Aller au contenuAller au menuAller à la recherche

Kelly TAN"Probing inhibitory circuits of the VTA with pharmacological and optogenetic tools"

Abstract :


Dopamine (DA) neurons of the ventral tegmental area (VTA) project to several target regions in the mesocorticolimbic system.
Their activity is controlled by excitatory and inhibitory afferents. In my presentation, I will focus on the GABA inputs that arise mainly from GABA interneurons and from the rostro-medial tegmentum, a small nucleus located dorsally to the VTA. I will examine how positive modulators of GABAA receptor transmission (i.e. benzodiazepines, BDZs) and direct manipulations (optogenetic tools) of VTA GABA neuron activity impact on circuit function and behavior.
We observed that the BDZ midazolam (MDZ) decreased the firing rate of GABA neurons, but increased DA neuron firing in vivo. I will provide evidence that MDZ causes a disinhibition of DA neurons that depends on α1-containing GABAA receptors, which are expressed on GABA but not DA neurons. As a consequence mice preferred a MDZ-containing drinking solution over a solution without MDZ, when given a choice. 
Conversely, an aversive stimulus (e.g. footshock) transiently increased the firing rate of GABA neurons, leading to a transient inhibition of DA neurons. A selective optogenetic activation of VTA GABA neurons with channelrhodopsin 2 mimicked these responses and caused place aversion. The observation that this behavior could be reproduced by direct inhibition of DA neurons using halorhodopsin 3 confirms the determinant role of DA neurons.
To conclude, the bidirectional modulation of VTA GABA neuron activity, most likely by increasing or decreasing DA levels in targets of the VTA, drives opposite behaviors.

Selected publications

Claire L. Padgett, Arnaud L. Lalive, Kelly R. Tan, Miho Terunuma, Michaelanne B. Munoz, Menelas N. Pangalos, Jose Martinez-Hernandez, Masahiko Watanabe, Stephen J. Moss, Rafael Lujan, Christian Lüscher and Paul A. Slesinger. Methamphetamine-Evoked Depression of GABA(B) Receptor Signaling in GABA Neurons of the VTA. Neuron. 2012 Mar 8;73(5):978-89.
Arnaud L. Lalive, Uwe Rudolph, Christian Lüscher, Kelly R. Tan. Is there a way to curb benzodiazepine addiction? Swiss Med Wkly. 2011 Oct 19;141:w13277.

Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction Trends Neurosci. 2011 Apr;34(4):188-97. Epub 2011 Feb 25. Review.

Kelly R. Tan, Matthew Brown, Gwenaël Labouèbe, Cédric Yvon, Cyril Creton, Jean-Marc Fritschy, Uwe Rudolph & Christian Lüscher. Neural bases for addictive properties of benzodiazepines. Nature 463, 469-474. Epub 2010 Feb 11.

Scientific focus :

After obtaining my PhD at the University of Bern, I joined the laboratory of Prof. C. Lüscher to complete a postdoctoral fellow. I am focusing on the effects of Benzodiazepines on the GABAergic transmission in the Ventral Tegmental Area. I am using patch-clamp electrophysiological techniques in midbrain acute slices as well as confocal imaging.

Marc Landry du Neurocentre Magendie