0039 Investigating the role of striatal dopamine in sleep and narcolepsy-cataplexy

Abstract

Abstract Introduction Dopamine release in the striatum is known to govern reward, motor, and sleep behaviors. There also exists a link between pharmacological manipulation of dopamine receptors and cataplexy occurrence, yet the precise spatial and temporal dynamics of dopamine release in relation to cataplexy onset are not understood. In the present study, we evaluate dopamine release dynamics in orexin knockout (OX KO) mice during cataplexy and physiological behaviors. Methods OX KO mice were implanted with EEG/EMG electrodes, and dLight1.1 was expressed in the nucleus accumbens core (NAcc), shell (NAcSh), and dorsolateral striatum (DLS) to perform in vivo fiber photometry of dopamine release in freely-moving animals. In NAcc and NAcSh mice, ChrimsonR was retrogradely expressed in the ventral tegmental area (VTA), to allow for precise optogenetic control of midbrain dopamine projections to different regions of the striatum. We also expressed dLight1.1 in the NAcc of wildtype (WT) mice as a control. Three different stimulation parameters were used in independent recordings: phasic 20 Hz stimulation, phasic 10-40 Hz variable stimulation, and tonic 2 Hz stimulation. Results First, we show that while dopamine release in response to rewarding behaviors is muted in OX KO animals, there is no difference in dopamine release across sleep state transitions between OX KO and WT animals. Second, we demonstrate that there is a striking increase in dopamine release in both the NAcc and NAcSh, but not in the DLS, at the onset of cataplexy. This increase occurs independently of the behaviors that the animals were engaged in immediately prior to cataplexy, suggesting that the increase is characteristic of all cataplexy episodes. Finally, we find that while high frequency phasic stimulation did not affect cataplexy frequency, low frequency, tonic stimulation reduced both cataplexy and REM occurrence. Conclusion We show that there are differences in dopamine release in response to rewarding events, but not changes in sleep states, in OX KO and WT animals. We also identify dopamine release in the ventral striatum as a key node in cataplexy regulation, which helps to further our understanding of the limbic circuitry that underlies narcolepsy symptoms. Support (if any) University of Michigan Gilmore Award and Rackham Graduate Research Award.