Dorsal hippocampus mediates light-tone sensory preconditioning task in mice

Daily choices are often influenced by environmental cues that are not directly linked to reinforcers. This process is known as higher-order conditioning and can be measured using sensory preconditioning tasks in rodents. This behavioral paradigm requires the repeated and simultaneous presentation of two low-salience stimuli, such as a light and a tone, followed by a devaluation phase where one stimulus is paired with an unconditioned stimulus, such as a mild footshock. The outcome is a conditioned response (i.e. freezing response) to both the conditioned stimulus (direct learning) and the non-conditioned stimulus (mediated learning). In our study, we set up a successful light-tone sensory preconditioning task in male and female mice. Sex differences were seen on the number of conditioning sessions required to acquire mediated learning and in the behavioral responses observed in certain control experimental groups. We used in vivo calcium imaging to characterize the activity of hippocampal neurons in the dorsal and ventral subregions of the hippocampus when associations between low-salience stimuli and reinforcers occur. Finally, we combined our sensory preconditioning task with chemogenetic approaches to assess the role of these two hippocampal subregions in mediated learning. Our results indicate that dorsal, but not ventral, CaMKII-positive cells mediate the encoding of low-salience stimuli during the preconditioning phase. Overall, we implemented a novel light-tone sensory preconditioning protocol in mice that allowed us to detect sex differences and to further elucidate the role of particular hippocampal subregions and cell types in regulating these complex cognitive processes.