Altered Behavior of Prenatally Valproic Acid-Exposed Rats Group-Housed in Automated Home Cages

Background: Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function and repetitive/restricted behaviors. Prenatal valproic acid (VPA) administration in rodents shows several similarities to ASD symptoms (also frequently seen after fetal VPA exposure in humans), hence it is used as a preclinical disease model of ASD with high translational value.

Objectives: The aim of the present study was to characterize ASD-relevant behaviors of communities of individually identifiable rats in automated home cages without human intervention.

Methods: Ten prenatally VPA-exposed (E12.5, 300 mg/kg i.p.) and ten control (E12.5, physiological saline i.p.) Wistar rats were housed in two IntelliCages (TSE Systems, Germany). An IntelliCage unit consisted of an open communal space and four recording chambers in the corners with two drinking bottles per corner behind remotely controlled doors. Rats were individually implanted with a transponder which allowed recording visits and drinking behavior. To open the controlled doors, animals had to perform a nosepoke. The behavior of the animals and activity within the corners of the cage was monitored using a tracking software (IntelliCage Plus, TSE Systems). The principal parameters reflecting activity were number of visits to any of the four corners, initiated nosepokes, lick number, and duration of these parameters. The stay at the IntelliCages was divided into phases of 1) acclimation (unlimited drinking opportunity), 2) nosepoke learning (drinking for 7 sec allowed after a nosepoke), 3) side preference learning (limited water access with bottles evenly assigned to rats), 4) reversal learning (pseudorandom switch of the previously allowed bottle) and 5) competition (water available from only one bottle for all the rats).

Results: Although rodents normally tend to explore their new environment, the prenatally VPA-exposed rats showed a drastic impairment in initial exploratory behavior (visit without drinking). A generally reduced exploratory behavior was seen throughout the experiment which may indicate an increased level of anxiety. The circadian activity peak of the VPA group was shifted by approximately two hours during the acclimation period when water was available without restriction. The VPA group displayed excessive drinking, which could be a sign of increased repetitive behavior, since the general physiological status and blood chemistry of the VPA group did not show a significant difference compared to the vehicle group. Vehicle and VPA group did not differ in side preference or reversal learning abilities. In the competitive phase, the vehicle group switched to uneven resource distribution, where only a few dominant animals had access to water. Interestingly, they secured their chance to drink with frequent iterating visits, thereby “guarding” the water resource. VPA animals did not switch to uneven distribution, they shared the water access more evenly between each other and displayed no evidence of guarding behavior.

Conclusions: Investigating prenatally VPA-exposed rats in the IntelliCage allowed us to detect novel features of the model that further increase the translational value of the model, potentially provide a better understanding of the disorder and may facilitate ASD drug discovery.