Divergent effects of sex and aging on the intrinsic physiology of substantia nigra dopamine neurons

Abstract

The largest population of dopamine‐producing neurons is in the ventral midbrain. Within this region, the neurons located in the substantia nigra are necessary for the initiation of voluntary movement. The degeneration of substantia nigra dopamine neurons is involved in the etiology for Parkinson's disease, a disease characterized by progressive loss of motor and cognitive functions. The biggest risk factor for Parkinson's disease is age, with most cases occurring after age 60. Moreover, Parkinson's is almost 2 times more prevalent in men than in women. While much research in Parkinson's has focused on the mechanisms underlying the dopamine neuron degeneration, very little work has considered the influence of normal aging on dopamine neurons which may contribute to disease risk and presentation.In this work, we performed whole cell patch clamp recordings in brain slices to study the changes in intrinsic firing properties of dopamine neurons in C57BL/6 mice across ages (4, 12, 18, ≥24 months) and compared between sexes. In addition, we assessed open field locomotion in these mice and performed a quantitative comparison of the numbers of substantia nigra dopamine neurons. Interestingly, we found a progressive decline in dopamine neuron function and number in males with age, while neurons in females remained largely unaffected. Behaviorally, there was a decrease in the distance travelled and speed of the mice with age, with females exhibiting higher activity levels at young ages. The effects of age and sex were further evaluated by comparing the transcriptomic profile of the substantia nigra pars compacta in these mice. The impairments in dopamine neuron function and locomotor activity in males that occurs with age may represent a vulnerability to further insults that could underlie the susceptibility to neurodegenerative processes like those seen in Parkinson's disease.Support or Funding InformationNIH grant (R01AG052606)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.