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Wallén-Mackenzie, ÅsaORCID iD iconorcid.org/0000-0002-8713-070x
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Publications (10 of 45) Show all publications
Bimpisidis, Z., König, N. & Wallén-Mackenzie, Å. (2020). Two Different Real-Time Place Preference Paradigms Using Optogenetics within the Ventral Tegmental Area of the Mouse. Journal of Visualized Experiments (156), Article ID e60867.
Open this publication in new window or tab >>Two Different Real-Time Place Preference Paradigms Using Optogenetics within the Ventral Tegmental Area of the Mouse
2020 (English)In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 156, article id e60867Article in journal (Refereed) Published
Abstract [en]

Understanding how neuronal activation leads to specific behavioral output is fundamental for modern neuroscience. Combining optogenetics in rodents with behavioral testing in validated paradigms allows the measurement of behavioral consequences upon stimulation of distinct neurons in real-time with high spatial and temporal selectivity, and thus the establishment of causal relationships between neuronal activation and behavior. Here, we describe a step-by-step protocol fora real-time place preference (RT-PP) paradigm, a modified version of the classical conditioned place preference (CPP) test. The RT-PP is performed in a three-compartment apparatus and can be utilized to answer if optogenetic stimulation of a specific neuronal population is rewarding or aversive. We also describe an alternative version of the RT-PP protocol, the socalled neutral compartment preference (NCP) protocol, which can be used to confirm aversion. The two approaches are based on extensions of classical methodology originating from behavioral pharmacology and recent implementation of optogenetics within the neuroscience field. Apart from measuring place preference in real time, these setups can also give information regarding conditioned behavior. We provide easyto-follow step-by-step protocols alongside examples of our own data and discuss important aspects to consider when applying these types of experiments.

Place, publisher, year, edition, pages
JOURNAL OF VISUALIZED EXPERIMENTS, 2020
Keywords
Behavior, Issue 156, aversion, conditioning, Cre-Lox, dopamine transporter (DAT), optogenetics, place preference, reward, transgenic mice, vesicular glutamate transporter (VGLUT2)
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-408090 (URN)10.3791/60867 (DOI)000518403300092 ()32116305 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2020-04-05 Created: 2020-04-05 Last updated: 2020-04-05Bibliographically approved
Dumas, S. & Wallén-Mackenzie, Å. (2019). Developmental Co-expression of Vglut2 and Nurr1 in a Mes-Di-Encephalic Continuum Preceeds Dopamine and Glutamate Neuron Specification. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 7, Article ID 307.
Open this publication in new window or tab >>Developmental Co-expression of Vglut2 and Nurr1 in a Mes-Di-Encephalic Continuum Preceeds Dopamine and Glutamate Neuron Specification
2019 (English)In: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, ISSN 2296-634X, Vol. 7, article id 307Article in journal (Refereed) Published
Abstract [en]

