Internal state modulation of striatal dopamine signaling

Abstract

Dopamine (DA) concentration in the striatum fluctuates on two timescales: fast, sub-second “phasic” changes, and slow, minutes to hours long, shifts in the “tonic” baseline. Phasic striatal DA fluctuations may represent a prediction error signal, or the difference between what an agent expects to happen and what actually happens. Animals are thought to implement this prediction error in a temporal difference learning framework to update policies mapping states to actions to learn how to attain rewards and avoid threats in the environment. Although much progress has been made to understand the heterogeneity of this phasic signal across striatal subregions and how different stimuli evoke different phasic dopaminergic signals, much less is known on the role that internal state of the agent plays in shaping phasic and tonic DA signaling. To investigate how internal state modulates phasic and tonic DA signaling, I employed fluorescence lifetime photometry at high temporal resolution (FLiP-R) coupled with novel DA sensors to measure absolute levels of DA in the striatum. I conducted recordings and manipulations of DA signaling in two striatal subregions - the nucleus accumbens core (NAC) in which phasic DA signaling is thought to represent a reward-prediction error, and the tail of striatum (TS) in which phasic DA signaling is thought to represent a threat-prediction error. In the TS, hunger increases tonic DA while suppressing the phasic TS DA response to modulate exploration of novel, potentially threatening stimuli. The hunger signal that modulates the phasic TS DA signaling pathway derives from the activity of hypothalamic agouti-related peptide (AgRP) neurons. In the NAC, hunger increases the tonic DA level, which in turn modulates an animal’s motivation to work for a fixed reward. I thus delineate how phasic and tonic DA signaling integrates internal state across different striatal subregions to modulate different aspects of behavior.