Appetitive 50 kHz calls in a pavlovian conditioned approach task in Cacna1c haploinsufficient rats

We have previously shown that rats emit high-frequency 50 kHz ultrasonic vocalizations (USV) during sign- and goal-tracking in a common Pavlovian conditioned approach task. Such 50 kHz calls are probably related to positive affect and are associated with meso-limbic dopamine function. In humans, the CACNA1C gene, encoding for the α_1C subunit of the L-type voltage-gated calcium channel Ca_V1.2, is implicated in several mental disorders, including mood disorders associated with altered dopamine signaling. In the present study, we investigated sign- and goal-tracking behavior and the emission of 50 kHz USV in Cacna1c haploinsufficent rats in a task where food pellet delivery is signaled by an appearance of an otherwise inoperable lever. Over the course of this Pavlovian training, these rats not only increased their approach to the reward site, but also their rates of pressing the inoperable lever. During subsequent extinction tests, where reward delivery was omitted, extinction patterns differed between reward site (i.e. magazine entries) and lever, since magazine entries quickly declined whereas behavior towards the lever transiently increased. Based on established criteria to define sign- or goal-tracking individuals, no CACNA1C rat met a sign-tracking criterion, since around 42% of rats tested where goal-trackers and the other 58% fell into an intermediate range. Regarding USV, we found that the CACNA1C rats emitted 50 kHz calls with a clear subject-dependent pattern; also, most of them were of a flat subtype and occurred mainly during initial habituation phases without cues or rewards. Compared, to previously published wildtype controls, Cacna1c haploinsufficent rats displayed reduced numbers of appetitive 50 kHz calls. Moreover, similar to wildtype littermate controls, 50 kHz call emission in Cacna1c haploinsufficent rats was intra-individually stable over training days and was negatively associated with goal-tracking. Together, these findings provide evidence in support of 50 kHz calls as trait marker. The finding that Cacna1c haploinsufficent rats show reductions of 50 kHz calls accompanied with more goal-tracking, is consistent with the assumption of altered dopamine signaling in these rats, a finding which supports their applicability in models of mental disorders.