Dataset Information

Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

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.

SUBMITTER: Lorsch ZS

PROVIDER: S-EPMC6713580 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

Lorsch Zachary S ZS Hamilton Peter J PJ Ramakrishnan Aarthi A Parise Eric M EM Salery Marine M Wright William J WJ Lepack Ashley E AE Mews Philipp P Issler Orna O McKenzie Andrew A Zhou Xianxiao X Parise Lyonna F LF Pirpinias Stephen T ST Ortiz Torres Idelisse I Kronman Hope G HG Montgomery Sarah E SE Loh Yong-Hwee Eddie YE Labonté Benoit B Conkey Andrew A Symonds Ann E AE Neve Rachael L RL Turecki Gustavo G Maze Ian I Dong Yan Y Zhang Bin B Shen Li L Bagot Rosemary C RC Nestler Eric J EJ

Nature neuroscience 20190819 9

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 promote ...[more]

PMID: 31427770

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Project description:Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite comparable self-administration and extinction, females displayed a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock, tested across a range of intensities, failed to potentiate cocaine-primed reinstatement in females. However, restraint potentiated reinstatement in both sexes. While sex differences in stressor-induced plasma corticosterone (CORT) elevations and defensive behaviors were not observed, differences were evident in footshock-elicited ultrasonic vocalizations. CORT administration, at a dose which recapitulates stressor-induced plasma levels, reproduced stress-potentiated cocaine-primed reinstatement in both sexes. In females, CORT effects varied across the estrous cycle; CORT-potentiated reinstatement was only observed during diestrus and proestrus. As in males, CORT-potentiated cocaine seeking in females was localized to the PrL-PFC and both CORT- and restraint-potentiated cocaine seeking required PrL-PFC CB1R activation. In addition, ex vivo whole-cell electrophysiological recordings from female layer V PrL-PFC pyramidal neurons revealed CB1R-dependent CORT-induced suppression of inhibitory synaptic activity, as previously observed in males. These findings demonstrate that, while stress potentiates cocaine seeking via PrL-PFC CB1R in both sexes, sensitivity to cocaine priming injections is greater in females, CORT-potentiating effects vary with the estrous cycle, and whether reactivity to specific stressors may manifest as drug seeking depends on biological sex.

Dataset Information

Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

Publications

Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.

Similar Datasets

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