Role of the anterior and posterior Paraventricular Nucleus of the Thalamus on Sign-Tracking in inbred C57BL/6J and DBA/2J mice

Aims: Sign-tracking (ST) behavior is a model of overwhelming attraction to rewards-associated stimuli due to incentive salience attribution as measured by the Pavlovian Conditioned Approach (PCA) paradigm. Previous studies suggested different strain-specific neurobiological substrates underlying ST behavior. This study was aimed at investigating the genotype-dependent networks mediating ST phenotype in C57BL/6J (C57) andDBA/2J (DBA) mice. Methods: In experiment 1 quantification of the c-fos protein was a marker of neural activation of strain-specific circuits during expression of ST behavior. After training, Paired (CS-food presentation) and Unpaired(random CS and food presentation) mice underwent a short exposure only to the lever-CS and then sacrificed for the immunohistochemistry. According to the results, in experiment 2 an excitotoxic lesion by NMDA infusion within the anterior and posterior Paraventricular Nucleus of the Thalamus (PVT) was performed before PCA training. Results: PVT was the only area expressing c-fos immunostaining in both strains though with opposite direction. Indeed, when compared to the respective Unpaired mice, c-fos expression was increased in C57Paired and decreased in DBA Paired mice. Moreover, while the aPVT showed to be more involved in ST expression for DBA mice, any antero-posterior gradient was found relative to the activation for C57 mice. However, lesion of the aPVT selectively reduced ST behavior in DBA mice, while the pPVT lesion selectively reduced ST behavior in C57 mice. Conclusions: This strain-dependent functional role of the PVT and its anatomical division confirm the hypothesis that ST phenotype may be mediated by different networks in these strains

Conditioned cues associated with aversive stimuli can induce opposite responses by the paraventricular thalamus depending on individuals’ genotype

Appetitive and aversive processes rely on largely overlapping brain systems allowing for flexible adaptation of values to variable contexts and subjective states. The paraventricular thalamus (PVT) has been involved in sign-tracking (ST), a measure of individual sensitivity to the incentive salience of conditioned rewards, and in late retrieval of conditioned response to aversive cues. Male mice from the C57BL/6J (C57) and DBA/2J (DBA) inbred strains, whose genotypes differ for ∼5 million known sequence variants, engage different brain areas in associative learning. In specific protocols mice from the two strains do not show differences in development of ST or incubation of cue-conditioned freezing. c-Fos expression measured in C57 mice following ST testing in extinction or after exposure to the fear-conditioned cue late after training (14 days) showed increased expression within the medial-posterior PVT (mpPVT). Instead, c-Fos expression was inhibited in DBA mice tested for ST but increased in mice of this strain exposed to the fear-conditioned cue, in both cases in the anterior PVT (aPVT). An antero-posterior distribution of specific neuronal populations in the PVT, previously associated with anatomic organization of cortical-subcortical connectivity, was confirmed in C57 but not in DBA mice. Finally, excitotoxic lesion of the pPVT were most effective in preventing ST development by C57 mice while only lesions targeting the aPVT were effective in DBA mice

Opposite genotype-specific effects of serotoninergic treatments on Pavlovian Conditioned Approach in mice of two inbred strains C57 BL/6J and DBA/2J

Individual variability in the response to pharmacological therapies is a major problem in the treatment of psychiatric disorders. Comparative studies of phenotypes expressed by mice of the C57BL/6J (C57) and DBA/2J (DBA) inbred strains can help identify neurobiological determinants of this variability at preclinical levels. We have recently demonstrated that whereas young adult mice of both strains develop sign-tracking in a Pavlovian Conditioned Approach (PCA), a trait associated with dysfunctional behavior in rat models, in full adult C57 mice acquisition of this phenotype is inhibited by pre-frontal cortical (PFC) serotonin (5HT) transmission. These findings suggest a different role of 5HT transmission on sign-tracking development in mice of the two genotypes. In the present experiments, we tested the effects of the 5-HT synthesis booster 5-hydroxytryptophan (5-HTP) and of the selective 5HT reuptake inhibitor (SSRI) fluoxetine on the development and expression of sign-tracking in young adult mice from both inbred strains. In mice of the C57 strain, administration of 5-HTP before each training session blocked the training-induced shift to positive PCA scores which indicates the development of sign-tracking, whereas the same treatment was ineffective in mice of DBA strain. On the other hand, a single administration of fluoxetine was ineffective in unhandled saline- and 5-HTP-treated C57 mice, whereas it enhanced the expression of positive PCA scores by mice of DBA strain treated with 5-HTP during training. These findings confirm the strain-specific inhibitory role of PFC 5-HT transmission on sign-tracking development by mice of the C57 strain and support the hypothesis that different genotype-specific neurobiological substrates of dysfunctional phenotypes contribute to variable effects of pharmacotherapies

Repetitive and Inflexible Active Coping and Addiction-like Neuroplasticity in Stressed Mice of a Helplessness–Resistant Inbred Strain

Dysfunctional coping styles are involved in the development, persistence, and relapse of psychiatric diseases. Passive coping with stress challenges (helplessness) is most commonly used in animal models of dysfunctional coping, although active coping strategies are associated with generalized anxiety disorder, social anxiety disorder, panic, and phobias as well as obsessive-compulsive and post-traumatic stress disorder. This paper analyzes the development of dysfunctional active coping strategies of mice of the helplessness–resistant DBA/2J (D2) inbred strain, submitted to temporary reduction in food availability in an uncontrollable and unavoidable condition. The results indicate that food-restricted D2 mice developed a stereotyped form of food anticipatory activity and dysfunctional reactive coping in novel aversive contexts and acquired inflexible and perseverant escape strategies in novel stressful situations. The evaluation of FosB/DeltaFosB immunostaining in different brain areas of food-restricted D2 mice revealed a pattern of expression typically associated with behavioral sensitization to addictive drugs and compulsivity. These results support the conclusion that an active coping style represents an endophenotype of mental disturbances characterized by perseverant and inflexible behavior