Exposure to chronic stress impairs the ability to cope with an acute challenge: Modulation by lurasidone treatment.

Chronic stress represents a major contributor for the development of mental illness. This study aimed to investigate how animals exposed to chronic mild stress (CMS) responded to an acute stress (AS), as a vulnerability's challenge, and to establish the potential effects of the antipsychotic drug lurasidone on such mechanisms. Adult male Wistar rats were exposed or not (controls) to a CMS paradigm for 7 weeks. Starting from the end of week 2, animals were randomized to receive vehicle or lurasidone for 5 weeks. Sucrose intake was used to measure anhedonia. At the end, half of the animals were exposed to an acute stress before sacrifice. Exposure to CMS produced a significant reduction in sucrose consumption, whereas lurasidone progressively normalized such alteration. We found that exposure to AS produced an upregulation of Brain derived neurotrophic factor (Bdnf) in the prefrontal cortex of controls animals. This response was impaired in CMS rats and restored by lurasidone treatment. While in control animals, AS-induced increase of Bdnf mRNA levels was specific for Parvalbumin cells, CMS rats treated with lurasidone show a significant upregulation of Bdnf in pyramidal cells. Furthermore, when investigating the activation of different brain regions, CMS rats showed an impairment in the global response to the acute stressor, that was largely restored by lurasidone treatment. Our results suggest that lurasidone treatment in CMS rats may regulate specific circuits and mechanisms, which will ultimately contribute to boost resilience under stressful challenges.

Dual influences of early life stress induced by limited bedding on walking adaptability and Bdnf/TrkB and Drd1/Drd2 gene expression in different mouse brain regions.

Introduction Evidence suggests early life stress impairs development, quality of life and increases vulnerability to disease. One important aspect of the stress experience is its impact on cognitive-motor performance, which includes the ability to adapt walking according to the environmental conditions. This study aimed to investigate how early-life stress affects walking adaptability of mice, while investigating BDNF/TrkB and Drd1/Drd2 expression in different brain regions. Methods Briefly, we exposed male C56BL/6 to the limited bedding protocol (LB) from post-natal day (PND) 2 to PND9 and then tested animals in the ladder walking task at PND60. RT-qPCR was used to investigate gene expression in the mPFC, hippocampus, motor cortex and cerebellum 2 h after the task Results LB induced a wide range of variability and therefore two distinct subgroups of animals within the LB group were established: a) superior performance (LB-SP); and b) inferior performance (LB-IP), compared to controls. Additionally, Drd1 gene expression was increased in the mPFC of LB-IP animals and in the cerebellum of LB-SP animals, while Drd2 expression was reduced in the hippocampus of the LB-IP group. BDNF exon IV gene expression in the mPFC and motor cortex was increased in both the LB-IP and LB-SP subgroups. TrkB gene expression in the hippocampus was reduced in the LB-IP group. A strong negative correlation was found between walking adaptability performance and BDNF exon IV gene expression in the motor cortex. Conversely, a positive correlation was found between walking adaptability performance and TrkB expression in the mPFC and a negative correlation in the hippocampus. Both Drd1 and Drd2 gene expression were negatively correlated with the ability to adapt walking. Conclusions Overall, our findings suggest exposure to early life stress leads to distinct walking adaptability phenotypes, which may be related to Drd1, Drd2, Bdnf exon IV and TrkB gene expression in brain regions that influence walking adaptability.