My first objective was to establish a complete behavioral phenotyping of our mouse model to validate its relevance as a model of ADHD. My work for the first year provided key elements demonstrating that our model develops the main features at the core of ADHD symptomatology including hyperlocomotion, deficits of attention and traits of impulsivity. Considering the limitations of our model involving irreversible neuronal loss and possible lesion-related compensatory mechanisms that do not reflect the human pathology, I developed an alternative one using a chemogenetic approach. These data demonstrated that my first observations were specific without involving unspecific compensatory effects.
A second objective was to dissect the mechanisms of psychostimulant calming effects. In the following year, I was able to highlight specific roles for each MA in these effects using different approaches including chemogenetics in combination with in vivo electrophysiology, and optogenetics.
Finally, I proposed to deconstruct the circuits involved and behavioral correlates of neuronal activity in both our model hyperactivity and psychostimulant calming effects as a third objective. To do so, by setting a new system consisting of in vivo electrophysiology, I could extract neuronal single unit activity in freely behaving mice from simultaneous recordings in various brain structures. The mastering and troubleshooting of this technique took longer than expected, explaining why preliminary results came only recently to finalize this last objective. The ultimate goal in the near future is to gather my results from the first two aims fully achieved within the two-year period covered and those recent ones that propose altogether a comprehensive mechanistic understanding of our model of ADHD and circuits involved in psychostimulants calming effects. This should be finalized in a scientific article that should be submitted by the end of March 2019.
Still during the covered period, I was able to finalize former projects that were on-going, which led to two original scientific articles published in peer-reviewed journals: 1) Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability. Journal of Neuroscience (2017), first co-author and co-corresponding author; 2) The GABAergic Gudden's dorsal tegmental nucleus: A new relay for serotonergic regulation of sleep-wake behavior in the mouse. Neuropsychopharmacology (2018), co-last and co-corresponding author. These papers brought critical advancements in our understanding of the brain major arousal systems including histamine and serotonin neurotransmissions, which are both relevant to psychostimulant actions and constitute the major axis of my future research as an independent investigator.
I also published recently one book chapter and one review presenting, respectively, an overview of the recent chemogenetic tools development and its latest contributions to sleep studies, and an updated review on the functions and organization of the basal ganglia, which was the major focus of my two-year Marie Curie fellowship research project.
