Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - ROSNPD (Selective vulnerability of neuronal degeneration in Parkinson’s disease: the load of routine behaviour)
Teaser
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...
Summary
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.
Work performed
In the experiments of this project we have recorded dopaminergic activity in the SNpc while performance of an automatic/habitual behavioural task in mice. We have used traditional methodology (electrophysiology) and state-of-the-art techniques (such as optogenetics and miniaturized fluorescence microscope) to monitor and characterize the neuronal activity of this specific group of neurons (dopaminergic neurons in the SNpc).Additionally, we have manipulated the neuronal activity with optogentics and we have found out that this set of neurons is responsible for the initiation of movement and its manipulation alters the animal behavior in a very specific manner.
The results from this project have validated the main hypothesis suggested here. We have shown that the dopaminergic neurons from the SNpc are involved in the execution of an automatic behavioural task. I have presented preliminary data obtained from this project in international meetings and Conferences and the main results will be published in a peer-reviewed journal in the following months (currently under preparation). I will present the final data during the following months to the final report in International meetings to spread and disseminate the results of this project.
Final results
The results of this project open a new venue for the study of vulnerability factors in the Parkinson disease field. There has been many previous works addressing the selective vulnerability of this neuronal population but this is the first time that a functional aspect of this population has been highlighted, becoming a potential additional factor in the contribution of the onset of the disease.
In this project, I have stablished a new hypothesis that will impact the field and bring other researchers to deepen in the knowledge of the mechanisms and factors that may cause this selective neurodegeneration. This, will hopefully contribute to slow down or arrest the disease progression as we advance forward in the development of new therapies applicable after the findings obtained from this project.
This grant has helped to stablish and consolidate a current collaboration with the Institution of the secondment. Personally, it has also helped me to consolidate my career and line of work, which I am going to keep pursuing with other financial sources and will for sure help to recruit additional funding with the results obtained from these experiments.