Examining the role of the anterior and posterior orbitofrontal cortex in emotional regulation in the common marmoset (Callithrix jacchus)

Change log

The dysfunction and structural abnormalities of the orbitofrontal cortex have been reported in a number of affective disorders, including depression and several anxiety disorders. However, research has largely centred around reward-guided decision-making and economic choice, as opposed to how it may influence the expression and regulation of positive and negative emotion. Moreover, most studies fail to recognise the precise anatomical sub-divisions of the primate orbitofrontal cortex, in particular the anterior (area 11, antOFC) and posterior (area 13, pOFC) sub-divisions of the central orbitofrontal cortex. Evidence from cytoarchitecture, connectivity and function supports the idea that the two sub-regions may have distinct functional contributions. Overall, the purpose of the research in this thesis was to explore the possible contributions of the anterior and posterior orbitofrontal cortex to emotional regulation in the common marmoset (Callithrix jacchus). Past research in the lab has shown that excitotoxic lesions of the anterior orbitofrontal cortex heighten anxiety-like behaviour on the human intruder test, a paradigm testing the responses to a distal threat. The first experimental chapter confirmed that this effect is also present with an acute temporary inactivation of the antOFC. Inactivation of the pOFC produced a trend towards a similar anxiogenic-like effect. To elaborate on these findings, the effects of separate antOFC and pOFC inactivation on discriminative conditioned responses to an aversive stimulus were also examined, as a means of studying responses to a more proximal and imminent threat. While inactivation of the pOFC did not produce any effects, inactivations of the antOFC surprisingly reduced conditioned behavioural responses to proximal threat. These findings from threat conditioning were also for the first time directly compared to a corresponding task of discriminative conditioning to reward, revealing considerable similarities: pOFC inactivation produced no effects and antOFC inactivation caused mild blunting of conditioned responses to reward. Finally, the thesis also presents work on the development of a novel touchscreen task designed to study the relative contributions of positive and negative feedback to learning in the marmoset. The final chapter includes the preliminary data, showing the effects of inactivation as well as the blockade of serotonin reuptake, and discusses the future prospects of the task. Together, the research presented here supports past data indicating that the central OFC, and in particular the antOFC, may have an important function in regulating responses to a distal threat. However, neither the antOFC nor the pOFC appear to play a role in downregulating responses to more proximal threats. The studies examining conditioning to reward and threat also importantly highlight that the separate inactivations of the antOFC and pOFC can produce distinct results, and should be treated as functionally distinct units. The data presented here offers a basis for future research elaborating on the nuances of antOFC and pOFC contributions to emotional regulation.

Roberts, Angela
orbitofrontal, threat, reward, Pavlovian, marmoset, imminence, anxiety
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Medical Research Council (1803314)
MRC DTP funding (Grant Number N013433-1) Pinsent Darwin Award Sackler Fund for Medical Sciences Supported by Prof. Roberts' MRC Grant (Grant Number MR/M023990/1)