Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder, typically characterized by
the progressive death of midbrain dopaminergic neurons projecting from the substantia nigra
to other areas within the basal ganglia. Historically, PD has been diagnosed as a purely motor
disorder dominated by bradykinesia (slowness of movement), rigidity, resting tremor, and
postural instability. While there are no approved disease-modifying therapies, these
symptoms can be counteracted by dopamine replacement therapies based on the use of LDopa
and dopamine receptor agonists.
In the past decades, the classic view of PD as an exclusively motor disease has been
challenged by increasing evidence showing that patients display a wide range of non-motor
symptoms (NMS), including hyposmia, sleep disturbances, cognitive impairment, depression
and anxiety. These ailments often appear in the early, pre-motor stage of the disease and
progressively worsen, significantly affecting the patient’s quality of life. The
neuropathological mechanisms underlying NMS are still poorly understood, but clinical
findings have consistently shown the involvement of both the dopaminergic and nondopaminergic
systems. Interestingly, these symptoms only partially respond to dopaminergic
treatments used to handle motor deficits, complicating the pharmacological management of
patients. The increasing demand for more effective therapies for NMS indicates the
importance of developing translational approaches based on the use of appropriate animal
models.
In this thesis, we developed and validated a mouse model of PD for the study of NMS. This
model is characterized by a bilateral partial degeneration of the dopaminergic system
achieved through intra-striatal injection of 6-hydroxydopamine (6-OHDA). We found that
this model presents only subtle gait modifications reminiscent of early stage PD. Most
importantly, we showed that the 6-OHDA lesion impairs olfactory discrimination, disrupts
circadian rhythm, causes long-term memory deficits, as well as depression- and anxiety-like
behaviors. Using a combination of anatomical and pharmacological approaches, we validated
this model for the study of NMS and described the effects produced on these deficits by
administration of dopaminergic and non-dopaminergic drugs.
Altogether, these studies provide a well-characterized tool for the study of NMS in PD, as
well as information on molecular and neural targets implicated, thereby opening new vistas
for the design of broader therapeutic interventions.
