Dèficits de filtratge sensoriomotor similars a l'esquizofrènia en rates consanguínies i no consanguínies intactesde la conducta als mecanismes cerebrals i viceversa

Resum

Schizophrenia is a debilitating mental disorder that involves several cognitive symptoms, including sensorimotor gating impairments. Sensorimotor gating can be measured via prepulse inhibition (PPI) of the startle response, in which the magnitude of a startle stimulus is attenuated by the presence of a pre-stimulus of lower intensity. Rodent studies evaluating the impact of brain-site specific manipulations on PPI have been very useful to provide insights into this basic schizophrenia-like deficiency. These studies show that PPI deficits are frequently accompanied by other symptoms, including psychomotor agitation, as well as alterations in the cortico-striatal-pallido-thalamic (CSPT) circuit. In particular, treatments that increase or decrease the activity of the medial prefrontal cortex (mPFC), hippocampus (HPC), or nucleus accumbens (NAc) reduce PPI. In this context, a dysfunctional cortical excitatory-inhibitory balance has been proposed as the main neural substrate for cognitive dysfunction in schizophrenia. Moreover, these studies show that PPI deficits can be improved by several antipsychotic drugs, including the neuropeptide oxytocin, which has been suggested as an alternative natural antipsychotic. In contrast to these rodent studies, human studies evaluate the association between natural behavioral differences (diagnosis, symptoms) and neural changes. Thus, in this Doctoral Dissertation, we aimed to contribute to bridge the gap between human and rodent studies by exploring whether spontaneous deficits in PPI in intact inbred and outbred rats are (i) associated with divergences in other schizophrenia-related behaviors, (ii) related to functional and structural differences in the CSPT circuit, and (iii) attenuated by oxytocin. Our subjects of study were the inbred Roman high-avoidance (RHA) and Low-avoidance (RLA) rats, and the outbred heterogeneous stock (HS) rats. RHA rats show lower PPI than RLAs, while HS rats were stratified in sub-groups according to their PPI levels. The present experiments also aimed to provide further face, construct, and predictive validity to our animal models of schizophrenia-relevant symptoms (RHA and HS Low-PPI rats). Regarding behavioral associations, our results show that increased exploration in response to novelty is associated with deficient PPI in HS and Roman rats. Moreover, a high anxious profile was found in rats with increased PPI, while no associations were seen with compulsive-like behavior. In relation to brain structural and functional associations with PPI, we combined structural magnetic resonance imaging and c-Fos expression after PPI in both HS and Roman rats. Our results indicate that lower PPI is associated with decreased mPFC activity in both Roman and HS rats and with increased NAc shell activity in HS rats. Reduced PPI is also associated with decreased mPFC and HPC volumes in Roman and HS rats. Additionally, using immunofluorescence after PPI, we observed a lower percentage of active inhibitory GABAergic parvalbumin interneurons in RHA than RLA rats. Regarding oxytocin administration, we found that oxytocin increased PPI in HS rats, attenuated PPI deficits in RHA rats, and did not affect PPI in RLAs. Consistent with the differential oxytocin effects on PPI (RHA>RLA), constitutive CD38 gen expression (regulator of oxytocin release) was reduced in the mPFC of RHA rats compared to the RLAs, while oxytocin administration increased oxytocin receptor (OXTR) gen expression in both strains. This Doctoral Dissertation shows a consistent pattern of behavioral and neurobiological abnormalities in the HS-Low-PPI rats and RHA rats that increases the face, construct, and predictive validity of these rats as models of schizophrenia-related features. Importantly, our results support the idea that sensorimotor gating is modulated by forebrain structures and highlight the relevance of the mPFC and the cortical excitatory-inhibitory balance in its regulation.