The research presented in this thesis investigates the causal role of area 25 of the subcallosal anterior cingulate cortex and area 46 of the dorsolateral prefrontal (dlPFC) cortex in depression- and anxiety-like behaviour in a non-human primate, the common marmoset. Depressed patients show hyperactivity in area 25, and hyperactivity and hypoactivity of area 46 in the right and left hemispheres respectively. Moreover, these two seemingly unrelated regions, one involved in emotion and visceral activities (area 25) and the other involved in cognition (area 46), have sparse direct anatomical connections yet their negative coupling is observed in the state of disease and after successful treatment. Furthermore, levels of the stress hormone cortisol, which is elevated in depression and anxiety, are positively correlated with activity within area 25. However, the causal role of cortisol in the activity of this region is unknown although it has been shown that area 25 expresses both mineralocorticoid and glucocorticoid receptors, which suggests elevated cortisol can directly modulate activity in this region.

Three subsections investigating the above, form three chapters of this thesis. Chapter three focuses on the effect of overactivation and inactivation of area 25 in two behavioural tests assessing motivational and consummatory behaviour of relevance to the symptom of anhedonia, the loss of pleasure. In chapter four the effect of the local increase of cortisol in area 25 in three domains of motivational, anticipatory, and anxiety-like behaviour is assessed. In chapter five the effect of overactivation and inactivation of area 46 within dlPFC on anxiety-like behaviour and basal cardiovascular activity is investigated under four conditions of vehicle control, left hemisphere, right hemisphere, and bilateral manipulations, in order to assess reports of asymmetry in dlPFC function.

Taken together, the findings provide evidence for bidirectional effects of area 25 manipulation on motivation, and consumption, albeit with a more complex relationship with reward value for the latter. Moreover, cortisol is shown to have a causal impact on area 25 function as manifested in anxiety-like behaviour and anticipatory anhedonia. Since the effects were observed only with a very short pre-treatment time, it implicates those cellular mechanisms known to underlie the rapid effects of cortisol. These effects were observed despite the low number of subjects (n = 4), however, whether the lack of effect on cardiovascular response is due to the low power could be investigated with more subjects. Finally, the results revealed that bilateral and left hemisphere inactivation of area 46 increased anxiety-like behaviour. However, to establish the role of area 46 in the central autonomic network, further investigation is required since ANOVA showed no effect of manipulation despite the significant effect observed with the Linear Mixed Effect Model. The current interpretation of the observed results is that the effect size is small and there are high individual differences, both of which can only be addressed with an increased number of subjects. In contrast, overactivity of the right hemisphere did not increase anxiety as implicated in the depression and anxiety literature. The evidence overall points to functional asymmetry within area 46. The opposing effects of area 25 and area 46 manipulations on anxiety-like behaviour reported here support the correlatory findings in humans for the negative relationship between subcallosal and dlPFC activity in human mood and anxiety disorders. When translating these preclinical findings to the clinical domain it should be noted that the reward used here, similar to many preclinical models, is a primary reward, which has an innate value essential for homeostasis. The neural circuit underlying primary and secondary rewards may vary and requires further investigation. Hence, these findings are only applicable with regard to primary rewards when translating to human studies.