Compromised circadian function in Parkinson's disease: Enucleation augments disease severity in the unilateral model

Abstract

Like enucleation, lateral hypothalamic (LH) lesions sever the connection between the retina and the pineal thereby simulating ambient exposure to constant darkness. While LH lesions have been employed to study either circadian function or Parkinson's disease (PD) independently, the application of such lesions to study circadian involvement specifically in this disease has never been attempted. In the present study, unilateral lesions of the LH, which compromise nigro-striatal dopamine (NSD) function, were combined with enucleation ipsilateral or contralateral to the hemisphere where 6-hydroxydopamine was applied. In addition to the observation that hemi-enucleation produced patterns of motor function that were grossly atypical compared to visually intact rats, hemi-enucleation ipsilateral to the side of NSD system denervation produced impairment of horizontal movement, limb retraction, ambulation and spontaneous or l-dopa induced turning. This impairment was more severe than that seen in rats with unilateral 6-OHDA lesions alone. Furthermore, hemi-enucleation contralateral to the side of unilateral NSD system denervation resulted in significantly improved performance on several parameters. While the rate of mortality in rats receiving unilateral 6-OHDA plus ipsilateral enucleation was similar to that occurring after bilateral lesions, it was not accompanied by severe weight loss and wasting that typically occurs in the acute stages of experimental PD. These results demonstrate the importance of the visual and circadian systems in PD and are consistent with reports that identify impaired circadian involvement as a major component in a wide range of neurological and neuropsychiatric conditions.