Midbrain dopamine (DA) neurons exist as several subtypes and are found in a heterogeneous environment including GABAergic and glutamatergic neurons as well as various types of co-releasing neurons. Developmental programs underlying this heterogeneity have remained elusive. In this study, combinatorial mRNA analysis was performed at stages when neuronal phenotypes are first specified. Vesicular transporters for dopamine and other monoamines (VMAT2), GABA (VIAAT), and glutamate (VGLUT2) were assessed by systematically applying fluorescent in situ hybridization through the mes-di-encephalon of the mouse embryo at embryonal days (E) 9.5-14.5. The results show that early differentiating dopamine neurons express the gene encoding VGLUT2 before onset of any dopaminergic markers. Prior to its down-regulation in maturing dopamine neurons, Vglut2 mRNA co-localizes extensively with Tyrosine hydroxylase (Th) and Nurr1, commonly used as markers for DA neurons. Further, Vglut2 and Nurr1 mRNAs are shown to overlap substantially in diencephalic neurons that maintain a glutamatergic phenotype. The results suggest that Vglut2/Nurr1-double positive cells give rise both to dopaminergic and glutamatergic neurons within the mes-di-encephalic area. Finally, analysis of markers representing subtypes of dopamine neurons, including the newly described NeuroD6 subtype, shows that certain subtype specifications arise early. Histological findings are outlined in the context of neuroanatomical concepts and the prosomeric model of brain development. The study contributes to the current decoding of the recently discovered heterogeneity among neurons residing along the cephalic flexure.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
Vglut2, Nurr1, dopamine, glutamate, heterogeneity, subtype, Viaat, Vmat2
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-407281 (URN)10.3389/fcell.2019.00307 (DOI)000514091500001 ()31850343 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2020-03-25 Created: 2020-03-25 Last updated: 2020-03-25Bibliographically approved
Bimpisidis, Z. & Wallén-Mackenzie, Å. (2019). Neurocircuitry of Reward and Addiction: Potential Impact of Dopamine-Glutamate Co-release as Future Target in Substance Use Disorder. JOURNAL OF CLINICAL MEDICINE, 8(11), Article ID 1887.
Open this publication in new window or tab >>Neurocircuitry of Reward and Addiction: Potential Impact of Dopamine-Glutamate Co-release as Future Target in Substance Use Disorder
2019 (English)In: JOURNAL OF CLINICAL MEDICINE, ISSN 2077-0383, Vol. 8, no 11, article id 1887Article, review/survey (Refereed) Published
Abstract [en]

Dopamine-glutamate co-release is a unique property of midbrain neurons primarily located in the ventral tegmental area (VTA). Dopamine neurons of the VTA are important for behavioral regulation in response to rewarding substances, including natural rewards and addictive drugs. The impact of glutamate co-release on behaviors regulated by VTA dopamine neurons has been challenging to probe due to lack of selective methodology. However, several studies implementing conditional knockout and optogenetics technologies in transgenic mice have during the past decade pointed towards a role for glutamate co-release in multiple physiological and behavioral processes of importance to substance use and abuse. In this review, we discuss these studies to highlight findings that may be critical when considering mechanisms of importance for prevention and treatment of substance abuse.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
addiction, reward, transgenic mice, optogenetics, self-administration, cocaine, amphetamine
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-402325 (URN)10.3390/jcm8111887 (DOI)000502294400130 ()31698743 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-14Bibliographically approved
Papathanou, M., Dumas, S., Pettersson, H., Olson, L. & Wallén-Mackenzie, Å. (2019). Off-Target Effects in Transgenic Mice: Characterization of Dopamine Transporter (DAT)-Cre Transgenic Mouse Lines Exposes Multiple Non-Dopaminergic Neuronal Clusters Available for Selective Targeting within Limbic Neurocircuitry. ENEURO, 6(5), Article ID ENEURO.0198-19.2019.
Open this publication in new window or tab >>Off-Target Effects in Transgenic Mice: Characterization of Dopamine Transporter (DAT)-Cre Transgenic Mouse Lines Exposes Multiple Non-Dopaminergic Neuronal Clusters Available for Selective Targeting within Limbic Neurocircuitry
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2019 (English)In: ENEURO, ISSN 2373-2822, Vol. 6, no 5, article id ENEURO.0198-19.2019Article in journal (Refereed) Published
Abstract [en]

