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 α1C subunit of the L-type voltage-gated calcium channel CaV1.2, 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.

PEAß Triggers Cognitive Decline and Amyloid Burden in a Novel Mouse Model of Alzheimer's Disease.

Understanding the physiopathology of Alzheimer's disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-ß (pEAß) species in the brain. The TAPS line was developed by intercrossing of the pEAß-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAß-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAß- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies.

Ultrasonic vocalizations and individual differences in rats performing a Pavlovian conditioned approach task.

Rats emit distinct types of ultrasonic vocalizations (USV), including high-frequency 50-kHz USV, which occur in appetitive situations. Such 50-kHz USV are thought to reflect positive affective states, for example in case of reward anticipation, and are linked to dopamine signaling. The present study was conducted to investigate whether rats emit 50-kHz USV during a Pavlovian conditioned approach task and whether trait-like differences in 50-kHz USV emission are associated with sign- versus goal-tracking. We hypothesize that individuals engaging more with a cue predicting a food reward will also elicit more 50-kHz USV. In order to test this, we investigated 34 female rats and gauged USV while they underwent a Pavlovian conditioned approach training and extinction paradigm. For one, we found a high subject-dependent variability in the emission of 50-kHz calls. These were not largely affected by state differences, since these 50-kHz USV were observed throughout the task. During task progress and in most subjects, there was a rather complete shift toward goal-tracking, but subjects engaging more with the cue predicting a reward also emitted higher numbers of appetitive 50-kHz calls. This supports the hypothesis that sign-tracking is positively associated with the emission of 50-kHz USV. The high subject-dependent variability in the emission of 50-kHz calls warrants special attention in future appetitive studies.