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Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation
NIDA, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 11, p. 2584-2591Article in journal (Refereed) Published
Abstract [en]

Dopamine neurons in the ventral tegmental area (VTA) were previously found to express vesicular glutamate transporter 2 (VGLUT2) and to co-transmit glutamate in the ventral striatum (VStr). This capacity may play an important role in reinforcement learning. Although it is known that activation of the VTA-VStr dopamine system readily reinforces behavior, little is known about the role of glutamate co-transmission in such reinforcement. By combining electrode recording and optogenetics, we found that stimulation of VTA dopamine neurons in vivo evoked fast excitatory responses in many VStr neurons of adult mice. Whereas conditional knockout of the gene encoding VGLUT2 in dopamine neurons largely eliminated fast excitatory responses, it had little effect on the acquisition of conditioned responses reinforced by dopamine neuron activation. Therefore, glutamate co-transmission appears dispensable for acquisition of conditioned responding reinforced by DA neuron activation.

Place, publisher, year, edition, pages
2017. Vol. 18, no 11, p. 2584-2591
Keywords [en]
glutamate co-transmission, intracranial self-stimulation, mesolimbic dopamine system, nucleus accumbens, reinforcement learning, reward, ventral striatum
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-318762DOI: 10.1016/j.celrep.2017.02.062PubMedID: 28297663OAI: oai:DiVA.org:uu-318762DiVA, id: diva2:1085268
Funder
NIH (National Institute of Health)Swedish Research Council, 2013-4657 2014-3804The Swedish Brain FoundationAvailable from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-01-13Bibliographically approved
In thesis
1. United in Diversity: A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry
Open this publication in new window or tab >>United in Diversity: A Physiological and Molecular Characterization of Subpopulations in the Basal Ganglia Circuitry
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry.

Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc.

In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 57
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1369
Keywords
Glutamate, Optogenetics, Amperometry, Histology, Midbrain, Subthalamic Nucleus, Parkinson's disease, Ventral Tegmental Area, Substantia Nigra, Co-release
National Category
Neurosciences Physiology Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:uu:diva-328038 (URN)978-91-513-0063-4 (ISBN)
Public defence
2017-10-23, Zootissalen, Norbyvägen 14-18, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-09-29 Created: 2017-09-05 Last updated: 2018-01-13

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Viereckel, ThomasKonradsson-Geuken, ÅsaArvidsson, EmmaWallén-Mackenzie, Åsa
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