An investigation of neuronal cell death and neuroinflammation in the middle cingulate cortex in Huntington’s Disease

Abstract

Huntington’s disease (HD) is a genetic, neurodegenerative disease. Patients with HD present with several clinical symptoms, including the loss of motor control, behavioural changes, mood and psychiatric symptoms, and cognitive decline. Symptoms of HD typically present in patients in their 40s, followed by the progression of the disease for 15-20 years before eventually resulting in death. The current lack of a cure for HD confers HD research critical in the development of targeted therapeutics for this disease. The cingulate cortex plays a vital role in learning, memory, emotion processing, and cognition. Previous research has indicated that the anterior cingulate cortex shows significant atrophy in HD and may underlie the development of mood symptoms in patients. However, very little research has been conducted in other regions of the cingulate cortex resulting in a poor understanding of the contribution of these areas to the progression of HD. This thesis focuses on the middle cingulate cortex (MCC), which contributes to cognitive processing and skeletomotor control. Significant evidence of neuroinflammatory changes in HD is evident in the literature and has been hypothesised to promote cell death. Microglia and astrocytes are non-neuronal cells, and the activation of these cells facilitates the neuroinflammatory response. In this thesis, I explored anatomical changes in the HD MCC and how they contribute to symptomatology. Additionally, I examined microglial and astrocytic changes in the MCC in HD and how these contributed to anatomical changes of the MCC. By utilising immunohistochemical techniques and design-based stereological sampling, I can conclude that the MCC shows no atrophic anatomical changes and is a relatively robust structure in HD. I also observed a lack of activation of microglia and astrocytes in the MCC, suggesting the absence of chronic inflammation in this region. The results of this thesis carry considerable significance as these findings reveal that the MCC is relatively unaffected in the progression of HD compared to other brain regions that have been previously investigated.