Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response
Identifieur interne : 002061 ( Main/Corpus ); précédent : 002060; suivant : 002062Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response
Auteurs : Jeff A. Beeler ; Zhen Fang Huang Cao ; Mazen A. Kheirbek ; Yunmin Ding ; Jessica Koranda ; Mari Murakami ; Un Jung Kang ; Xiaoxi ZhuangSource :
- Annals of Neurology [ 0364-5134 ] ; 2010-05.
Abstract
Objective: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods: To examine this question, we took advantage of PITx3‐deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results: We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation: This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639–647
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DOI: 10.1002/ana.21947
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Beeler</name><affiliation><mods:affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Cao, Zhen Fang Huang" sort="Cao, Zhen Fang Huang" uniqKey="Cao Z" first="Zhen Fang Huang" last="Cao">Zhen Fang Huang Cao</name><affiliation><mods:affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Kheirbek, Mazen A" sort="Kheirbek, Mazen A" uniqKey="Kheirbek M" first="Mazen A." last="Kheirbek">Mazen A. Kheirbek</name><affiliation><mods:affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation><affiliation><mods:affiliation>Current Address: Departments of Neuroscience and Psychiatry, Columbia University, 1051 Riverside Dr, New York, NY 10032</mods:affiliation></affiliation></author><author><name sortKey="Ding, Yunmin" sort="Ding, Yunmin" uniqKey="Ding Y" first="Yunmin" last="Ding">Yunmin Ding</name><affiliation><mods:affiliation>Department of Neurology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Koranda, Jessica" sort="Koranda, Jessica" uniqKey="Koranda J" first="Jessica" last="Koranda">Jessica Koranda</name><affiliation><mods:affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Murakami, Mari" sort="Murakami, Mari" uniqKey="Murakami M" first="Mari" last="Murakami">Mari Murakami</name><affiliation><mods:affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Kang, Un Jung" sort="Kang, Un Jung" uniqKey="Kang U" first="Un Jung" last="Kang">Un Jung Kang</name><affiliation><mods:affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author><author><name sortKey="Zhuang, Xiaoxi" sort="Zhuang, Xiaoxi" uniqKey="Zhuang X" first="Xiaoxi" last="Zhuang">Xiaoxi Zhuang</name><affiliation><mods:affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation><affiliation><mods:affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-05">2010-05</date><biblScope unit="volume">67</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="639">639</biblScope><biblScope unit="page" to="647">647</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">1D2EA8532CCF1980A264F64494674980CA47957A</idno><idno type="DOI">10.1002/ana.21947</idno><idno type="ArticleID">ANA21947</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods: To examine this question, we took advantage of PITx3‐deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results: We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation: This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639–647</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Jeff A. Beeler PhD</name><affiliations><json:string>Department of Neurobiology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Zhen Fang Huang Cao BA</name><affiliations><json:string>Department of Neurobiology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Mazen A. Kheirbek PhD</name><affiliations><json:string>Committee on Neurobiology, University of Chicago, Chicago, IL</json:string><json:string>Current Address: Departments of Neuroscience and Psychiatry, Columbia University, 1051 Riverside Dr, New York, NY 10032</json:string></affiliations></json:item><json:item><name>Yunmin Ding PhD</name><affiliations><json:string>Department of Neurology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Jessica Koranda BA</name><affiliations><json:string>Committee on Neurobiology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Mari Murakami</name><affiliations><json:string>Department of Neurobiology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Un Jung Kang MD</name><affiliations><json:string>Committee on Neurobiology, University of Chicago, Chicago, IL</json:string><json:string>Department of Neurology, University of Chicago, Chicago, IL</json:string></affiliations></json:item><json:item><name>Xiaoxi Zhuang PhD</name><affiliations><json:string>Department of Neurobiology, University of Chicago, Chicago, IL</json:string><json:string>Committee on Neurobiology, University of Chicago, Chicago, IL</json:string></affiliations></json:item></author><articleId><json:string>ANA21947</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods: To examine this question, we took advantage of PITx3‐deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results: We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation: This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639–647</abstract><qualityIndicators><score>7.856</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1581</abstractCharCount><pdfWordCount>5066</pdfWordCount><pdfCharCount>32525</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>238</abstractWordCount></qualityIndicators><title>Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response</title><genre><json:string>article</json:string></genre><host><volume>67</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>9</total><last>647</last><first>639</first></pages><issn><json:string>0364-5134</json:string></issn><issue>5</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1002/ana.21947</json:string></doi><id>1D2EA8532CCF1980A264F64494674980CA47957A</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/1D2EA8532CCF1980A264F64494674980CA47957A/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/1D2EA8532CCF1980A264F64494674980CA47957A/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/1D2EA8532CCF1980A264F64494674980CA47957A/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2010</date></publicationStmt><notesStmt><note>NIH NIDA - No. DA025875;</note><note>NIH NINDS - No. NS064865;</note><note>American Parkinson's Disease Association Center for Advanced Research</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response</title><author><persName><forename type="first">Jeff A.</forename><surname>Beeler</surname></persName><roleName type="degree">PhD</roleName><note type="biography">These authors contributed equally to this work.</note><affiliation>These authors contributed equally to this work.</affiliation><note type="correspondence"><p>Correspondence: 924 E 57th St R222, Chicago, IL 60637</p></note><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Zhen Fang Huang</forename><surname>Cao</surname></persName><roleName type="degree">BA</roleName><note type="biography">These authors contributed equally to this work.</note><affiliation>These authors contributed equally to this work.</affiliation><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Mazen A.