Biology subjects

Woods, L. C. S.

Publications and source records attributed to Woods, L. C. S..

3 recordsLinked to original sources

bioRxiv2025

A mutation in the transmembrane domain of Adenylate cyclase 3 impairs enzymatic function to cause sex-specific depression- and anxiety-like behaviors and food seeking in a rat model

We have previously demonstrated that a transmembrane domain mutation in Adenylate cyclase 3 (Adcy3) causes increased adiposity and negative emotion-like behaviors in a rat model. We set out to replicate and expand upon our previous study by conducting comprehensive behavioral testing, and we also investigated the molecular changes that result from this mutation. Rats with a mutation in the second transmembrane helix of ADCY3 (Adcy3mut/mut) and wild-type rats were fed a high-fat diet for 12 weeks. We measured body weight, body composition, and depression-like and anxiety-like behaviors using the following tests: sucrose splash test, sucrose preference test, forced swim test, open field test, elevated plus maze, successive alleys test, and novelty-suppressed feeding. We also measured serum leptin levels, hypothalamic cyclic AMP (cAMP) production, and membrane fraction ADCY3 content. Adcy3mut/mut male and female rats had increased adiposity. Adcy3mut/mut males showed increased despair- and anxiety-like behaviors, food seeking, and higher leptin levels relative to wild-type males. Adcy3mut/mut females showed only mildly increased anxiety-like behaviors relative to wild-type females. Adcy3mut/mut rats of both sexes had decreased cAMP production in the hypothalamus, with no changes in ADCY3 content in the membrane fraction. We conclude that the transmembrane domain of ADCY3 plays a critical role regulating adiposity and behavior, as well as cAMP production. There were key differences between males and females for the observed phenotypes. This study supports the idea that Adcy3 contributes to emotion-like behaviors and potentially mental health disorders, and that the transmembrane domain of ADCY3 is important for protein function.

neuroscience↗

bioRxiv2025

Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats

The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci, one of which involved a sialyltransferase gene and Paraprevotella. We found a similar association in a human cohort, between ST6GAL1 and Paraprevotella, both of which have been linked with immune and infectious diseases. Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".

genetics↗

bioRxiv2022

Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats

Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.

neuroscience↗