Time‐of‐Day Variation in Learning, Reward‐Associated Behaviors, and Rapid Dopamine Release

Abstract

Research has shown that circadian rhythms in physiology and behavior play a role in a number of psychiatric disorders, like depression and substance use disorder (SUD). For example, time-of-day variation has been observed in craving for nicotine, heroin, and cocaine in abstinent individuals. However, we have yet to fully delineate how these rhythms mediate variations in motivated behavior, learning, and reward seeking. This is critical as aberrant motivation and learning are hallmarks in these disorders. Additionally, the mesolimbic dopamine (DA) system is implicated in the neurobiology of motivation and learning, and research has shown time-of-day variations in DA tone. Less work has focused on rapid DA signals that are critical for motivation and learning. Thus, the purpose of this study was to examine time-of-day variations in incentive motivational properties of reward-associated cues and learning and the degree to which the magnitude of mesolimbic DA release in the nucleus accumbens (NAc) corresponded to dynamic shifts in motivation and learning across time-of-day. Our central hypothesis is that there are critical times within the day that confer increased sensitivity to reward-associated cues, which are mediated by time-of-day variations in the magnitude of phasic DA signaling. Initially, we examined the magnitude of NAc DA signaling to stimulations that mimic both tonic and phasic firing of mesolimbic DA neurons in rats. We used ex vivo fast scan cyclic voltammetry (FSCV) at four different time points across the 12:12 light/dark cycle. Our data demonstrate robust time-of-day differences in DA release magnitude following stimulations that model both phasic (≥20 Hz) and tonic (5 Hz) firing. Given that the phasic/tonic ratio of DA release magnitude was greatest midway through the dark cycle and lowest midway through the light cycle, we examined whether behavioral paradigms sensitive to DA release magnitude would fluctuate consistently with these DA oscillations. We therefore utilized Pavlovian paradigms in rodents to measure incentive motivational aspects and conditioned approach towards a reward-associated cue, during midway through the light cycle and midway through the dark cycle. Furthermore, since DA release and motivated behavior is modulated by striatal cholinergic interneuron (CIN) activity via nicotinic receptors (nAChRs) located on DA axons, we examined whether both DA release and incentive motivation was altered following nicotine exposure. To unmask the circuitry underlying these variations, we utilized ex vivo optogentics. We found a robust increase in DA release magnitude without the contribution of CIN activity midway through the dark cycle. In contrast, DA release was significantly higher in DA release magnitude modulated by CIN activity midway through the light cycle. Lastly, we are currently using in vivo optogenetics to mediate the magnitude of DA release during Pavlovian paradigms at times throughout the light cycles. Collectively, our data suggest that rats midway through their dark cycle exhibit increased sensitivity to reward-associated cues, which may be mediated by rapid DA release that is modulated by oscillations in CIN activity throughout the day.