Genotype-dependent functional role of the anterior and posterior paraventricular thalamus underlying the incubation of conditioned fear memories

Understanding the neural circuits underlying individual differences in psychiatric disorders is essential for advancing personalized treatment strategies. Using two inbred mouse strains—C57BL/6J (C57) and DBA/2J (DBA)—we have observed similar appetitive and aversive conditioned behaviors, but with distinct recruitment of cortico-limbic circuits. The paraventricular nucleus of the thalamus (PVT) plays a central role in these circuits, and recent findings have demonstrated that the anterior (aPVT) and posterior (pPVT) subregions function in opposing ways in C57 and DBA mice when exposed to appetitive conditioning. The present study aims to investigate the role of the aPVT and pPVT in both the acquisition and expression of aversive conditioned behaviors, modeled by the fear incubation paradigm, in C57 and DBA mice. To this aim, mice from both strains received selective lesions (NMDA) in the aPVT or pPVT prior to the fear incubation paradigm (acquisition, Exp. 1), or selective inactivation (DREADDs) of these subregions before re-exposure to the cue 14 days after fear incubation training (expression, Exp. 2). The results confirmed an opposing role for these PVT subregions in C57 and DBA mice, both during acquisition and expression of conditioned fear incubation. This study identifies the PVT as a key source of heterogeneity in brain networks underlying psychopathological vulnerability and provides new insights into how genetic factors shape neural processes, in line with the precision psychiatry approach.