The importance of rat social behavior for translational research: An ethological approach

Abstract

At present, the preclinical research interest in rodent social behavior is focused on its use as readout parameter in animal models for neuropsychiatric disorders (‘translational research’). However, there are some major limitations that hamper progress. Pivotal is the limited translational value of the animal models. This becomes apparent by the lack of reproducibility of research results and an overestimation of treatment effects. In this thesis I argue that this can be partly attributed to a currently common practice in behavioral neuroscience: i.e. a limited and too simplistic analysis of animal behavior which ignores behavioral complexity both in approach and analysis. To overcome this problem, I have adopted an ethological approach combined with automation of behavioral analysis to facilitate measurements of rat social behavior. To this end, I have developed a methodology allowing continuous monitoring of social interactions in an experimental setup, including species-specific characteristics. Next, this approach has been applied and tested on two established animal models of impaired social behavior: a chronic phencyclidine (PCP) model and the play deprivation model. Both models were chosen because of their known efficacy to reduce social behavior. An adjusted large home-cage enclosure permitting observations of group-housed rats was used in which rat behavior can be automatically followed and ultrasonic vocalizations can be recorded. First, I show that rat social behavior can be categorized in three distinct modes of inter-individual distances, ‘in contact’, ‘in proximity’ and ‘not in proximity’. A combination of the social modes with the velocity modes, ‘moving with low or high speed’ yields specific categories of behavior. These are susceptible to pharmacological treatments and environmental manipulations. Furthermore, the behavioral categories we defined with our automated analysis approach are consistent with the categories obtained with human scoring of these behaviors (hand scoring of the same experiments). Therefore, automated recognition of patterns in social behavior is a powerful tool for data analysis. Screening of rat exposed to PCP for 2 weeks revealed that the validity of chronic PCP administration as a model for diminished social behavior is limited to short term effects. Because, it only results in a temporarily reduction of social behavior. Moreover, the consummatory phase, i.e. the phase of active social interaction behavior, is not permanently affected, yet, the appetitive phase of social behavior seems permanently effected by chronic PCP, as reflected by a reduction in motivation to engage in social behavior. In the play deprivation model, play deprivation during the sensitive period leads to diminished adult social behavior, according to current literature. However, my behavioral analysis revealed a different effect of play deprivation on adult social behavior. Rather than diminishing sociability, play-deprived rats were actually more sensitive to social contact, i.e. effect of play deprivation merely on the appetitive phase. Also, play-deprived animals were more sensitive to a novel environment, when tested individually. Thus, the studies in this thesis show that an ethological approach in combination with automated methodology reveal differential effects of drug treatment or environmental manipulation on social behavior of rats.