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Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
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2014 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 21, 7837-7842 p.Article in journal (Refereed) Published
Abstract [en]

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Place, publisher, year, edition, pages
2014. Vol. 111, no 21, 7837-7842 p.
Keyword [en]
Parkinson disease, deep brain stimulation, vesicular transporter, optogenetics, striatum
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-227717DOI: 10.1073/pnas.1323499111ISI: 000336411300073OAI: oai:DiVA.org:uu-227717DiVA: diva2:731042
Note

N.S. and S.P. contributed equally to this work.

Available from: 2014-06-30 Created: 2014-06-30 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Motion and Emotion: Functional In Vivo Analyses of the Mouse Basal Ganglia
Open this publication in new window or tab >>Motion and Emotion: Functional In Vivo Analyses of the Mouse Basal Ganglia
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems.

The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry.

In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes.

In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1019
Keyword
Dopamine, Basal Ganglia, Reward System, In Vivo Chronoamperometry, Optogenetics, Deep Brain Stimulation, Parkinson’s Disease, Addiction, Glutamate, Vesicular Glutamate Transporter, VGLUT2, Sex, Age, Subthalamic Nucleus, Striatum, Nucleus Accumbens, Ventral Tegmental Area
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-229910 (URN)978-91-554-9006-5 (ISBN)
Public defence
2014-10-03, B42, BMC, Husargatan, 3, 751 24 Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-10 Created: 2014-08-16 Last updated: 2015-01-22
2. Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
Open this publication in new window or tab >>Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The basal ganglia are the key circuitry controlling movement and reward behavior. Both locomotion and reward-related behavior are also modified by dopaminergic input from the substantia nigra and the ventral tegmental area (VTA). If the basal ganglia are severed by lesion or in disease, such as in Parkinson’s disease, the affected individuals suffer from severe motor impairments and often of affective and reward-related symptoms. The subthalamic nucleus (STN) is a glutamatergic key area of the basal ganglia and a common target for deep brain stimulation in Parkinson’s disease to alleviate motor symptoms. The STN serves not only motoric, but also limbic and cognitive functions, which is often attributed to a tripartite anatomical subdivision. However, the functional output of both VTA and STN may rely more on intermingled subpopulations than on a strictly anatomical subdivision. In this doctoral thesis, the role of subpopulations within and associated with the basal ganglia is addressed from both a genetic and a behavioral angle. The identification of a genetically defined subpopulation within the STN, co-expressing Paired-like homeodomain transcription factor 2 (Pitx2) and Vesicular glutamate transport 2 (Vglut2), made it possible to conditionally reduce glutamatergic transmission from this subgroup of neurons and to investigate its influence on locomotion and motivational behavior, giving interesting insights into the mechanisms possibly underlying deep brain stimulation therapy and its side-effects. We address the strong influence of the Pitx2-Vglut2 subpopulation on movement, as well as the more subtle changes in reward-related behavior and the impact of the alterations on the reward-related dopaminergic circuitry. We also further elucidate the genetic composition of the STN by finding new markers for putative STN subpopulations, thereby opening up new possibilities to target those cells genetically and optogenetically. This will help in future to examine both STN development, function in the adult central nervous system and defects caused by specific deletion. Eventually identifying and characterizing subpopulations of the STN can contribute to the optimization of deep brain stimulation and help to reduce its side-effects, or even open up possibilities for genetic or optogenetic therapy approaches.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1177
Keyword
subthalamic nucleus, STN, basal ganglia, locomotion, hyperlocomotion, rearing, ventral tegmental area, VTA, dopamine, glutamate, vesicular glutamate transporter 2, Vglut2, Parkinson's disease, deep brain stimulation, subpopulation, conditional knock-out, optogenetic, co-expression, in situ hybridization, self-administration, reward behavior, mouse genetics
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-275165 (URN)978-91-554-9469-8 (ISBN)
Public defence
2016-03-18, Zootissalen, Norbyvägen 14-18, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-02-26 Created: 2016-01-31 Last updated: 2016-03-09

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Schweizer, NadineArvidsson, EmmaNordenankar, KarinLeao, Richardson N.Wallén-Mackenzie, Åsa

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