Mesolimbic dopamine and circuit level mechanisms in action initiation and restraint

Thesis

Beneficial decision making does not just involve selecting which action to make based on anticipated future reward but also being able to withhold responding at appropriate times. Mesolimbic dopamine is associated with both reward processing and the activation of reward seeking action. Yet an understanding of how phasic dopamine signals may influence reward guided action, and how extended circuits may act in concert with dopamine when action must be controlled, remains lacking. To probe these questions, we applied different causal manipulations within a common behavioural paradigm – a reward-guided Go/No-Go task – where animals must either restrain or enact action to obtain different sizes of reward. In Chapter 3 we demonstrate that transient activation of VTA dopamine neurons can promote action over inaction, in a manner dependent on the magnitude of activation and its timing relative to task relevant cues. Though effects on behaviour were observed most strongly on trials receiving stimulation, we also found stimulation influenced within-session behavioural strategy, biasing animals towards premature action as the session progressed. In Chapter 4, we show that the ability to successfully restrain action depends on prelimbic and infralimbic, but not the medial orbital, subregions of the medial prefrontal cortex. However, while pharmacological inactivation of prelimbic and infralimbic cortex both increased premature responses on No-Go trials, analysis of the patterns of errors showed distinct contributions of these areas to action restraint. Conversely all three subregions are shown to be crucial for executing the correct action sequence for reward. In Chapter 5 we determined that potentiating endocannabinoid signalling did not boost motivation as had been observed in simpler behavioural paradigms, but rather selectively increased the likelihood of entering into an unfocused state when needing to complete the Go trial action sequence to gain reward. Together, this thesis demonstrates the capacity for phasic dopamine signals to causally influence reward guided action, and highlights how medial prefrontal circuits and the endocannabinoid system contribute to the initiation and restraint of action, key information for progressing towards an integrated understanding of the systems governing appropriate action control.

Authors: Jenkins, G

• DOI: 10.5287/ora-6r8b1d5mb
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: action control; action restraint; medial prefrontal cortex; reward seeking action; decision making; endocannabinoid signaling; mesolimbic dopamine
• Subjects: Neurosciences