Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis
Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. How...
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| Format: | Article |
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Frontiers Media S.A.
2020-07-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00721/full |
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| author | Jason A. Bubier Vivek M. Philip Price E. Dickson Price E. Dickson Guy Mittleman Elissa J. Chesler |
| author_facet | Jason A. Bubier Vivek M. Philip Price E. Dickson Price E. Dickson Guy Mittleman Elissa J. Chesler |
| author_sort | Jason A. Bubier |
| collection | DOAJ |
| description | Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification of Rab3b as a functional correlate of the locomotor response to cocaine in rodents. This gene encodes a member of the RAB family of Ras-like GTPases known to be involved in trafficking of secretory and endocytic vesicles in eukaryotic cells. The convergent evidence for a role of Rab3b includes co-occurrence in previously published genetic mapping studies of cocaine related behaviors; methamphetamine response and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) transcript abundance; evidence related to other addictive substances; density of polymorphisms; and its expression pattern in reward pathways. To evaluate this finding, we examined the effect of RAB3 complex perturbation in cocaine response. B6;129-Rab3btm1Sud Rab3ctm1sud Rab3dtm1sud triple null mice (Rab3bcd–/–) exhibited significant deficits in habituation, and increased acute and repeated cocaine responses. This previously unidentified mechanism of the behavioral predisposition and response to cocaine is an example of many that can be identified and validated using aggregate genomic studies. |
| first_indexed | 2024-12-21T06:33:22Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-21T06:33:22Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-dd4646bee8a64168a84671bcedca49fb2022-12-21T19:12:56ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-07-011410.3389/fnins.2020.00721554351Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic AnalysisJason A. Bubier0Vivek M. Philip1Price E. Dickson2Price E. Dickson3Guy Mittleman4Elissa J. Chesler5The Jackson Laboratory, Bar Harbor, ME, United StatesThe Jackson Laboratory, Bar Harbor, ME, United StatesThe Jackson Laboratory, Bar Harbor, ME, United StatesDepartment of Biomedical Sciences, Marshall University, Huntington, WV, United StatesDepartment of Psychological Science, Ball State University, Muncie, IN, United StatesThe Jackson Laboratory, Bar Harbor, ME, United StatesSubstance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification of Rab3b as a functional correlate of the locomotor response to cocaine in rodents. This gene encodes a member of the RAB family of Ras-like GTPases known to be involved in trafficking of secretory and endocytic vesicles in eukaryotic cells. The convergent evidence for a role of Rab3b includes co-occurrence in previously published genetic mapping studies of cocaine related behaviors; methamphetamine response and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) transcript abundance; evidence related to other addictive substances; density of polymorphisms; and its expression pattern in reward pathways. To evaluate this finding, we examined the effect of RAB3 complex perturbation in cocaine response. B6;129-Rab3btm1Sud Rab3ctm1sud Rab3dtm1sud triple null mice (Rab3bcd–/–) exhibited significant deficits in habituation, and increased acute and repeated cocaine responses. This previously unidentified mechanism of the behavioral predisposition and response to cocaine is an example of many that can be identified and validated using aggregate genomic studies.https://www.frontiersin.org/article/10.3389/fnins.2020.00721/fullgeneticQTLgenomicscocaine sensitizationhabituation |
| spellingShingle | Jason A. Bubier Vivek M. Philip Price E. Dickson Price E. Dickson Guy Mittleman Elissa J. Chesler Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis Frontiers in Neuroscience genetic QTL genomics cocaine sensitization habituation |
| title | Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis |
| title_full | Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis |
| title_fullStr | Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis |
| title_full_unstemmed | Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis |
| title_short | Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis |
| title_sort | discovery of a role for rab3b in habituation and cocaine induced locomotor activation in mice using heterogeneous functional genomic analysis |
| topic | genetic QTL genomics cocaine sensitization habituation |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.00721/full |
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