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Morrison, S. E.

Publications and source records attributed to Morrison, S. E..

3 recordsLinked to original sources

A distinct adolescent profile for activity and dopamine release in the nucleus accumbens during Pavlovian conditioning

Across species, adolescence is a time of heightened reward sensitivity and enhanced impulsivity and risk-taking. In adults, these behavioral features are linked with a tendency to approach and interact with reward-associated cues - a behavior known as sign tracking - which is thought to reflect the transfer of incentive salience from reward to cue. Counterintuitively, adolescents are less likely to exhibit sign tracking, compared with adults, and more likely to exhibit goal tracking, or approach to the site of reward. To investigate a possible neural basis for this age difference, we recorded the activity of individual neurons in the nucleus accumbens (NAc) of male and female rats during Pavlovian conditioning in adolescence and adulthood. In a separate group, we used a fluorescent indicator (GRABDA) to measure dopamine release at the same ages. We found that cue-evoked NAc activity increased over the course of training in adolescents and then further in adulthood. The majority of adolescents were goal trackers or intermediates, for whom reward-evoked activity peaked during adolescence and declines in adulthood, correlating with increased prevalence and intensity of sign tracking. Meanwhile, cue-evoked dopamine release was markedly higher in sign trackers than in goal trackers at all time points. These results suggest that the progression from adolescence to adulthood may be accompanied by changes in the engagement of the mesolimbic dopamine system and/or the responsivity of NAc neural signaling to dopamine, contributing to limited sensitivity to reward cues, coupled with heightened sensitivity to primary rewards, in adolescent animals. Significance StatementAdolescence is a time of enhanced reward sensitivity, impulsivity, and risk-taking, making adolescents vulnerable to drug use and other risky behaviors. In adults, attraction to reward-associated cues - which can be modeled in animals using a behavior called sign tracking - plays an important role in risky behaviors. Surprisingly, we find that adolescents exhibit less sign tracking compared with adults. Here, we investigate the neural circuits underlying this age difference by monitoring neural activity and dopamine release in the nucleus accumbens (NAc), a key brain area for reward-seeking behavior, in the same animals as adolescents and as adults. We find that the majority of adolescents show a reduced neural sensitivity to reward cues, but a heightened neural response to the reward itself.

neuroscience↗

Overcoming Cisplatin Resistance in TP53-null Colon Cancer Organoids

Cisplatin chemotherapy of colorectal cancer (CRC) is associated with dose-limiting side effects and the development of drug resistance, resulting in reduced therapeutic effectiveness. The resistant phenotype in colon cancer is primarily due to changes in p53-regulated DNA damage signaling and /or defects in the cellular mismatch-repair pathway. Therefore, enhancing the efficacy of cisplatin chemotherapy remains a significant challenge. In this study, we used a TP53-KO patient-derived colon tumor organoid model to perform a genome-wide CRISPR KO screen in the absence and presence of cisplatin and identified gene knockouts that re-sensitize cisplatin-resistant TP53-KO colon cancer organoids to cisplatin treatment. Knockout of genes in the DNA Repair pathways, including Fanconi Anemia (FA cause re-sensitization of TP53-KO colon cancer cells to cisplatin. Inhibition of genes ERCC6, FANCL, and BRIP1 enhances cisplatin-induced cell death in TP53-KO colon cancer organoids. These findings suggest that targeting these pathways could be an effective approach to overcome chemoresistance of TP53-muatnt colon cancer cells to cisplatin.

molecular biology↗

StarTrace: A Multiplex Organoid Avatar Drug Testing Platform for Personalized Medicine

The goal of precision medicine is to improve clinical outcomes of cancer patients by choosing treatments most likely to work. One idea is to match tumor response to cancer-causing somatic mutations, but this strategy still faces limitations in colorectal cancer due to poorly understood genetic influences on drug resistance. We describe here a simple direct drug sensitivity assay platform applied to mixtures of patient-derived organoid avatars as a practical solution for choosing therapy, sidestepping the need for exhaustive knowledge of drug-genetic interactions. This approach rank orders individual patient organoid avatars responses to various drugs to be used to guide treatment choices. The platform multiplexes organoids using a clonal barcoding method, called StarTrace, which simultaneously tests pools of multiple patients organoid avatars for sensitivity or resistance to small molecule inhibitors. We utilized both quantitative real-time PCR-based and single-molecule sequencing assays to track the relative Darwinian fitness of each barcoded organoid within the pool. StarTrace offers a rapid, cost effective and sensitive testing platform that could be useful for either preclinical drug development or tailoring personalized therapy.

molecular biology↗