Mathieson, E. | bioRxiv Science

bioRxiv2021

Spontaneously Hypertensive Rat substrains show differences in premorbid addiction vulnerability traits and cocaine self-administration: Implications for a novel rat reduced complexity cross

Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine vulnerability traits relative to another substrain, SHR/NHsd. Direct substrain comparisons are a necessary first step before implementing an RCC. We evaluated a number of premorbid addiction vulnerability traits and cocaine self-administration behaviors using a longitudinal within-subjects design. Trait impulsivity and compulsivity were greater in SHR/NCrl than SHR/NHsd, as were reactivity to sucrose reward, sensitivity to acute psychostimulant effects of cocaine, and cocaine abuse liability studied under fixed-ratio and chained schedules of cocaine self-administration. Trait compulsivity correlated with the acute psychostimulant effects of cocaine, which in turn correlated with cocaine taking under the chained schedule. Trait compulsivity also was the best predictor of cocaine seeking responses. Heritability estimates indicated that 22%-40% of the variances for the above phenotypes can be explained by additive genetic factors, providing sufficient genetic variance to conduct genetic mapping in F2 crosses of SHR/NCrl and SHR/NHsd. These results provide compelling support for using an RCC approach in SHR substrains to uncover candidate genes and variants that are of relevance to cocaine use disorders. HighlightsO_LIClosely related SHR substrains have distinct cocaine vulnerability traits C_LIO_LIInhibitory control was poorer in SHR/NCrl than SHR/NHsd C_LIO_LISHR/NCrl were more sucrose reactive and sensitive to acute cocaine than SHR/NHsd C_LIO_LICocaine abuse liability was greater in SHR/NCrl than SHR/NHsd C_LIO_LISHR substrains can be used in an RCC to uncover cocaine vulnerability genes & variants C_LI

animal behavior and cognition↗

bioRxiv2020

Discovery of drugs to treat cytokine storm-induced cardiac dysfunction using human cardiac organoids

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory cytokine-storm, a cocktail of interferon gamma, interleukin 1{beta} and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

cell biology↗