</forename><surname>Kheirbek</surname></persName><roleName type="degree">PhD</roleName><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Current Address: Departments of Neuroscience and Psychiatry, Columbia University, 1051 Riverside Dr, New York, NY 10032</affiliation></author><author><persName><forename type="first">Yunmin</forename><surname>Ding</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Jessica</forename><surname>Koranda</surname></persName><roleName type="degree">BA</roleName><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Mari</forename><surname>Murakami</surname></persName><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Un Jung</forename><surname>Kang</surname></persName><roleName type="degree">MD</roleName><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Department of Neurology, University of Chicago, Chicago, IL</affiliation></author><author><persName><forename type="first">Xiaoxi</forename><surname>Zhuang</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-05"></date><biblScope unit="volume">67</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="639">639</biblScope><biblScope unit="page" to="647">647</biblScope></imprint></monogr><idno type="istex">1D2EA8532CCF1980A264F64494674980CA47957A</idno><idno type="DOI">10.1002/ana.21947</idno><idno type="ArticleID">ANA21947</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods: To examine this question, we took advantage of PITx3‐deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results: We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation: This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. 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University of Chicago, Chicago, IL</unparsedAffiliation></affiliation><affiliation xml:id="curr1" countryCode="US"><unparsedAffiliation>Departments of Neuroscience and Psychiatry, Columbia University, 1051 Riverside Dr, New York, NY 10032</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>NIH NIDA</fundingAgency><fundingNumber>DA025875</fundingNumber></fundingInfo><fundingInfo><fundingAgency>NIH NINDS</fundingAgency><fundingNumber>NS064865</fundingNumber></fundingInfo><fundingInfo><fundingAgency>American Parkinson's Disease Association Center for Advanced Research</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_A-LowSpeedRun"></mediaResource><caption>Vedio A: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_B-Exploration"></mediaResource><caption>Vedio B: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_C-Turn"></mediaResource><caption>Vedio C: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_D-HighSpeedRun"></mediaResource><caption>Vedio D: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_E-Recovery"></mediaResource><caption>Vedio E: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21947:ANA_21947_sm_F-Fall"></mediaResource><caption>Vedio F: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F).</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear.</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>To examine this question, we took advantage of PITx3‐deficient mice (<i>aphakia</i> mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience.</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p>This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639–647</p></section></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>These authors contributed equally to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>LDR in an Animal Model</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response</title></titleInfo><name type="personal"><namePart type="given">Jeff A.</namePart><namePart type="family">Beeler</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation><description>These authors contributed equally to this work.</description><description>Correspondence: 924 E 57th St R222, Chicago, IL 60637</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhen Fang Huang</namePart><namePart type="family">Cao</namePart><namePart type="termsOfAddress">BA</namePart><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mazen A.</namePart><namePart type="family">Kheirbek</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Current Address: Departments of Neuroscience and Psychiatry, Columbia University, 1051 Riverside Dr, New York, NY 10032</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yunmin</namePart><namePart type="family">Ding</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, University of Chicago, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jessica</namePart><namePart type="family">Koranda</namePart><namePart type="termsOfAddress">BA</namePart><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mari</namePart><namePart type="family">Murakami</namePart><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Un Jung</namePart><namePart type="family">Kang</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Department of Neurology, University of Chicago, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Xiaoxi</namePart><namePart type="family">Zhuang</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurobiology, University of Chicago, Chicago, IL</affiliation><affiliation>Committee on Neurobiology, University of Chicago, Chicago, IL</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2010-05</dateIssued><dateCaptured encoding="w3cdtf">2009-07-08</dateCaptured><dateValid encoding="w3cdtf">2009-12-03</dateValid><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">8</extent><extent unit="references">40</extent><extent unit="words">5624</extent></physicalDescription><abstract lang="en">Objective: Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. Methods: To examine this question, we took advantage of PITx3‐deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3‐deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. Results: We show that the deficiency in motor skill learning in PITx3(−/−) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. Interpretation: This observation resembles the long‐duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long‐duration response to chronic levodopa treatment is a manifestation of rescued motor learning. ANN NEUROL 2010;67:639–647</abstract><note type="funding">NIH NIDA - No. DA025875; </note><note type="funding">NIH NINDS - No. NS064865; </note><note type="funding">American Parkinson's Disease Association Center for Advanced Research</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Vedio A: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - Vedio B: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - Vedio C: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - Vedio D: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - Vedio E: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - Vedio F: The accelerating rotarod task is sometimes viewed as a simple coordination and timing task in which performance involves timed and coordinated alternation of paw movements. We argue the task is one of acquiring a repertoire of sensory‐motor stimulus responses in which the sensory input is comprised of the animal's position in the task (ie., vestibular, proprioceptive, position in space, position on rod) and the motor response a learned series of adaptations to maintain a stable position. At lower speeds, the animal's movements are not constant. In fact, their performance is mainly a set of corrective actions, where the animal climbs up the rod when it senses its body is slipping (Video A). In addition, and animal may also display distractive behavior such as exploration (Video B) and turning (Video C) at lower speeds. In order to successfully maintain itself on the rod, the animal must learn to suppress these behaviors or make corrective actions when their position becomes precarious. At higher speeds, the animal's movements become more constant, though still requiring corrections (Video D). If the animal starts slipping, it must once again employ a set of corrective actions in order to recover and continue its performance (Video E). If the animal is unable to produce the appropriate set of actions, their errors will result in a fall (Video F). - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>67</number></detail><detail type="issue"><caption>no.</caption><number>5</number></detail><extent unit="pages"><start>639</start><end>647</end><total>9</total></extent></part></relatedItem><identifier type="istex">1D2EA8532CCF1980A264F64494674980CA47957A</identifier><identifier type="DOI">10.1002/ana.21947</identifier><identifier type="ArticleID">ANA21947</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2010 American Neurological Association</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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