Transgenic mouse lines are instrumental in our attempt to understand brain function. Promoters driving transgenic expression of the gene encoding Cre recombinase are crucial to ensure selectivity in Cre-mediated targeting of floxed alleles using the Cre-Lox system. For the study of dopamine (DA) neurons, promoter sequences driving expression of the Dopamine transporter (Dat) gene are often implemented and several DAT-Cre transgenic mouse lines have been found to faithfully direct Cre activity to DA neurons. While evaluating an established DAT-Cre mouse line, reporter gene expression was unexpectedly identified in cell somas within the amygdala. To indiscriminately explore Cre activity in DAT-Cre transgenic lines, systematic whole-brain analysis of two DAT-Cre mouse lines was performed upon recombination with different types of floxed reporter alleles. Results were compared with data available from the Allen Institute for Brain Science. The results identified restricted DAT-Cre-driven reporter gene expression in cell clusters within several limbic areas, including amygdaloid and mammillary subnuclei, septum and habenula, areas classically associated with glutamatergic and GABAergic neurotransmission. While no Dat gene expression was detected, ample co-localization between DAT-Cre-driven reporter and markers for glutamatergic and GABAergic neurons was found. Upon viral injection of a fluorescent reporter into the amygdala and habenula, distinct projections from non-dopaminergic DAT-Cre neurons could be distinguished. The study demonstrates that DAT-Cre transgenic mice, beyond their usefulness in recombination of floxed alleles in DA neurons, could be implemented as tools to achieve selective targeting in restricted excitatory and inhibitory neuronal populations within the limbic neurocircuitry.

Keywords
amygdala, Gad1, habenula, mammillary, septum, Vglut2
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-397678 (URN)10.1523/ENEURO.0198-19.2019 (DOI)000494278900027 ()31481399 (PubMedID)
Funder
Swedish Research Council, 2017-02039Swedish Research Council, 2014-3804Swedish Research Council, 2013-4657
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Bimpisidis, Z., König, N., Stagkourakis, S., Zell, V., Vlcek, B., Dumas, S., . . . Wallén-Mackenzie, Å. (2019). The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement. eNeuro, 6(3), Article ID e0066-19.2019.
Open this publication in new window or tab >>The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
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2019 (English)In: eNeuro, E-ISSN 2373-2822, Vol. 6, no 3, article id e0066-19.2019Article in journal (Refereed) Published
Abstract [en]

Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2(Cre)(lox/lox;NEX-) conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE, 2019
Keywords
accumbens, dopamine, mouse genetics, optogenetics, reward, ventral tegmental area
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-390531 (URN)10.1523/ENEURO.0066-19.2019 (DOI)000473806900022 ()31097625 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Vrettou, M., Nilsson, K. W., Tuvblad, C., Rehn, M., Åslund, C., Andershed, A.-K., . . . Comasco, E. (2019). VGLUT2 rs2290045 genotype moderates environmental sensitivity to alcohol-related problems in three samples of youths. European Child and Adolescent Psychiatry, 28(10), 1329-1340
Open this publication in new window or tab >>VGLUT2 rs2290045 genotype moderates environmental sensitivity to alcohol-related problems in three samples of youths
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2019 (English)In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 28, no 10, p. 1329-1340Article in journal (Refereed) Published
Abstract [en]

The importance of Vesicular Glutamate Transporter 2 (VGLUT2)-mediated neurotransmission has been highlighted in studies on addiction-related phenotypes. The single nucleotide polymorphism rs2290045 in VGLUT2 has been associated with alcohol dependence, but it is unknown whether or how this association is affected by environmental factors. The present study determined whether the association of alcohol-related problems with the rs2290045 in the VGLUT2 gene was modified by negative and positive environmental factors. Three samples were included: a clinical sample of 131 adolescents followed from age 17 to 22; a general population sample of 1794 young adults; and a general population sample of 1687 adolescents followed from age 14 to 17. DNA was extracted from saliva and the rs2290045 (T/C) was genotyped. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test. Stressful life events (SLE) and parenting were assessed by questionnaires. Gene-environment interactions were investigated using a dual statistical approach. In all samples (effect sizes 0.6-6.2%), and consistent with the differential susceptibility framework, T carriers exposed to SLE reported more alcohol-related problems if they had experienced poor parenting, and lower alcohol-related problems if they had received supportive parenting. T carriers not exposed to SLE reported higher alcohol-related problems if they had received supportive parenting and lower alcohol-related problems if they had received poor parenting. Among CC carriers, alcohol-related problems did not vary as a function of negative and positive environmental factors. In conclusion, in three samples of youths, alcohol-related problems were associated with an interaction of VGLUT2 rs2290045, SLE, and parenting.

