Combined Restraint Stress and Metal Exposure Paradigms in Rats: Unravelling Behavioural and Neurochemical Perturbations.

Accumulation of heavy metals (Mn and Ni) and prolonged exposure to stress are associated with adverse health outcomes. Various studies have shown the impacts of stress and metal exposures on brain function. However, no study has examined the effects of co-exposure to stress, Mn, and Ni on the brain. This study addresses this gap by evaluating oxidative and glial responses, apoptotic activity, as well as cognitive processes in a rat model. Adult Wistar rats were exposed to vehicle (control), restraint stress, 25 mg/kg of manganese (Mn) or nickel (Ni), or combined restraint stress plus Mn or Ni. Following treatment, rats were subjected to several behavioural paradigms to assess cognitive function. Enzyme activity, as well as ATPase levels, were evaluated. Thereafter, an immunohistochemical procedure was utilised to evaluate neurochemical markers of glial function, myelination, oxidative stress, and apoptosis in the hippocampus, prefrontal cortex (PFC), and striatum. Results showed that stress and metal exposure increased oxidative stress markers and reduced antioxidant levels. Further, combined stress and metal exposure reduced various forms of learning and memory ability in rats. In addition, there were alterations in Iba1 activity and Nrf2 levels, reduced Olig2 and myelin basic protein (MBP) levels, and increased caspase-3 expression. These neurotoxic outcomes were mostly exacerbated by co-exposure to stress and metals. Overall, our findings establish that stress and metal exposures impaired cognitive performance, induced oxidative stress and apoptosis, and led to demyelination effects which were worsened by combined stress and metal exposure.