Futher characterization of the roman rats as a model of behavioral, neuroanatomical and neurochemical schizophrenia-relevant features

Resumen

The present Doctoral Dissertation gathers a series of studies in which we have tried to collect as much evidence as possible in a behavioral, neuroanatomical and molecular level with the aim of validating a new animal model for the study of schizophrenia-relevant symptoms. Such model is constituted by the Roman rats, two inbred strains of rats that have been psychogenetically selected by their good (RHA-I) versus extremely poor (RLA-I) acquisition of the two-way active avoidance task in the shuttle box, giving as a result two strains with well-defined and differential profiles in stress sensitivity, anxiety/fearfulness, impulsivity, vulnerability to drugs of abuse and phenotypes related to the dopaminergic, serotoninergic and glutamatergic neurotransmission systems. In the present work, we have carried out a number of experiments devoted to complete the characterization of the Roman rats in different behavioral, neurochemical and neuroanatomical phenotypes related to schizophrenia. We have conducted studies on behavioral paradigms relevant for schizophrenia, such as the prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) effect (studies 1 and 2) in which we have obtained that RHA-I rats present an impaired PPI as well as LI, which suggest that these two phenotypes are somehow related and may share common underlying mechanisms. We have also tested the effects of a chronic environmental manipulation such as the isolation rearing of the animals (study 3), in (i) a behavioral level with an extensive battery of tests for schizophrenia-relevant phenotypes, (ii) a molecular level, with the analysis of the 5HT2A receptor density and (iii) an anatomical level with the volume estimation of three areas relevant for schizophrenia, such as the prefrontal cortex (PFC), the dorsal striatum (dST) and the hippocampus (HPC). We have observed that, while the behavioral profile has followed our initial expectations of more profound deficits induced by social isolation in the RHA-I rats, we have obtained paradoxical results on the binding studies and volume estimation analysis. Thus, although no differences have been observed in the 5HT2A receptor binding density, we have found between-strain differences in the volume of PFC, HPC and dST (RLA-I>RHA-I in every area), and a global effect of the treatment in the PFC volume. From the need of transferring the Roman rats from the animal facilities in our lab (where they have been maintained since 1993) to a new SPF animal facility within the Autonomous University of Barcelona, we carried out an embryo transfer procedure (study 4), and we phenotyped the 5th generation of animals from this new SPF colony. We observed that this new SPF colony of Roman rats display the typical between-strain differences in the G5 in every phenotype tested, both behavioral and hormonal. Lastly, according to the results obtained in study 3, in which we observed a difference in the mPFC volume between RHA-I and RLA rats, we decided to study some of the possible causes of this difference in the new SPF colony of Roman rats. In this regard, we studied two parameters that are thought to be altered in schizophrenia, the dendritic spine density and the number of parvalbumin-expressing (PV+) neurons in the PFC (study 5). We observed that there is a significant difference in spine density between the two strains, with a higher percentage of small spines in RHA-I rats and a higher percentage of large spines in the RLA-I rats, while the number of PV+ neurons was not different between the strains. The data gathered in the present Dissertation adds value to the proposition of the RHA-I rat strain as a useful tool for the study of some relevant symptoms and neurobiological features relevant to schizophrenia.