Nurr1 deficiency shortens free running period, enhances photoentrainment to phase advance, and disrupts circadian cycling of the dopamine neuron phenotype

Abstract

Neurological and neuropsychiatric disorders, including addiction, schizophrenia, and Parkinson's disease (PD), involve dysfunction in midbrain dopamine (DA) neurotransmission with severity of disease symptoms and progression associated with disrupted circadian rhythms. The nuclear transcription factor Nurr1, essential for DA neuron (DAN) development, survival, and maintenance, is also known to interact with circadian rhythm regulating clock proteins. In the Nurr1-null heterozygous (+/-) mice, a Nurr1 deficient model which reproduces some of the alterations in DA function found in schizophrenia and PD, we measured, using wheel-running activity, the free running period (tau) and photoperiod entrainment. Because Nurr1 has a role in regulating the DA phenotype, we also measured the circadian fluctuations in the number of DANs using tyrosine hydroxylase (TH) immunofluorescence. In Nurr1 +/- mice, tau was significantly shorter and entrainment to a 6 h earlier shift in the dark cycle was accelerated. The Nurr1 wild-type (+/+) mice cycled DAN numbers across time, with a significantly greater number (∼2-fold increase) of DANs at zeitgeber time (ZT) 0 than ZT12. The +/- mice, however, did not cycle the DA phenotype, as no differences in DAN numbers were observed between ZT0 and ZT12. Additionally, the +/- mice had significantly fewer DANs at ZT0 but not at ZT12 as compared to +/+ mice. Based these data, circadian rhythms and fluctuations in the DA phenotype requires normal Nurr1 function. A better understanding is needed of the mechanisms regulating the DA phenotype and subsequent neurotransmission across the circadian cycle and how this is altered in circadian rhythm and DA neurotransmission-associated disorders.

Keywords: Circadian rhythms; Dopamine; Dopamine phenotype switching; NR4A2; Nurr1.