Lemen, P. M. | bioRxiv Science

bioRxiv2022

PeerPub: A device for concurrent operant oral self-administration by multiple rats

The social environment has long been recognized to play an important role in substance abuse disorders (SUD). Operant conditioning is the most widely used rodent model of SUD. However, most operant chambers do not accommodate more than one rat at a time. Here, we introduce PeerPub - a novel social operant chamber. PeerPub uses a touch sensor to record the number of licks on drinking spouts. It then delivers a drop of solution with a fixed volume as the reward to the tip of the spout when the number of licks meets the requirement of a reinforcement schedule. A radio-frequency identification (RFID) chip implanted on top of each rats skull tracks the identity of the rat. The system is controlled by a Raspberry Pi computer. We tested PeerPub using male Wistar Kyoto rats in daily one-hour sessions where supersac, a solution containing glucose and saccharin, was delivered under a fixed ratio 5 schedule. We found that male rats consumed more supersac in group housing rather than in isolated conditions. These data demonstrated the utility of PeerPub in modeling the interaction between motivated behavior and social context. We anticipate devices like PeerPub will help demonstrate the role of the social environment in SUD phenotypes. The design of PeerPub is available at http://github.com/nijie321/PeerPub

animal behavior and cognition↗

bioRxiv2022

Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS finding

Exploring the molecular genetic cascades responsible for behavioral responses to opioids can improve our understanding of drug use initiation. We generated high-precision time-series data for 105 morphine-and naloxone-related traits across [~]700 young adult BXD mice (64 diverse strains and both sexes) for 3 hours after a single morphine injection. Variations in responses were mapped using high-precision genome sequencing-based genotypes. The initial locomotor responses to morphine mapped precisely to the {micro} opioid receptor gene (Oprm1) on chromosome (Chr) 10 with a peak linkage of 12.4 (-logP, genome-wide significance level is approximately 3.8). The B allele inherited from C57BL/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of opioid-induced locomotion emerged after approximately 100 min. This locus, also associated with a high B allele, was located on Chr 16 with peak linkage of 10.6 (-logP) in females. This locus included only one compelling candidate, fibroblast growth factor 12 (Fgf12), a 600 Kb gene that controls sodium current kinetics at the axon hillock. A strong and transient epistatic interaction existed between the Oprm1 and Fgf12 loci during a short time window (45-75 min). The combination of a B haplotype at Oprm1 with a D haplotype from DBA/2J at Fgf12 was associated with unusually high activity. In a complementary study in heterogeneous stock rats, we demonstrated that Oprm1 and Fgf12 were co-expressed in one specific subtype of Drd1+ medium spiny neuron. A Bayesian network analysis supported an Oprm1-to-Fgf12 network that involves a MAP kinase cascade that modulates FGF12 phosphorylation and locomotor activation. OPRM1 and FGF12 networks in human GWAS data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.

genetics↗