Evidence for the involvement of extinction-associated inhibitory learning in the forced swimming test.

The forced swimming test (FST) remains one of the most used tools for screening antidepressants in rodent models. Nonetheless, the nature of immobility, its main behavioral measure, is still a matter of debate. The present study took advantage of our recent finding that mice of the inbred DBA/2J strain require a functioning left dorsolateral striatum (DLS) to consolidate long-term memory of FST to test whether immobility is the outcome of stress-related learning. Infusion of the GABA-A agonist muscimol in the left DLS immediately after a single experience of FST prevented and infusion in the left or the right amygdala impaired recall of the acquired levels of immobility in a probe test performed 24h later. Post-training left DLS infusion of muscimol, at a dose capable of preventing retention of FST-induced immobility, did not influence 24h retention of inhibitory avoidance training or of the escape response acquired in a water T-maze. However, this same treatment prevented 24h retention of the extinction training of the consolidated escape response. These results indicate that a left DLS-centered memory system selectively mediates memory consolidation of FST and of escape extinction and support the hypothesis that immobility is the result of extinction-like inhibitory learning involving all available escape responses due to the inescapable/unavoidable nature of FST experience.

Either the dorsal hippocampus or the dorsolateral striatum is selectively involved in consolidation of forced swim-induced immobility depending on genetic background.

Healthy subjects differ in the memory system they engage to learn dual-solution tasks. Both genotype and stress experience could contribute to this phenotypic variability. The present experiments tested whether the hippocampus and the dorsal striatum, the core nodes of two different memory systems, are differently involved in 24 h retention of a stress-associated memory in two genetically unrelated inbred strains of mice. Mice from both the C57BL/6J and the DBA/2J inbred strains showed progressive increase of immobility during 10 min exposure to forced swim (FS) and retrieved the acquired levels of immobility when tested 24h later. The pattern of c-fos immunostaining promoted by FS revealed activation of a large number of brain areas in both strains, including CA1 and CA3 fields of the hippocampus. However, only DBA/2J mice showed activation of the dorsolateral striatum (DLS). In addition, FS induced a positive correlation between c-fos expression in the amygdala and CA1 and CA3 in C57BL/6J mice whereas it induced a positive correlation between c-fos expression in the amygdala and DLS in DBA/2J mice. Finally, temporary post-training inactivation of the dorsal hippocampus, by local infusion of lidocaine, prevented 24h retention of immobility in C57BL/6J mice only, whereas inactivation of the DLS prevented retention in DBA/2J mice only. These findings support the view that genetic factors can determine whether the dorsal hippocampus or the DLS are selectively engaged to consolidate stress-related memory.

Association between striatal accumulation of FosB/ΔFosB and long-term psychomotor sensitization to amphetamine in mice depends on the genetic background.

Previous results demonstrated association between increased FosB/ΔFosB immunostaining in the ventromedial striatum and behavioral sensitization to amphetamine promoted by repeated stress or by repeated pairings of the psychostimulant and the testing cage in mice of the C57BL/6J strain. The present experiments tested this association in an additional protocol, its stability following the end of the sensitizing procedure and its generalization to mice from a different inbred strain. Eleven days after repeated administration of amphetamine within their home-cages, mice of the C57BL/6J strain expressed sensitization to the psychomotor effects of the psychostimulant when tested in a novel cage. At this time-point the same mice showed increased FosB/ΔFosB immunostaining in the ventromedial striatum. Instead, mice of the genetically unrelated DBA/2J inbred strain expressing robust sensitization in the same protocol did not show changes in FosB/ΔFosB immunostaining throughout the striatal complex. Lack of effects in FosB/ΔFosB immunostaining was also observed in DBA/2J mice behaviorally sensitized by repeated pairings of amphetamine with the test cage. These results demonstrate that mice, depending on the genetic background, can develop robust and long-lasting behavioral sensitization to amphetamine in the absence of striatal ΔFosB accumulation.

Strain-specific proportion of the two isoforms of the dopamine D2 receptor in the mouse striatum: associated neural and behavioral phenotypes.

Genetic variability in the proportion of the two alternative dopamine D2 receptor (D2R) mRNA splice variants, D2R-long (D2L) and D2R-short (D2S), influence corticostriatal functioning and could be implicated in liability to psychopathology. This study compared mesostriatal D2L/D2S ratios and associated neural and behavioral phenotypes in mice of the DBA/2J and C57BL/6J-inbred strains, which differ for schizophrenia- and addiction-like phenotypes. Results showed that DBA/2J mice lack the striatal predominance of D2L that has been reported in the rat and in C57BL/6J mice and confirmed in the latter strain by this study. Only C57BL/6J mice showed enhanced striatal c-Fos expression under D1R and D2/3R co-stimulation, indicating synergistic interaction between the subtypes of DA receptors. Instead, DBA/2J mice were characterized by opposing effects of D2/3R and D1R stimulation on striatal c-Fos expression, in line with a more pronounced influence of D2S isoform, and did not express stereotyped climbing under D1R and D2/3R co-stimulation, as reported for D2L-/- mice. Finally, strain-specific modulation of c-Fos expression by D1R and D2/3R co-stimulation was selectively observed in striatal compartments receiving inputs from the prefrontal cortex and involved in the control of motivated behaviors. These results show differences in tissue-specific D2R splicing in mice with intact genotypes and support a role for this phenotype in individual variability of corticostriatal functioning and in liability to psychopathology.

DeltaFosB accumulation in ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by both repeated amphetamine and stress.

Both repeated psychostimulants and stress have the ability to promote behavioral sensitization, i.e. enhanced behavioral response to drug challenge. To test whether the behavioral phenotype is also accompanied by similar neuroplastic adaptations, the present study evaluated changes in Fos and FosB/DeltaFosB transcription factors induced in the brain of C57BL/6J mice behaviorally sensitized by repeated amphetamine or repeated restraint stress. Groups of mice received repeated injections of D-amphetamine or saline in group-specific environments. Different groups of mice experienced 2 h of restraint daily for 10 consecutive days. Amphetamine- pre-treated mice, drug-challenged in the environment in which they received drug treatments (Paired), as well as repeatedly stressed mice expressed robust sensitization to the locomotor effects of amphetamine. Both stress- and amphetamine-pre-treated groups showed changes in amphetamine-induced Fos expression; however, none of these changes was shared by the two sensitizing treatments. Instead, accumulation of FosB/DeltaFosB immunoreactivity in the ventro-medial caudate was common to both pre-treatments. These results support the hypothesis that a common neuroadaptive process involving DeltaFosB accumulation in the ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by different conditions.