You presented your research at the MultiPark Café recently. But for those who could not attend, can you please tell them about your research?
Levo-dopa is the golden standard for treating patients affected by Parkinson’s disease. It is a precursor that is converted into dopamine inside the brain to compensate for the loss of dopamine-producing neurons and maintain the patient’s ability to move. However, as the disease progress, an imbalance between the signaling through different dopamine receptor subtypes arises. This leads to abnormal involuntary movements, referred to as dyskinesia, as a side-effect of the levo-dopa treatment. In the clinic, patients are often treated with levo-dopa in combination with a dopamine agonist to reduce the levo-dopa dosage. Although less prone to induce dyskinesia, dopamine agonists have a high liability to induce neuropsychiatric side effects, in particular, impulsive-compulsive behaviors.
To improve treatments of these motor and neuropsychiatric complications, we need better animal models to study what goes wrong in the brain. Therefore, the focus of my thesis has been to develop improved experimental models and biomarkers to advance translational research on both motor and neuropsychiatric complications of therapies for Parkinson’s disease.
I used rat models of parkinsonism with dopamine denervation in the striatum. Then I induced dyskinesia by treating these rats with different combinations of dopaminergic treatments, using either levodopa or dopamine agonists selective for D1 or D2 receptors. Thereafter I monitored their motoric and neuropsychiatric behaviors and measured neuronal signaling with electrophysiology as well as markers of neuroplasticity.
What did you discover?
That the dopamine receptor subtypes matter. The dyskinetic effects of D1 and D2 receptor agonists are associated with different patterns of neuronal activity in the cortico-basal ganglia network. We see that D1 receptor stimulation induces network-wide neuronal oscillatory activity around 80 Hz referred to as narrowband gamma, whereas D2 receptor stimulation induces weaker and topographically more restricted narrowband gamma activity while increasing theta oscillations in the deep basal ganglia nuclei. These narrowband gamma oscillations can be used as a biomarker to indicate dyskinesia since they share great similarity across species.
Moreover, we established a new experimental model of dyskinesia mimicking the clinical setting, by treating rats with levodopa, either as a monotherapy or in combination with a dopamine agonist selective for D2-type receptors. Importantly, this adjuvant treatment with a dopamine agonist altered the neuroplasticity related to levodopa-induced dyskinesia. For example, we detected a normalized formation of new microvessels and blood brain barrier permeability, which are known to depend on D1 receptor stimulation. Furthermore, the combined treatment altered the pharmacological response profile of levodopa-induced dyskinesia. When evaluating the efficacy of potential anti-dyskinetic treatments preclinically, it is therefore important to use models of dyskinesia induced by levodopa monotherapy as well as the combined treatment with levodopa and a D2 receptor agonist.
What difference could your project make for patients?
Most patients with Parkinson’s disease will sooner or later get to a point when they start to experience issues with their initially successful treatments. Dyskinesia is a prevalent side effect impacting a patient’s daily life. To offer better treatment and avoid dyskinesia as long as possible, it is crucial to understand its neurological origins. And to elucidate the details of this, we are dependent on realistic animal models and translatable biomarkers. We show that dopamine agonists with specificity for different receptor subtypes induce different oscillation patterns in the brain. Moreover, the combination therapy of levodopa and a dopamine agonist induces diverse neuroplasticity responses, despite similar improvement of motor symptoms. These molecular differences that we have previously been unaware of may be one of the reasons why many preclinical discoveries fail when translated into clinical reality. Deepened molecular knowledge and relevant animal models are necessary to increase the translatability of Parkinson’s research. Understanding how different regiments of dopaminergic treatments give rise to specific profiles of motor and neuropsychiatric complications in Parkinson’s disease is essential for designing drugs exclusively targeting specific symptoms.
What is the most crucial thing you learnt during your Ph.D. that you will bring into your future career?
Project management, for sure! To plan and pursue an idea and establish collaborations and experiments that can answer your scientific question. For me, it has been to get the know-how to conduct a pre-clinical study based on clinically relevant questions in a way that facilitates to later apply the findings in the clinic.
Can you tell us more about the cover of your thesis?
It is a human brain with rats inside to illustrate the importance of translatability to eventually make a difference for the patients. The rats are interacting with a turntable as a symbol of the oscillations investigated as well as with symbols of gambling representing the impulsive behavior I assessed in my rats. Moreover, a flower is representing the degeneration of the dopaminergic neurons.
How did you end up at MultiPark?
I was doing my master’s project in pharmaceutical sciences about Alzheimer’s disease at Lundbeck. A colleague of mine was from Per Peterson’s research group here at MultiPark, so I came here to start a Ph.D. project in collaboration between his and Angela Cenci Nilsson’s groups.
How has it been to simultaneously be in two of MultiPark’s research groups?
It has been very advantageous for my professional development, I would say. From Angela Cenci Nilsson’s group, I got to learn everything regarding dyskinesia and animal behavioral analysis, and colleagues from Per Petersson’s group taught me what I needed to know about programming and how to custom-build electrodes to simultaneously record neuronal activities from cortical and basal ganglia circuits. Taken together, I think it gave me a unique combination of skills, although I must say it has also been challenging to relate to objectives from two different teams at the same time. It is critical to establish a common language to bridge the two worlds to begin with.
What did you like the most during your thesis work at MultiPark?
I loved the MultiPark Café. It was a great pleasure to be invited there to present my research in an understandable way to the general public and to meet patients. And, of course, also the lunch seminars arranged by the graduate school. Indeed, we have a friendly environment to learn from each other, and sometimes I wish that I had more time to engage in this.
What have been the most challenging during your Ph.D.?
To have two active supervisors is something to be grateful for. But the backside of that coin is that you sometimes feel squeezed in the middle of everybody else’s expectations. To develop your own scientific voice while you are surrounded by so many talented people is not evident. At some point, I had to ask myself where I wanted to go with my project and learn to trust my directions.
I also have a family, so I am naturally motivated to work efficiently with the hours I have. To me, it was important to establish a sustainable work- and family-life balance early on, which is hard when pursuing a PhD.
And the most rewarding?
I feel a lot of purpose in what I am doing. To see something that you started, planning from the very beginning until now, when the paper is finally out, is a great feeling. The fact that it is out there and living for others to continue building on findings that I have made.
What are you most proud of?
That I have been able to put four different projects into a common perspective. And that I, starting as a pharmacist, have been capable of learning how to build electrodes and how to program. I learnt so many things during these few years.
What do you like to do when you are not at work?
I have a child (enough to fill up the remaining hours while not working). Until this last year of Ph.D. studies, I was also pretty active as a scout, engaging in the national board and before that as an international commissioner. As I am Danish and we live close to Denmark, we also spend quite some time visiting friends and family over the bridge.
What advice do you want to give to new Ph.D. students?
Do not be afraid of standing up for yourself and your needs for recovery. Create a balance between work and spare time from the beginning, and avoid being soaked into others’ expectations of you. Create your own encouragement and purpose for what you are doing instead of trying to live up to other people’s aims.
What happens after your defence?
I want to work in the industry, but I have no concrete plan right now.
