Changes in the functional connectome and behavior after exposure to chronic stress and increasing neurogenesis

Abstract

Addition of new neurons to the dentate gyrus might change the activity of neural circuitry in the areas which the hippocampus projects to. The size of the hippocampus and the number of adult newborn granule cells are decreased by unpredictable chronic mild stress (UCMS). Additionally, one of the notable effects of chronic stress is the induction of {Delta}FosB, an unusually stable transcription factor which accumulates over time in several brain areas. This accumulation has been observed in many animal models of depression and it could have a protective role against stress, but no studies so far have explored how a specific increase in neurogenesis might regulate the induction and which brain networks might be predominately affected. We attempted to investigate the role of increasing adult hippocampal neurogenesis on stress-related behavior and the functional brain circuitry involved in mice exposed to UCMS. We used iBax mice, in which the pro-apoptotic gene Bax can be selectively ablated in neural stem cells, therefore inducibly enhancing survival of newborn neurons after tamoxifen administration. The animals were exposed to UCMS for 9 weeks and treated with tamoxifen in week 3 after the beginning of UCMS. In week 8, they were submitted to a battery of behavioral tests to assess depressive-like and anxiety-like behavior. In week 9, blood was collected to assess basal corticosterone levels, and the animals were sacrificed and their brain collected for {Delta}FosB immunohistochemistry. Brain-wide maps of {Delta}FosB expression were constructed and graph theoretical analyses were used to study the changes in brain networks after stress. UCMS induced negative correlations between the lateral entorhinal cortex and both the hippocampal structures and the nucleus accumbens in the VEH-treated mice, which were not present in other groups. Ranking nodes by degree reveals a strong thalamic-cortical signature in both non-stress (NS) groups. Exposure to UCMS seems to induce activity in thalamic areas and cerebral nuclei, with a different signature in the UCMS TAM group, which seems to completely "disengage" the neocortex and has most of its nodes with the most connections in the thalamic areas.