Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disorder that is associated with repetitive head injury (RHI), which includes both traumatic and subclinical brain injuries. Early CTE is a tauopathy that has patchy distribution of hyperphosphorylated tau within the depths of sulci which progressively spreads. Recent studies of RHI show that deep areas of the brain are most affected during head impacts, with strain due to shearing forces peaking at deep brain regions on the midline. The anterior cingulate cortex (ACC), which is directly on the midline, is likely one of the first regions to be affected by shearing forces yet there have been few studies of the cellular irregularities in the ACC at early stages of CTE. The present study investigated the proportions of inhibitory to excitatory neurons in a midline ACC area, Area 25 (A25), in neurotypical and stage II CTE cases using immunohistochemistry and Nissl staining to investigate neuronal subpopulation densities. Inhibitory neuron subpopulations in the human cortex can be labeled by three calcium binding proteins: parvalbumin (PV), calbindin (CB), and calretinin (CR). CB and PV interneurons differentially inhibit excitatory neurons while CR neurons in the upper cortical layers inhibit other inhibitory neurons, resulting in a disinhibitory effect. The results showed that the density of CB neurons significantly decreased in stage II CTE. In addition, CR neuron density may also be reduced but results for PV neurons were inconclusive. The disruption of inhibitory neurons in A25 may be an early change and may contribute to the early clinical presentation of CTE. A25 of the ACC is known to be involved in affective disorders and specifically is overactive in major depressive disorder, which is also experienced by individuals in the early stages of CTE. / 2026-09-26T00:00:00Z

The heterogeneity intrinsic to the ventromedial prefrontal cortex (vmPFC) is evidenced in both its anatomy and implicated function: vmPFC subregions have roles in positive affect, negative affect and autonomic/endocrine regulation. Whether different subregions serve fundamentally different functions, or whether they perform similar computations on different inputs, remains unclear. Nevertheless, the role of the vmPFC in psychopathology is widely appreciated - in mood and anxiety disorders, over-activity within constituent regions of the vmPFC is consistently implicated in symptomatology, together with its normalisation following successful treatment. However, the precise locus of change varies between studies. The work presented in this thesis investigates the causal contributions of over-activity within two key subregions of the vmPFC - the subgenual anterior cingulate cortex (sgACC, area 25) and perigenual anterior cingulate cortex (pgACC, area 32) - in discrete dimensions of behaviour and physiology affected in psychiatric disorders. Specifically, the impact of over-activity is assessed on (i) baseline physiological function; (ii) the regulation of anticipatory, motivational and consummatory aspects of reward-related behaviour; and (iii) negative affect including fear learning, stress recovery and the intolerance of uncertainty. To provide further insight into the mechanism of action of antidepressants, the efficacy of selected treatments is tested on changes induced by over-activity of these regions. Beyond the direct relevance of the results presented here to psychiatric disorders and their treatment, the thesis aims to emphasise the importance of broader themes associated with the measurement and quantification of emotion in preclinical animal studies. First, a multi-faceted approach is utilised enabling quantification of both the autonomic and behavioural aspects of emotion. In so doing, the experiments maintain relevance to studies which assess these correlates in isolation, both in humans (which typically measure subjective responses and physiology) and in rodents (which frequently assess behaviour in isolation). The assessment of more than one dimension of emotion confers these studies with improved power to detect maladaptive changes. Second, the experiments described were conducted in the marmoset, a new-world primate. The extensive anatomical homology between marmoset and human prefrontal cortex facilitates the forward-translation of functional results. In combination with the appropriate assays, this renders marmosets as an invaluable species to study the causal contributions of vmPFC subregions to symptoms of psychiatric disorders. I believe that the results of these experiments provide important insights into the causal role primate vmPFC has in relation to the behavioural and physiological aspects of psychiatric symptomatology. Most importantly, I hope that they serve as the foundation for future work to further elucidate the neuropathological processes underlying mental disorders.