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Though risk for cocaine use disorder is subject to substantial inter-individual variation, the sources of that variation – including, genetics and sex – are too often ignored in studies of this phenomenon. In genetically diverse laboratory mice, these individual differences explain the majority of variance in important cocaine-related behavioral, physiological, and striatum transcriptional responses traits. This individual variation represents a missed opportunity for discovery and translation of addiction mechanisms.

The Excello Shale member is the laterally extensive core shale of the Lower Fort Scott major cyclothem of the Desmoinesian Marmaton Group in the Midcontinent Basin of the central United States. It is the first major cyclothem of the group and lies above the Mulky Coal, which marks the transition between the Cherokee and Marmaton groups. The Excello Shale member can generally be divided into a lower black shale facies and an upper gray shale facies. Phosphate laminations as well as phosphate nodules occur through the lower black shale, as well as rare acrotretid brachiopods. Three sections of the Excello Shale member in a south to north transect were sampled in small stratigraphic intervals (5-10 cm) and small samples (200 g) of the shale were completely processed in bleach to obtain an accurate census of conodont genera and species. Rare abundance data was converted to approximate numbers of conodont individuals. Idiognathodus elements were divided into three species, I. acutus, I. species 2 and I. sp. 3. Neognathodus comprises four species, N. dilatus, N. roundyi, N. sp. 3 and N. sp. 4. Gondolella was separated into two species, G. wardlawi and the much rarer G. sp. 2.The Excello conodont fauna is significantly different than the more diverse conodont fauna of the highest major Cherokee cyclothem, the Verdigris. The Excello fauna resembles more closely the younger Marmaton conodont faunas, such as the Lost Branch fauna at the top of the Marmaton Group. The distribution of conodont genera in the Excello Shale member is compatible with the Midcontinent conodont biofacies model. The species provide some additional biofacies information, with differences in proportions of Idiognathodus and Neognathodus species occurring across the offshore to onshore transect. However, these species-level biofacies changes are not seen in the vertical succession of lithofacies in any one section. This may because the geographic spacing of sections provides greater ecological separation than can be resolved in the condensed vertical lithofacies section of the cyclothem.

Substance use disorders (SUDs) are heritable disorders characterized by compulsive drug use, but the biological mechanisms driving addiction remain largely unknown. Genetic correlations reveal that predisposing drug-naïve phenotypes, including anxiety, depression, novelty preference, and sensation seeking, are predictive of drug-use phenotypes, implicating shared genetic mechanisms. Because of this relationship, high-throughput behavioral screening of predictive phenotypes in knockout (KO) mice allows efficient discovery of genes likely to be involved in drug use. We used this strategy in two rounds of screening in which we identified 33 drug-use candidate genes and ultimately validated the perturbation of 22 of these genes as causal drivers of substance intake. In our initial round of screening, we employed the two-bottle-choice paradigms to assess alcohol, methamphetamine, and nicotine intake. We identified 19 KO strains that were extreme responders on at least one predictive phenotype. Thirteen of the 19 gene deletions (68%) significantly affected alcohol use three methamphetamine use, and two both. In the second round of screening, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15 KO strains that were extreme responders across the predisposing drug-naïve phenotypes. Eight of the 15 gene deletions (53%) significantly affected intake or preference for three alcohol, eight methamphetamine or three both (3). We observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further.