Abstract

Transgenic rat strains differ in attribution of incentive value to reward-associated cues

Westbrook SR, Iglesias AG, Lopez SA, Davies HE, Li F, Akil H, Desseroth K, Herman JP, Flagel SB
50th Annual Meeting of the Society for Neuroscience, Virtual. 2021.

Transgenic rat strains are becoming increasingly available and popular for use in neuroscience research. However, the behavioral phenotypes of these transgenic rat strains are often not studied or overlooked in favor of their utility for probing neural mechanisms. Here, we compared the tendency of three transgenic rat strains—glucocorticoid receptor (GR)-CRISPR, tyrosine hydroxylase (TH)-Cre, and Orexin-Cre—to attribute incentive value to a reward-associated cue in a Pavlovian conditioned approach (PavCA) task. All three transgenic strains were bred in-house at the University of Michigan. GR-CRISPR rats have a Sprague Dawley background, while TH-Cre and Orexin-Cre rats have a Long Evans background. Adult rats were exposed to a PavCA task for 5 sessions, during which an illuminated lever (conditioned stimulus, CS) was extended for 8 seconds before it was retracted, and a food pellet (unconditioned stimulus, US) was delivered into an adjacent food cup. Each session consisted of 25 lever-food (CS-US) pairings. Upon Pavlovian learning, rats developed a conditioned response directed towards the lever-CS (sign-trackers, STs), the food cup-US (goal-trackers, GTs), or they vacillated between the two (intermediate responders, IRs). Rats were classified as STs, GTs, or IRs based on a composite PavCA index that incorporates the numbers of contacts with, the probability to approach, and the latency to approach the lever vs. the food cup during lever presentations. We found that the three transgenic strains differed in their distribution of these behavioral phenotypes. The GR-CRISPR strain is heavily skewed towards STs (87%) with zero GTs to date after 6 litters across F1 and F2 generations. The TH-Cre strain is also skewed towards STs (72%). The Orexin-Cre strain shows a more even distribution between STs (41%), IRs (39%), and GTs (20%), which is similar to what we have observed in outbred rat strains (~33% each). Importantly, these differences in transgenic strains are not due to breeding protocols, as all were bred in-house with similar procedures and precautions to minimize inbreeding. Nor can these findings be explained by background strain, as both TH-Cre and Orexin-Cre rats have a Long Evans background, yet the TH-Cre line is skewed towards STs. These findings demonstrate that we should not assume the distribution of behavioral phenotypes in transgenic rat strains is the same as outbred strains or as other transgenic strains based on genetic background or breeding factors. Further, these findings have significant implications for the use of transgenic rat strains and emphasize the need to determine behavioral phenotypes prior to probing neural mechanisms.