Keywords
Adolescents, Alcohol, Gene, Glutamate, Stress, VGLUT2
National Category
Psychiatry Medical Genetics
Identifiers
urn:nbn:se:uu:diva-381816 (URN)10.1007/s00787-019-01293-w (DOI)000489301800006 ()30805764 (PubMedID)
Funder
The Swedish Brain Foundation, PS2013-0052Åke Wiberg Foundation, M15-0239Forte, Swedish Research Council for Health, Working Life and Welfare, 2015-00897Swedish Research Council, 2013-4657Swedish Research Council, 2014-3804Swedish Research Council, VR: 2015-00495
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-11-06Bibliographically approved
Papathanou, M., Creed, M., Dorst, M., Bimpisidis, Z., Dumas, S., Pettersson, H., . . . Wallén-Mackenzie, Å. (2018). Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio. Frontiers in Neural Circuits, 12, 1-20, Article ID 64.
Open this publication in new window or tab >>Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio
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2018 (English)In: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 12, p. 1-20, article id 64Article in journal (Refereed) Published
Abstract [en]

Expression of the Vglut2/Slc17a6 gene encoding the Vesicular glutamate transporter 2 (VGLUT2) in midbrain dopamine (DA) neurons enables these neurons to co-release glutamate in the nucleus accumbens (NAc), a feature of putative importance to drug addiction. For example, it has been shown that conditional deletion of Vglut2 gene expression within developing DA neurons in mice causes altered locomotor sensitization to addictive drugs, such as amphetamine and cocaine, in adulthood. Alterations in DA neurotransmission in the mesoaccumbal pathway has been proposed to contribute to these behavioral alterations but the underlying molecular mechanism remains largely elusive. Repeated exposure to cocaine is known to cause lasting adaptations of excitatory synaptic transmission onto medium spiny neurons (MSNs) in the NAc, but the putative contribution of VGLUT2-mediated glutamate co-release from the mesoaccumbal projection has never been investigated. In this study, we implemented a tamoxifen-inducible Cre-LoxP strategy to selectively probe VGLUT2 in mature DA neurons of adult mice. Optogenetics-coupled patch clamp analysis in the NAc demonstrated a significant reduction of glutamatergic neurotransmission, whilst behavioral analysis revealed a normal locomotor sensitization to amphetamine and cocaine. When investigating if the reduced level of glutamate co-release from DA neurons caused a detectable post-synaptic effect on MSNs, patch clamp analysis identified an enhanced baseline AMPA/NMDA ratio in DA receptor subtype 1 (DRD1)-expressing accumbal MSNs which occluded the effect of cocaine on synaptic transmission. We conclude that VGLUT2 in mature DA neurons actively contributes to glutamatergic neurotransmission in the NAc, a finding which for the first time highlights VGLUT2-mediated glutamate co-release in the complex mechanisms of synaptic plasticity in drug addiction.

Keywords
cocaine, amphetamine, addiction, substance use disorders, ventral tegmental area, striatum, medium spiny neurons
National Category
Biological Sciences Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-289078 (URN)10.3389/fncir.2018.00064 (DOI)000443136100001 ()
Funder
Swedish Research Council, 2011-4747, 2013-4657, 2017-02039The Swedish Brain FoundationKnut and Alice Wallenberg FoundationStiftelsen Olle Engkvist Byggmästare, SOEB 2015/586
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2018-11-01Bibliographically approved
Viereckel, T., Konradsson-Geuken, Å. & Wallén-Mackenzie, Å. (2018). Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus. Journal of Neurochemistry, 145(2), 125-138
Open this publication in new window or tab >>Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus
2018 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 145, no 2, p. 125-138Article in journal (Refereed) Published
Abstract [en]

Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of invivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinsons disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of invivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience.

