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The Role of Dopamine in the Regulation of Sleep and Circadian Rhythms

Periodic Reporting for period 1 - CircaDopamine (The Role of Dopamine in the Regulation of Sleep and Circadian Rhythms)

Reporting period: 2015-07-01 to 2017-06-30

• What is the problem/issue being addressed?
Among the many neuromodulators used by the nervous system to regulate physiological functions and plasticity, dopamine (DA) stands out as one of the most behaviorally potent factors (Trisch and Sabatini, 2012). DA plays an important role in the control of multiple physiological functions including; motor actions, food intake, reward, cognitive functions such as learning, memory, attention and decision making. Given this broad physiological implication of DA, it is not surprising that dysfunctions in the DA neurotransmission would be associated with several neurological and neuropsychiatric disorders (Trisch and Sabatini, 2012). The majority of the patients affected by these disorders display in their diagnosis debilitating sleep and circadian disorders (Videnovic & Golombek, 2013). For example, in Parkinson’s disease (PD), it is now clinically established that sleep and circadian disruptions are among the most debilitating non-motor symptoms of the disease. Yet, the role as well as the mechanisms by which DA modulate and/or regulate sleep and circadian physiology is not well understood. This very short recall of the background of CircaDA project constitute the overall scientific rational behind the execution, and the still ongoing related experiments, of the project.
• Why is it important for society?
At a fundamental level, results of our project should provide a basis for understanding the molecular and physiological mechanisms of the synchronizing role of DA in striatal-related functions. By emphasising the critical importance of the circadian component of DA neurotransmission, our results are therefore expected to stimulate further research in the diverse DA-related fields.
At the clinical level, DA-related pathologies such as addiction, Parkinson’s and Huntington’s diseases are characterised by serious debilitating circadian and sleep abnormalities (Videnovic & Golombek, 2013). Currently, no effective therapeutic strategies are available to alleviate these symptoms. Additionally, the currently stochastic intake of DA medication over the day is associated with adverse side effects that contribute to the low quality of life in these patients. Advancing our knowledge on the role of DA in the regulation of sleep/wake behavior and the physiological significance of the circadian component of DA signalling is expected to significantly contribute towards overcoming these problems and to disentangle possible targets for therapeutic strategies.
• What are the overall objectives?
Our project has two overall scientific objectives:
1) Determine the role of DA in the modulation of circadian and sleep homeostatic processes.
2) Characterization of the circadian component of DA signalling and its role in driving and/or synchronizing striatal and cortical neuronal activity and physiological functions that are under control of DA.
And two main training objectives:
1) To learn in vivo electrophysiology.
2) To advance and develop my proficiency towards attending independency.
As stated above, the scientific objectives consist of elucidating the role of DA in 1) the modulation of circadian and homeostatic processes of sleep regulation and 2) in the modulation of multi-unit activity in the SCN, striatal and DA neurons. To achieve these objectives, we used wild-type and two transgenic mouse models:
Experimental set1; Circadian and homeostatic modulation of MUA in Midbrain DA and striatal structures:
Using wild-type animals, we investigated the circadian modulation of electrical activity in the VTA and SN and their striatal targets. Using different light regimes, we additionally assessed the effect of homeostatic pressure on the MUA of these neuronal structures.
Experimental set 2; The effect of light on sleep and on MUA of DA and striatal structures:
This project aims to assess whether photoperiod affects 1) sleep/wakefulness behavior and 2) the circadian and magnitude of the MUA in DA and striatal structures. The rational of this project is to assess the potential of light to modulate the electrophysiology of DA and striatal structures.
Experimental set 3; The effect of DA loss on sleep and neuronal activity:
This is the first project that used MitoPark mice to answer both our scientific objectives. We simultaneously recorded cortical EEG and MUA in SN and dorsal striatal in MitoPark mice at different stages of parkinsonism. By using multiple light regimes and behavioural tests, we assessed in details the impacts of DA loss on 1) the circadian modulation of MUA in dopamine and striatal structures and on 2) the homeostatic process of sleep regulation.
Experimental set 4; The role of clock genes on DA signal:
In this project, we used a second transgenic model we called ‘CircaDA’ mice. These mice lack Bmal1, a canonical gene required for clock function, in DA neurons leading to the loss of a functional clock selectively in DA neurons. Like in MitoPark mice, we are currently assessing features of both circadian and homeostatic processes of sleep/wakefulness regulation.
Training objectives achieved so far:
Our project has 3 training objectives:
1) To gain expertise in in vivo and in vitro electrophysiology.
2) to strengthen my competences in the role of DA in the modulation of sleep and circadian rhythms.
3) to widen my management competences and tutoring skills, so that I could attain a leading independent position in the near future.
Thankfully, the first two objectives have been achieved by the execution of multiple set of experiments of our project. The third objective have been achieved by;
1) Management of all aspects of the current project.
2) Writing research proposals.
3) and supervision of 3 students on 3 related projects.
As explained above, the role of DA in the modulation of circadian and homeostatic processes of sleep regulation remains largely unknown. Additionally, the role of circadian modulation of DA in driving and regulation of DA-related physiology and behaviour is still in its infancy. The results we have gathered (and still expected) will advance these two fields significantly and will set the background for further studies.
From this project, we still expect to achieve the following scientific objectives:
1) Assessment of the relative contribution of DA vs non-DA neurotransmission in the modulation of sleep.
2) The impact of sexual dimorphism of PD-related motor and sleep alterations.
3) The impact of short and long photoperiods on sleep and the electrophysiology of the DA neurotransmission.
Potential impact:
The first scientific impact consists of achieving a degree of professional and scientific maturity of the fellow. We expect this to exteriorise in his establishment as an independent researcher in the near future. The fellow has achieved a profile that would make him a competitive researcher in any advanced neurobiology department or medical research center.
Regarding the wider societal scientific and translational impact of our project, we believe it is still premature to asses this aspect. However, there is clear potential of the results of this project to translate to the following areas:
1) Management of sleep alterations in a number of DA-related psychological and neurological disorders.
2) Implementation of light therapy in PD patients.
3) Development of efficient therapies into DA-related drugs that incorporate the concept of chronomedicine during their stage of development.
New role of dopamine signalling.