Parkinson disease (PD) is characterized by striatal dopamine (DA) depletion due to loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Understanding the mechanisms underlying the onset and progression of SNpc damage is a primary unmet goal in PD research. Cell loss occurs earliest and foremost in the ventro-lateral region of the SNpc. Previous work defines anatomical factors determining the vulnerability of the ventro-lateral SNpc: their large axonal arborisations, bursting activity with high Ca++ inflow, high oxidative stress and sensitivity to aging. However, all of these features are shared by SNpc neurons but neurodegeneration in PD begins specifically in the ventro-lateral tier area. This DA depletion first occurs in the posterior striatum, which is involved and required for habit formation and routine behaviour. Indeed, the earliest motor features of PD are commonly associated with impairment of automatic movements. The striatum is well known to be engaged in learning and habit formation, a process that is DA dependent. Striatal DA is released phasically (SNpc firing related) triggered by emotional responses, whereas tonic dopaminergic modulation (non-SNpc firing related), predominates in routine behaviour. The precise mechanism whereby DA regulates the learning of a routine is not well defined but SNpc dopaminergic neurons are engaged in behavioural tasks showing an activation of their firing rate at the start of an instrumental task. This provides support to the notion that DA signals the onset/offset of a task and perhaps switching between tasks. In addition, they have a higher response to external stimuli (alertness, sensory) and to emotional behaviours (i.e. reward, salience). In this project it is hypothesized that in order to control the whole spectrum of a task, from goal directed to habitual, the ventro-lateral SNpc neurons are under higher functional demand, and the consequent metabolic overload makes them more susceptible to degeneration.
Unveiling the origin of such specific neurodegeneration is key to advance in the understaning and treatment of this disease, with the main goal to halter if not stopping the disease progression. This would have an incredible impact on society, since PD is the second most prevalent neurodegenerative disorders after Alzheimer’s disease. An estimated seven million to 10 million people worldwide have Parkinson’s disease. The prevalence of the disease ranges from 41 people per 100,000 in the fourth decade of life to more than 1,900 people per 100,000 among those 80 and older. An estimated 4 percent of people with Parkinson’s are diagnosed before the age of 50. The disease affects patients’ quality of life, making social interaction more difficult and worsening patients’ financial condition — due to the medical expenses associated with it.
