Behavioral And Molecular Profiles Of A Heuristic Genetic Model Of Vulnerability To Stress-Induced Depression And Schizophrenia-Related Symptoms: The Roman Low- Vs High-Avoidance Rat Lines/Strains

Depression and schizophrenia (SCZ) are major contributors to the enormous burden in terms of health care costs and major social and economic issues of psychiatric illnesses. Animal models of these disorders are all-important preclinical tools for the investigation of their neurobiological basis. According to epidemiologic studies depression is approximately 35% heritable, while tween studies and a genome wide association study (GWAS) demonstrate that SCZ is predominantly a genetic disorder with heritability estimated to be around 80%. Genetic factors influence the overall risk of these illnesses but also influence the sensitivity of individuals to the depression- or schizophrenia-inducing effects of environmental adversities. The combination of genetics, early life stress and ongoing stress may determine the individual responsiveness to stress and the vulnerability to depression or SCZ, but also to the impairments of cellular plasticity observed in these pathologies. The neurotrophic hypothesis proposes that depression may be caused by dysfunction of the mechanisms underlying the plasticity of neuronal networks, and that the vulnerability to stress-induced depression results from the abnormal expression of genes that encode trophic factors, such as BDNF. The Roman High- (RHA) and Low-Avoidance (RLA) rats represent a model that provides a valid approach to the investigation of the contribution of the genotype and its interactions with environmental factors on the neural substrates of depression and SCZ. Neurobehavioral and pharmacological evidence suggesting that RLA rats may be considered as a genetic model of vulnerability to stress-induced depression, whereas RHA rats have been proposed as a potential genetic model of schizophrenia-relevant features. In the first study we evaluated the behavioral and neurochemical responses of roman rats acutely exposed to Tail Pinch (TP), a mild stressor, or Forced Swimming (FS), a stressor of relatively higher intensity. The expression of the neurotrophic factor BDNF and its receptor trkB was measured by means of Western blots to assess the neural plasticity activity elicited by TP and FS in the Prefrontal Cortex, involved in the process of decision-making, and the Hippocampus, which plays a major role in the control of emotions and in the consolidation of new memories. In the second study we evaluated social interaction (SI) in RHA and RLA rats under basal conditions. Furthermore, in view of the long-term consequences elicited by early-life events on mental health, we studied whether NH may impact in adulthood, on social interaction and anxiety/fear related behaviors. In STUDY I, we demonstrated that, when exposed to TP and FS, RLA rats display a depression-like behavior while their RHA counterparts exhibit a proactive coping style characterized by active behaviors aimed at gaining control over the stressors. Moreover, line- and brain region-dependent differences were observed in the expression of BDNF and trkB upon exposure to either stressor. In STUDY II we found that, in RHA rats, which show a low level of SI under basal conditions, NH significantly increased sociality in the SI test, as reflected by a longer social time and higher social preference in the first 5 minutes of the test; in RLA rats, which are strongly emotional under basal conditions, NH reduced anxiety as indicated by a significant decrease in Grooming time. The results of these studies provide further experimental support to the view that the Roman rats may represent a valid experimental approach to investigate the neural substrates and molecular mechanisms that impact on the individual vulnerability or resistance to stress-induced depression and to identify the mechanisms whereby early-life positive events interact with the genetically determined vulnerability to develop psychotic disorders. Therefore, they may provide useful leads for the development of innovative drugs for the treatment of Depression and SCZ.