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Biology subjects

Vlach, L.

Publications and source records attributed to Vlach, L..

3 recordsLinked to original sources

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

neuroscience↗

SETD2 safeguards the genome against isochromosome formation

Factors governing the faithful replication of chromosomes are essential for cellular and genomic integrity. While a variety of mechanisms to manage breaks and promote repair of DNA are widely recognized, epigenetic landmarks that preserve telomere-to-telomere replication fidelity and prevent genome instability are not well-understood. SETD2 is the histone methyltransferase responsible for trimethylation on histone H3 lysine 36 and is newly recognized as a tumor suppressor that acts to maintain genome stability. Importantly, SETD2 is frequently lost in cancers that exhibit extensive intratumoral heterogeneity. Here, we demonstrate that loss of SETD2 and H3K36me3 promotes chromosome segregation errors and DNA bridging during mitosis, and that these bridges are driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these chromosomes were comprised of mirror-imaged isochromosomes and isodicentric chromosomes that contain two active centromeres. These data demonstrate that the SETD2 histone methyltransferase is essential to prevent a palindromic replication intermediate, whose loss precipitates the formation of a mutable chromatin structure known to initiate a cascade of genomic instability in cancer.

cancer biology↗

Bud13 Promotes a Type I Interferon Response By Countering Intron Retention in Irf7

Intron retention (IR) has emerged as an important mechanism of gene expression control. Despite this, the factors that control IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified Bud13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in Bud13 led to increased IR, decreased mature Irf7 transcript and protein levels, and consequently to a dampened type I interferon response. This impairment of Irf7 production in Bud13-deficient cells compromised their ability to withstand VSV infection. Global analysis of Bud13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a Bud13-dependent manner. Deficiency of Bud13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, Bud13 facilitates the expression of genes at which IR occurs.

molecular biology↗