PhD grant : Intracellular signaling cascades involved in the integration of neuromodulatory signals in the striatum / nucleus

PhD grant from CNRS: https://www2.cnrs.fr/DRH/doctorants-09/

Title: Intracellular signaling cascades involved in the integration of neuromodulatory signals in the striatum / nucleus accumbens

Project:
As a majority of neuropsychiatric diseases affect neuromodulatory systems, it becomes
increasingly important to gain a better understanding of the cellular processes involved in signal integration. For example, dopamine plays a key role in controlling the output of basal ganglia such as complex motor sequences (dorsal
striatum) or behavioral orientation ("motivation", ventral striatum). Imbalances in the dopaminergic system indeed result in debilitating conditions such as Parkinson disease, addiction, psychosis...

In the striatum, medium spiny neurons (MSN) express either dopamine D1 or D2 receptors which are coupled in an opposite way to the cAMP/ PKA cascade. These neurons also express proteins isoforms involved in the cAMP/PKA cascade which are rare or absent in any other brain region, such as DARPP-32, Gαolf, type V adenylyl
cyclase, type 10 phosphodiesterase... This signaling cascade is therefore expected to perform differently in the striatum than in other region of the brain.

The very recent development of FRET biosensors now allow a direct assessment of the cAMP/ PKA cascade in living neurons. There are indicators for various steps of the cascade (cAMP concentration, PKA activity and CREB phosphorylation level) and we routinely record D1 responses in medium spiny neurons in specific cellular domains (cytosol, nucleus, dendrites). In addition, we are developing a unique method to record this signal in the striatum at the cellular level in the living animal. Our preliminary results demonstrated a more complex regulation of the PKA signal in MSN as compared to our former results obtained in the cortex, which must now be explained at the molecular level. Our project is to study the cAMP/PKA signalisation in different cellular domains in physiological and pathological situations in animal models of Parkinson disease and drug addiction.

We thus use very innovative methodologies to combine mechanistic studies performed ex vivo with cellular recordings performed in vivo, in an attempt to bridge the gap between cellular and integrated physiology.

References
Gervasi, Hepp, Tricoire, Zhang, Lambolez, Paupardin-Tritsch and Vincent, 2007, "Dynamics of PKA Signaling at the Membrane, in the Cytosol and in the Nucleus of Neurons in Mouse Brain Slices" J. Neurosci. 27 p2744-50.

Vincent, Maskos, Charvet, Bourgeais, Stoppini, Leresche, Changeux, Lambert, Meda and
Paupardin-Tritsch, 2006, "Live imaging of neural structure and function by fibred fluorescence microscopy." EMBO Rep. 7 p1154-61.

Vincent, Gervasi and Zhang, 2008, "Real-time monitoring of cyclic nucleotide signaling in neurons using genetically encoded FRET probes." Brain Cell Biol 36
p3-17.

Contact:
Pierre VINCENT; Equipe Intégration Cellulaire des Signaux Neuromodulateurs Neurobiologie des Processus Adaptatifs UMR7102 CNRS UPMC, Paris, France.
phone: 33 (0)1 44 27 25 88; e-mail: pierre.vincent@ upmc.fr