Effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease

Neuromelanin (NM) is a dark pigment that accumulates with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral area's name. Although NM has long been associated with Parkinson's disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, using an NM-producing rat model generated by viral vector-induced expression of human tyrosinase (hTyr), we inspected NM impact on survival and activity of nigral DA neurons, nigral mitochondrial functionality, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex differences in NM effects on the nigrostriatal dopamine circuit and PD-like behaviors. We found higher NM levels in nigral DA neurons of males and down-regulation of nigral tyrosine hydroxylase (TH) irrespective of sex, as well as sex-biased alterations in neuronal firing activity and underlying intrinsic currents of nigral DA neurons, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses novel NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD. • Biological sex shapes neuromelanin effects on nigrostriatal dopamine circuit. • Neuromelanin buildup induces sex-specific functional changes of SNpc dopamine neurons. • Neuromelanin accumulation promotes early manifestation of anxiety in male rats.