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Dopamine modulation of inhibitory microcircuits in the barrel cortex

Applicant Tan Kelly
Number 142663
Funding scheme Ambizione
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2012 - 30.09.2014
Approved amount 356'390.00
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Keywords (2)

Dopamine; Inhibition

Lay Summary (English)

Lead
The ventral tegmental area (VTA) is a component of the mesolimbic reward circuit essential for learning the association between predicting stimuli and motivationally-relevant outcomes. We report here the identification of a peculiar VTA neuronal population that sends long-range projections to innervate the hippocampus in the mouse. This cellular population present mixed GABAergic/glutamatergic phenotype.
Lay summary

The ventral tegmental area (VTA) is a component of the mesolimbic reward circuit essential for learning the association between predicting stimuli and motivationally-relevant outcomes. While dopaminergic cells, the principal VTA neuronal population, attracted most of the interest for this structure, not as much attention has been focused on the less represented GABAergic or glutamatergic populations. 
We report here the identification of a peculiar VTA neuronal population that sends long-range projections to innervate the hippocampus in the mouse. 
Using GAD65-Cre mice, retrograde tracing and optogenetic tools combined with in vitro electrophysiological recordings of acute VTA and hippocampal brain slices, we show that VTA GABAergic neurons make functional synapses in the granule cell layer of the dentate gyrus (DG) and, to a lesser extent, in the strata radiatum, pyramidale and oriens of the CA2 region. In vitro optical stimulation of these ChR2-expressing terminals during voltage clamp recordings gives rise to small postsynaptic currents (PSCs) onto DG granule cells. Surprisingly, pharmacological antagonism or blockade of the ionotropic GABAA receptor with bicuculline or picrotoxin, is not able to completely abolish light-evoked PSCs, revealing a residual current that is sensitive to the AMPA/kainate receptor antagonist NBQX. Similarly, using VGLUT2-Cre mice we show the presence of glutamate-releasing neurons in the VTA that project onto DG granule cells, where they elicit bicuculline- and NBQX- sensitive PSCs. 
Altogether, the present data hints at the existence of a previously undescribed population of VTA neurons with mixed GABAergic/glutamatergic phenotype that provides a direct connection with the DG.

Direct link to Lay Summary Last update: 22.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
“Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity
Lalive A.L. Munoz M. Bellone C. Slesinger P. Lüscher C. and Tan K.R (2014), “Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity, in Journal of Neuroscience, 9(34 (15)), 5107-5114.
VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems
Meaghan Creed Niels Ntamati Kelly R. Tan (2014), VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems, in Frontiers of Neuroscience, 8(8), 1-7.
Cocaine disinhibits dopamine neurons by potentiation of GABA transmission in the VTA
Bocklisch C. Pascoli V. Wong J.C. House D.R.C. Yvon C. de Roo M. Tan K.R. and Lüscher C. (2013), Cocaine disinhibits dopamine neurons by potentiation of GABA transmission in the VTA, in Science, 341(6153), 1521-1525.

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Giessbach Meeting German-speaking Switzerland 2014
Talks/events/exhibitions NIH Summer School International 2014
Talks/events/exhibitions SSCT meeting International 2014

Awards

Title Year
DebioPharm 2012

Associated projects

Number Title Start Funding scheme
155830 Remodeling of cognitive circuits in Parkinson’s disease 01.02.2015 Temporary Backup Schemes

