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Across Borders: A Histological and Physiological Study of the Subthalamic Nucleus in Reward and Movement
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
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 [en]
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: urn:nbn:se:uu:diva-275165ISBN: 978-91-554-9469-8 (print)OAI: oai:DiVA.org:uu-275165DiVA: diva2:899108
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
List of papers
1. Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
Open this publication in new window or tab >>Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity
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2015 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 220, no 4, 2171-2190 p.Article in journal (Refereed) Published
Abstract [en]

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-239640 (URN)10.1007/s00429-014-0778-9 (DOI)000356874700020 ()24802380 (PubMedID)
Funder
Swedish Research Council, 2007-5742, 2011-4747
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05Bibliographically approved
2. Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
Open this publication in new window or tab >>Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
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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.

Keyword
Parkinson disease, deep brain stimulation, vesicular transporter, optogenetics, striatum
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-227717 (URN)10.1073/pnas.1323499111 (DOI)000336411300073 ()
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
3. Reply to Konsolaki and Skaliora: Habituation, hyperlocomotion, and "genuine hyperlocomotion"
Open this publication in new window or tab >>Reply to Konsolaki and Skaliora: Habituation, hyperlocomotion, and "genuine hyperlocomotion"
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 1, E5-E5 p.Article in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-246836 (URN)10.1073/pnas.1417574112 (DOI)000347447100004 ()
Available from: 2015-03-11 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
4. Reduced consumption of sugar identifies a regulatory role for a Pitx2/Vglut2 co-expressing subpopulation in the structure and function of the mouse subthalamic nucleus
Open this publication in new window or tab >>Reduced consumption of sugar identifies a regulatory role for a Pitx2/Vglut2 co-expressing subpopulation in the structure and function of the mouse subthalamic nucleus
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(English)Manuscript (preprint) (Other academic)
Keyword
STN, deep brain stimulation, DBS, reward, Parkinson's disease, self-administration, conditional knock-out, Pitx2, Vglut2, in vivo chronoamperometry, dopamine, glutamate, globus pallidus, entopeduncular nucleus
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-274855 (URN)
Available from: 2016-01-31 Created: 2016-01-26 Last updated: 2017-03-28
5. Identification of novel markers for the subthalamic nucleus in mice
Open this publication in new window or tab >>Identification of novel markers for the subthalamic nucleus in mice
(English)Manuscript (preprint) (Other academic)
Keyword
vglut2, vesicular glutamate transporter 2, pitx2, paired-like homeodomain transcription factor 2, gria1, glutamate receptor ionotropic AMPA 1, foxA1, forkhead box transcription factor A1, lmx1a, LIM homeobox transcription factor 1a, lmx1b, LIM homeobox transcription factor 1b, calb2, calbindin 2, in situ hybridization, mRNA, embryonic, STN, subthalamic nucleus, screen
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-275162 (URN)
Available from: 2016-01-31 Created: 2016-01-31 Last updated: 2016-05-11

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