A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions. Author summary: Biological rhythms allow animals to carry out behaviours at a suitable time, but ultradian rhythms with a period shorter than a day do not match the period of any cycles in the physical environment. They remain mysterious in both their biochemical mechanisms and their functional significance. Previous studies have demonstrated a link between striatal dopamine (DA) and ultradian behavioural rhythms. Based on mechano-biological findings of DA regulatory processes, we proposed a model where DA self-feedback through D2 autoreceptors generates ultradian oscillations. Using simulations, we were able to reproduce ultradian DA rhythms that resemble behavioural rhythms. We further explored how these rhythms respond to circadian regulation and external stimuli, the two major signals of behavioural relevance. The results show that the presence of ultradian rhythms within a functional circadian system offers organized daily behaviours, with increased flexibility and heightened responsiveness to significantly arousing experiences. [ABSTRACT FROM AUTHOR]