, Bilezikjian L, Vale W, and Chen A
- Subjects
- 5' Flanking Region genetics, Amino Acid Sequence, Animals, Base Sequence, Cell Differentiation, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutant Proteins metabolism, Myoblasts cytology, Myoblasts metabolism, Myogenic Regulatory Factors chemistry, Myogenic Regulatory Factors metabolism, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Corticotropin-Releasing Hormone metabolism, Retinol-Binding Proteins, Plasma genetics, Retinol-Binding Proteins, Plasma metabolism, Signal Transduction genetics, Stress, Physiological genetics, Up-Regulation genetics, Gene Expression Regulation, Developmental, Muscle Development genetics, Muscle, Skeletal metabolism, Receptors, Corticotropin-Releasing Hormone genetics
- Abstract
Corticotropin-releasing factor receptor type 2 (CRFR2) is highly expressed in skeletal muscle (SM) tissue where it is suggested to inhibit interactions between insulin signaling pathway components affecting whole-body glucose homeostasis. However, little is known about factors regulating SM CRFR2 expression. Here, we demonstrate the exclusive expression of CRFR2, and not CRFR1, in mature SM tissue using RT-PCR and ribonuclease protection assays and report a differential expression of CRF receptors during C2C12 myogenic differentiation. Whereas C2C12 myoblasts exclusively express CRFR1, the C2C12 myotubes solely express CRFR2. Using cAMP luciferase assays and calcium mobilization measurements, we further demonstrate the functionality of these differentially expressed receptors. Using luciferase reporter assays we show a differential activation of CRFR promoters during myogenic differentiation. Transfections with different fragments of the 5'-flanking region of the mCRFR2β gene fused to a luciferase reporter gene show a promoter-dependent expression of the reporter gene and reveal the importance of the myocyte enhancer factor 2 consensus sequence located at the 3'-proximal region of CRFR2β promoter. Furthermore, we demonstrate that CRFR2 gene transcription in the mature mouse is stimulated by both high-fat diet and chronic variable stress conditions. Performing a whole-genome expression microarray analysis of SM tissues obtained from CRFR2-null mice or wild-type littermates revealed a robust reduction in retinol-binding protein 4 expression levels, an adipokine whose serum levels are elevated in insulin-resistant states. In correlation with the SM CRFR2β levels, the SM retinol-binding protein 4 levels were also elevated in mice subjected to high-fat diet and chronic variable stress conditions. The current findings further position the SM CRFR2 pathways as a relevant physiological system that may affect the known reciprocal relationship between psychological and physiological challenges and the metabolic syndrome.
- Published
- 2011
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44. Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis.
- Author
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Kuperman Y, Issler O, Regev L, Musseri I, Navon I, Neufeld-Cohen A, Gil S, and Chen A
- Subjects
- Animals, Anxiety genetics, Genetic Vectors genetics, Lentivirus genetics, Mice, Mice, Transgenic, Urocortins genetics, Anxiety metabolism, Behavior, Animal, Energy Metabolism, Homeostasis, Stress, Physiological, Urocortins metabolism
- 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 responses 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 neuromodulator 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.
- Published
- 2010
- Full Text
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45. A novel corticotropin-releasing factor receptor splice variant exhibits dominant negative activity: a putative link to stress-induced heart disease.
- Author
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Sztainberg Y, Kuperman Y, Issler O, Gil S, Vaughan J, Rivier J, Vale W, and Chen A
- Subjects
- Animals, Base Sequence, DNA, Complementary isolation & purification, Genes, Dominant, Mice, Molecular Sequence Data, Myocardium chemistry, Protective Agents, Protein Isoforms genetics, RNA, Messenger analysis, Gene Expression Regulation physiology, Heart Diseases etiology, Heart Diseases genetics, Receptors, Corticotropin-Releasing Hormone genetics, Stress, Physiological
- Abstract
A growing body of experimental and clinical studies supports a strong association between psychological stress and cardiovascular disease. An important endogenous cardioprotective role in heart physiology has been attributed to corticotropin-releasing factor receptor type 2beta (CRFR2beta). Here, we report the isolation of cDNA from mouse (m) heart encoding a novel CRFR2beta splice variant. Translation of this insertion variant (iv)-mCRFR2beta isoform produces a 421-aa protein that includes a unique C-terminal cytoplasmic tail. Our functional analysis and cellular localization studies demonstrated that when coexpressed with wild-type mCRFR2beta, iv-mCRFR2beta significantly inhibited the wild-type mCRFR2beta membrane expression and its functional signaling by ER-Golgi complex retention, suggesting a dose-dependent dominant negative effect. Interestingly, mice exposed to a 4-wk paradigm of chronic variable stress, a model of chronic psychological stress in humans, presented significantly lower levels of mCRFR2beta and higher levels of iv-mCRFR2beta mRNA expression in their hearts, compared to nonstressed control mice. The dominant-negative effect of iv-mCRFR2beta and its up-regulation by psychological stress suggest a new form of regulation of the mCRFR2beta cardioprotective effect and a potential role for this novel isoform in stress-induced heart disease.
- Published
- 2009
- Full Text
- View/download PDF
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