Investigating the involvement of different hippocampal cell populations in the molecular changes associated with vulnerability and resilience to stress-induced anhedonia: focus on redox balance mediators

Major depressive disorder (MDD) is a severe psychiatric disorder characterized by low mood, anhedonia and other debilitating behavioural, cognitive and emotional symptoms. Over the past decades, preclinical and clinical studies have shown that a maladaptive stress response is strongly associated with the onset of MDD, with a consequent deregulation of several molecular systems. It is noteworthy that the effects of stress are highly variable, with most exposed individuals being resilient and able to cope positively with the adverse situation, and a smaller percentage being susceptible and developing psychopathology. The molecular mechanisms underlying resilience and susceptibility are still elusive and their characterization is crucial to identify new targets for a more effective therapeutic strategy. In this context, using the well-known Chronic Mild Stress (CMS) animal model of depression, our group has previously reported that stress-induced vulnerability to anhedonia is associated with increased levels of pro-inflammatory and oxidative stress mediators in the brain. Since both glial and neuronal cells are known to be either actively involved in these processes or severely affected by their dysregulation, the aim of the present study was to investigate the potential involvement of different cell populations in the vulnerability or resilience to the anhedonic-like phenotype induced by 2 weeks of CMS. Specifically, by using the sucrose consumption test (SCT) we differentiated between vulnerable and resilient animals, while immunofluorescence staining was used to assess the co-localisation of astrocytic (GFAP) and microglial (IBA-1) markers with HO-1, an antioxidant mediator, in ventral (VH) and dorsal (DH) hippocampal slices. Our results showed that the CMS paradigm affected both glial cell density and HO-1 expression, with most of the changes occurring within the hippocampal dentate gyrus (DG). Specifically, we observed increased astrocyte numbers in the DH and VH of both stress-vulnerable and resilient groups, suggesting that astrocytic reactivity reflects a general stress response. Conversely, we found increased microglial numbers only in the VH of vulnerable rats, whereas resilient rats showed either unchanged (VH) or decreased (DH) IBA1-positive cell numbers, suggesting that microglial activation appears to be related to stress vulnerability and pointing to the VH as a potential hub for this process. Furthermore, we observed that the HO-1 signal was only partially attributable to glial cells, as neuron-like cells appeared to be mainly responsible for its expression. In conclusion, although further studies are required, our data provide novel information on the cell populations involved in development of stress-induced vulnerability or resilience to anhedonia.