Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ADHDLightUp (Circuit-based deconstruction of Attention deficit and Hyperactive disorder with optogenetic Light control)

Teaser

Attention-deficit/hyperactivity disorder (ADHD) like many other mental illnesses probably results from a combination of genetic and developmental factors pointing at abnormalities in brain monoamines (MA) that include dopamine, serotonine and noradrenaline. Imaging studies in...

Summary

Attention-deficit/hyperactivity disorder (ADHD) like many other mental illnesses probably results from a combination of genetic and developmental factors pointing at abnormalities in brain monoamines (MA) that include dopamine, serotonine and noradrenaline. Imaging studies in ADHD patients also indicate deficits in activity of various brain regions including the prefrontal cortex (PFC) and basal ganglia (BG). The mechanisms by which PFC and BG dysfunctions are triggered, and can be corrected with MA-based treatment are unknown. Although there is a consistent frontal hypoactivity detected in ADHD, some variations are seen amongst executive processes including attention or impulse control, in which MA have specific functions. Besides, the limited spatial resolution of brain imaging does not allow to detect certain subregions or discriminate neuronal subpopulations. In order to identify brain network impairments in ADHD, we need models to further dissect frontal dysfunctions looking at MA signaling, cell excitability and behavioral correlates of activity in identified neurons.
The goal of the ADHD LightUp project was to untangle brain circuits involved in a novel mouse model of ADHD, which fulfills the major criteria reflecting human condition, showing MA involvement. Innovative approaches have been chosen to accomplish this challenge that include transgenesis, opto- and chemo-genetics, and in vivo measurement of neuronal activity in translational behavioral tasks assessing attention and impulsivity. Importantly, while the most common medication using psychotimulants has proven the best efficiency, it has also been shown to affect children growth and their adult mental health highlighting the urge for alternatives. The model developed here and the multidisciplinary experimental approach that was chosen aimed to provide new insights in ADHD ætiology and will allow to develop new concepts and/or targets for therapeutic alternatives further based on the manipulation of neurons activity to reverse or attenuate ADHD symptoms.

Work performed

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.

Final results

The ADHD LightUp research project delved into the mechanisms underlying Attention Deficit Hyperactivity Disorder (ADHD), one of the most common childhood psychiatric disorder with a growing prevalence affecting 8-12% children worldwide and estimated to contribute to a global cost of €5.2 billion across European countries. Boosting research efforts on this psychiatric condition is timely. The clinical impact and the lack of therapeutic alternatives emphasize the urge to look deeper into i) what is causing ADHD, ii) how the brain dysfunctions and iii) the mechanisms underlying psychostimulant effective treatment, which remain unknown. Second, I believe that a deconstruction of ADHD symptomatology based on neural circuits identification is mandatory to understand how brain networks operate in normal and pathological conditions. Here I developed cutting-edge neuroscience techniques in pair with bevioral tests that provide real-time control over neural circuits in action, using optogenetics, in vivo electrophysiology and imaging in behaving animal models of ADHD. My results provide new insights related to ADHD ætiology that will allow to develop new concepts and/or targets for therapeutic alternatives further based on the manipulation of neurons activity to reverse or attenuate ADHD symptoms.