Keywords
amperometry, basal ganglia, electrochemistry, Parkinson's disease, subthalamic nucleus
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-355695 (URN)10.1111/jnc.14288 (DOI)000430917900003 ()29292502 (PubMedID)
Funder
Swedish Research Council, Vetenskapsradet 2013-4657]Swedish Research Council, 2014-3804]The Swedish Brain Foundation
Available from: 2018-07-04 Created: 2018-07-04 Last updated: 2018-07-04Bibliographically approved
Wang, D. V., Viereckel, T., Zell, V., Konradsson-Geuken, Å., Broker, C. J., Talishinsky, A., . . . Ikemoto, S. (2017). Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation. Cell reports, 18(11), 2584-2591
Open this publication in new window or tab >>Disrupting Glutamate Co-transmission Does Not Affect Acquisition of Conditioned Behavior Reinforced by Dopamine Neuron Activation
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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.

Keywords
glutamate co-transmission, intracranial self-stimulation, mesolimbic dopamine system, nucleus accumbens, reinforcement learning, reward, ventral striatum
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-318762 (URN)10.1016/j.celrep.2017.02.062 (DOI)000397330000005 ()28297663 (PubMedID)
Funder
NIH (National Institute of Health)Swedish Research Council, 2013-4657 2014-3804The Swedish Brain Foundation
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-09-21Bibliographically approved
Vrettou, M., Granholm, L., Todkar, A., Nilsson, K. W., Wallén-Mackenzie, Å., Nylander, I. & Comasco, E. (2017). Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress. Addiction Biology, 22(2), 369-380
Open this publication in new window or tab >>Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress
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2017 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 2, p. 369-380Article in journal (Refereed) Published
Abstract [en]

Alcohol use disorder is the outcome of both genetic and environmental influences and their interaction via epigenetic mechanisms. The neurotransmitter glutamate is an important regulator of reward circuits and implicated in adaptive changes induced by ethanol intake. The present study aimed at investigating corticolimbic and corticostriatal genetic signatures focusing on the glutamatergic phenotype in relation to early-life stress (ELS) and consequent adult ethanol consumption. A rodent maternal separation model was employed to mimic ELS, and a free-choice paradigm was used to assess ethanol intake in adulthood. Gene expression levels of the Vesicular Glutamate Transporters (Vglut) 1, 2 and 3, as well as two key regulators of DNA methylation, DNA (cytosine-5)-methyltransferase 1 (Dnmt1) and methyl-CpG-binding protein 2 (Mecp2), were analyzed. Brain regions of interest were the ventral tegmental area (VTA), nucleus accumbens (Acb), medial prefrontal cortex (mPFC) and dorsal striatum (dStr), all involved in mediating aspects of ethanol reward. Region-specific Vglut, Dnmt1 and Mecp2 expression patterns were observed. ELS was associated with down-regulated expression of Vglut2 in the VTA and mPFC. Rats exposed to ELS were more sensitive to ethanol-induced changes in Vglut expression in the VTA, Acb, and dStr and in Dnmt1 and Mecp2 expression in the striatal regions. These findings suggest long-term glutamatergic and DNA methylation neuroadaptations as a consequence of ELS, and show an association between voluntary drinking in non-preferring, non-dependent, rodents and different Vglut, Dnmt1 and Mecp2 expression depending on early-life history.

Keywords
Alcohol, DNA methylation, glutamate, rats, stress, Vgluts
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-276528 (URN)10.1111/adb.12331 (DOI)000394988500008 ()26610727 (PubMedID)
Funder
Swedish Research Council, K2012-61X-22090-01-3 2013-4657 2014-3804Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-0627Lars Hierta Memorial FoundationThe Swedish Brain Foundation, PS2013-0052
Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2018-09-04Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8713-070x

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