VTechWorks staff will be away for the Thanksgiving holiday beginning at noon on Wednesday, November 27, through Friday, November 29. We will resume normal operations on Monday, December 2. Thank you for your patience.

Browsing by Author "Issler, Orna"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Crystallin Mu in Medial Amygdala Mediates the Effect of Social Experience on Cocaine Seeking in Males but Not in Females
    Walker, Deena M.; Zhou, Xianxiao; Cunningham, Ashley M.; Ramakrishnan, Aarthi; Cates, Hannah M.; Lardner, Casey K.; Pena, Catherine J.; Bagot, Rosemary C.; Issler, Orna; van der Zee, Yentl; Lipschultz, Andrew P.; Godino, Arthur; Browne, Caleb J.; Hodes, Georgia E.; Parise, Eric M.; Torres-Berrio, Angelica; Kennedy, Pamela J.; Shen, Li; Zhang, Bin; Nestler, Eric J. (Elsevier, 2022-06-30)
    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.
  • Thumbnail Image
    Estrogen receptor α drives pro-resilient transcription in mouse models of depression
    Lorsch, Zachary S.; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel; Walker, Deena M.; Parise, Eric M.; Salery, Marine; Cahill, Michael E.; Hodes, Georgia E.; Pfau, Madeline L.; Kronman, Hope; Hamilton, Peter J.; Issler, Orna; Labonte, Benoit; Symonds, Ann E.; Zucker, Matthew; Zhang, Tie Yuan; Meaney, Michael J.; Russo, Scott J.; Shen, Li; Bagot, Rosemary C.; Nestler, Eric J. (Nature Publishing Group, 2018-03-16)
    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.