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The essential role of Nurr1 in the circadian regulation of the dopamine phenotype
Author(s) -
Eells Jeffrey,
Barker Samantha,
Partington Heath,
Nutter Jennifer
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04203
Alterations in dopamine neurotransmission from mesencephalic dopamine neurons contribute to symptoms of addiction, depression, schizophrenia, and Parkinson's disease. All of these diseases have a strong circadian component and previous data has also observed fluctuations in dopamine neurotransmission across the circadian cycle, including the number of neurons actively expressing the dopamine phenotype. The current study investigated how deficits in Nurr1, an essential transcription factor for expression of the dopamine phenotype and expression of tyrosine hydroxylase (TH) during development, affect the circadian fluctuations in the dopamine phenotype. Addition, we describe a transgenic mouse model with Cre recombinase expression under control of dopamine transporter (DAT) and yellow fluorescent protein (YFP) Cre reporter which, when combined with immunofluorescence, can be used differentiate between ‘former’ (YFP + /TH ‐ ) and ‘current’ (TH + ) DA neurons. The Nurr1 wild‐type (+/+) mice showed circadian cycling of dopamine neuron numbers, with a significantly greater number (~2‐fold increase) of dopamine neurons at circadian time (CT) 0 (when lights come on) than CT12. In contrast, the Nurr1‐null heterozygous (+/‐) mice did not show a circadian cycling of the dopamine phenotype, as no differences in the numbers dopamine neurons were observed between CT0 and CT12. Additionally, the +/‐ mice had significantly fewer dopamine neurons at CT0 but not at CT12 as compared to +/+ mice. Using the DAT cre/YFP reporter mice, we found a significant difference in the proportion of TH + and YFP + /TH ‐ between CT0 and CT 12. These data demonstrate the capability of visualizing current and former dopamine neurons and show an essential role for Nurr1 expression in the circadian cycling of the dopamine phenotype. Since aging, stress, toxins, and inflammation can reduce Nurr1 expression, these perturbations could have a similar effect on the circadian cycling of the dopamine phenotype with the consequences of this unknown.