Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Individual differences of brain networks of aberrant conditioned motivation: role of the Paraventricular Nucleus of the Thalamus

Background: An individualized approach to mental diseases might help increase the now-limited efficacy of therapies. However, this approach needs the understanding of variable sensitivity to treatment by individuals presenting the same symptom profile. We have previously found that mice of two inbred strains (C57BL/6J: C57 and DBA/2J: DBA) show the same behavioral phenotype that is only susceptible to a serotonin-targeted treatment in C57 mice. The phenotype (sign tracking: ST) is a marker of high seeking of a conditioned reward. Moreover, it is listed amongst the behavioral units of analysis identified as targets of preclinical research by NMIH-RDoC. Finally, comparative studies in inbred mouse strains can best reveal genotype-dependent variability of multifactorial polygenic phenotypes. Aim and Rationale: The present study investigated whether the brain networks mediating response to conditioned stimuli differ in the two strains. To this aim, we tested ST sensitivity to dopamine transmission in the ventral striatum, the activation of the early gene c-Fos by reward- and threat-associated stimuli in brain areas involved in motivational processes, the effects of targeted brain lesions on the development of ST, the strain differences in the neuroanatomy of the brain area thus identified. Results: We found: 1) strain differences in the striatal dopamine receptors mediating ST expression; 2) the involvement of different areas of the paraventricular nucleus of the thalamus (PVT) in the development of ST by mice of the two strains (anterior for DBA, posterior for C57); 3) opposite responses to a threat-associated stimulus in term of c-Fos expression in the medial PVT (increase in DBA, decrease in C57); 4) the strain-dependent distribution of a specific neuronal population within the medial PVT of DBA mice. Conclusion:These findings support a genotype-specific engagement of different PVT-centred circuits in response to motivationally salient stimuli. This variability is not associated with the expression of different behavioral phenotypes. Nonetheless, it can well explain the different sensitivity of these phenotypes to the same therapeutic intervention.