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Age- and Sex-Dependence of Dopamine Release and Capacity for Recovery Identified in the Dorsal Striatum ofC57/Bl6J Mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. (Functional Neurobiology)
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, Functional Pharmacology. (Functional Neurobiology)
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, e99592- p.Article in journal (Refereed) Published
Abstract [en]

The dorsal striatum is the main input structure of the basal ganglia and the major target area of dopaminergic projections originating in the substantia nigra pars compacta. Heavily involved in the regulation of voluntary movement and habit formation, this structure is of strong importance in Parkinson's disease, obsessive-compulsive disorder, Tourette's syndrome and addiction. The C57/Bl6J mouse strain, the most commonly used strain in preclinical research today, is frequently used as a model organism for analysis of dopaminergic parameters implicated in human pathophysiology. Several components of the dopamine system have been shown to vary with age and sex, however knowledge of the contribution of these factors for dopamine release kinetics in the C57/Bl6J mouse strain is lacking. In the present study, we used an intracranial KCl-stimulation challenge paradigm to provoke release from dopaminergic terminals in the dorsal striatum of anaesthetized C57/Bl6J mice. By high-speed in vivo chronoamperometric recordings, we analyzed DA release parameters in male and female mice of two different ages. Our experiments demonstrate elevated DA amplitudes in adult compared to young mice of both sexes and higher DA amplitudes in females compared to males at both ages. Adult mice exhibited higher recovery capabilities after repeated stimulation than did young mice and also showed a lower variability in the kinetic parameters trise and t80 between stimulations. These results identified age- and sex- dimorphisms in DA release parameters and point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J mouse strain as model for neurological and neuropsychiatric disorders.

Place, publisher, year, edition, pages
2014. Vol. 9, no 6, e99592- p.
National Category
Neurosciences Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-229825DOI: 10.1371/journal.pone.0099592ISI: 000338701300080PubMedID: 24925086OAI: oai:DiVA.org:uu-229825DiVA: diva2:737957
Available from: 2014-08-14 Created: 2014-08-14 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

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