SLEEP-PHASE DEPENDENT DOPAMINE FLUCTUATIONS IN A MOUSE MODEL OF ADHD

The dopamine system is classically known to be involved in wake-related processes, such as reward and addiction. However, we now know that dopamine is also differentially active during sleep phases. Dopamine neurons of the midbrain are similarly active during rapid eyemovement (REM) sleep as during reward, leading researchers to hypothesize how activated dopamine during sleep mediates consolidation of reward-based memories.
Both reward-based learning and sleep functions are impaired in attention-deficit/hyperactivity disorder (ADHD). We therefore hypothesize that impaired dopamine signaling during sleep may exacerbate behavioral deficits in ADHD.
To investigate this speculation in ADHD we use a transgenic mouse line with two patient-derived knock in (KI) mutations in the dopamine transporter, I321F/D421N. Transient dopamine dynamics are impaired in the striatum of these KI mice during an open field test. Moreover, KIs have impaired reward-based learning in an appetitive operant task along with blunted striatal dopamine signaling during training.
Using dual EEG/EMG and fiber photometric recordings we measure dopamine in the ventral striatum and prefrontal cortex during sleep and appetitive Pavlovian learning in KI and control mice. Preliminary data indicate that basal dopamine fluctuations are impaired during both wake, non-REM, and REM sleep in KI mice, where the peak frequency is higher during wake and lower during both NREM and REM sleep. Moreover, dopamine levels are elevated and prolonged during transitions between sleep ​and wake states.
These results will enhance the understanding of mechanisms underlying behavioral deficits in ADHD and our current knowledge of the link to poor sleep.