Abstract

Background: The barrel cortex contains the somatosensory representation of rodent’s whiskers and forms an early stage of cortical processing for tactile information. It contains interconnected networks of pyramidal cells and interneurons, which represent only 10-20% of all cortical neurons. Extensive work has been dedicated to classify interneurons and their connectivity to interneurons and to principal cells1,2. Neuromodulation by acetylcholine, serotonin or dopamine on inhibitory interneurons3 has been studied in the prefrontal cortex4, visual cortex5,6 or auditory cortex7. However very little has been done in the barrel cortex, especially for DA modulation even though a growing body of evidence suggests that it participates to associative learning8,9. The whisker detection task10, a behavioral paradigm used to study sensory processing in the barrel cortex may depend on DA since it is based on reward. In the prefrontal cortex, DA increases the excitability of fast spiking interneurons4 which in turn modulates synaptic transmission onto principal cells11, thereby shaping working memory12. Preliminary experiments presented in this project proposal show that only few cells expressed the DA receptor type 1 (D1R) but not type 2 within the superficial layers L1 (mainly composed of fibers and interneuron cell bodies13) and L2 of the barrel cortex. Based on this new evidence, I hypothesize that DA primarily modulates the activity of a selective subtype of interneuron in the barrel cortex and this implies a fine-tuning of this interneuron-network activity during whisker stimulation and behavioral learning. Aims: To test these hypotheses I propose the following specific aims:Part 1: Identify the S1 barrel cortex DA system.a.Determine the selective expression of D1Rs in interneuron subtypes.b.Reveal the DA projection and its origin. c.Examine the levels of DA in vivo in the barrel cortex.Part 2: Investigate DA modulation of barrel cortex circuits in vitro.d.Examine the morphological and electrophysiological properties of D1R-expressing interneurons.e.Establish the connectivity of D1R-expressing interneurons.f.Characterize in vitro the effects of DA onto the circuit of D1R-expressing interneurons.Part 3: Characterize the role of DA in mice performing a whisker detection task.g.Determine the response of neurons involved of the defined circuit to whisker stimulation.h.Examine the changes induced by DA during the detection task. i.Manipulate bi-directionally learning behavior by optogenetic control of D1R-expressing neurons.Methods: To technically tackle this project, I will first of all perform immunohistochemical staining in transgenic mouse lines in order to identify D1R-expressing interneurons and reveal DA projections in the S1 barrel cortex. Then, specific interneuron cre-mouse lines14 and stereotactic gene delivery to express fluorescent markers in D1R-expressing interneurons will be used to study these interneuron electrical properties in vitro. I will then use optogenetic effectors to probe these D1R-expressing interneurons input and output connectivity and apply DA pharmacology to study the modulation of the identified circuit. In vivo fluorescence-targeted whole cell recordings will be performed during the detection task. Finally the rate of behavioral learning will be measured while bi-directionally manipulating the activity of D1R-expressing interneurons with optogenetic tools.Expected value: My research project will dissect the role of DA in the barrel cortex during learning behavior. A successful completion of the present proposal will represent a significant step in further revealing the role of inhibitory networks in cellular mechanisms underlying sensory processing. References: 1.Rudy, B., Fishell, G., Lee, S. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Devel Neurobio 71, 45-61 (2010).2.Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5, 793-807 (2004).3.Bacci, A., Huguenard, J. R. & Prince, D. A. Modulation of neocortical interneurons: extrinsic influences and exercises in self-control. Trends Neurosci. 28, 602-610 (2005).4.Gorelova, N. Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex. J Neurophysiol 88, 3150-3166 (2002).5.Xiang, Z. Cholinergic Switching Within Neocortical Inhibitory Networks. Science 281, 985-988 (1998).6.Kawaguchi, Y. Selective cholinergic modulation of cortical GABAergic cell subtypes. J Neurophysiol 78, 1743-1747 (1997).7.Rao, D. et al. Hearing Loss Alters Serotonergic Modulation of Intrinsic Excitability in Auditory Cortex. Journal of Neurophysiology 104, 2693-2703 (2010).8.Siucinska, E., Kossut, M. & Stewart, M. G. GABA immunoreactivity in mouse barrel field after aversive and appetitive classical conditioning training involving facial vibrissae. Brain Res 843, 62-70 (1999).9.Rosselet, C., Fieschi, M., Hugues, S. & Bureau, I. Associative learning changes the organization of functional excitatory circuits targeting the supragranular layers of mouse barrel cortex. Front Neural Circuits 4, 126 (2011).10.Stüttgen, M. C. & Schwarz, C. Psychophysical and neurometric detection performance under stimulus uncertainty. Nat Neurosci 11, 1091-1099 (2008).11.Povysheva, N. V. et al. Properties of excitatory synaptic responses in fast-spiking interneurons and pyramidal cells from monkey and rat prefrontal cortex. Cereb. Cortex 16, 541-552 (2006).12.Seamans, J. K. & Yang, C. R. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology 74, 1-58 (2004).13.Xu, X. & Callaway, E. M. Laminar Specificity of Functional Input to Distinct Types of Inhibitory Cortical Neurons. Journal of Neuroscience 29, 70-85 (2009).14.Taniguchi, H. et al. A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex. Neuron 71, 995-1013 (2011).
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