Homepage for Mouse Behavior Genetics (Koide's Lab)

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Mouse Genomics Resource Laboratory (MGRL)

Behavior Genetics
After the rediscovery of the Mendel's law, most genetic researches had been focused on analyses of genetic mutants and their causative genes. These studies successfully clarified the causative genes for the mutant phenotype in a variety of animals including humans. Although the studies provided a large amounts of information on the molecular function of the genes, we have rather limited idea how individual differences are regulated by underlying genetic mechanism.
My research projects focus on understanding genetic basis of strain difference of behavior in mice. In particular, we are interested in differences between wild and laboratory strains, wildness and tameness as well as anxiety-like behavior. We have been using a series of wild strains, which have been established in our institute, to characterize strain differences of behavioral pattern.


Published a paper on genome editing of wild mouse strains using the i-GONAD methodA new paper "Efficient genome editing in wild strains of mice using the i-GONAD method" has been published in Scientific Reports.  2022 August 15 DOI:10.1038/s41598-022-17776-x
Until now, it was considered difficult to generate genetically modified mice from wild strains. We have demonstrated that genome-edited mice can be produced efficiently using the i-GONAD method. This research was conducted by Mr. Imai, a technical staff member, and was published in Scientific Reports. (17 August 2022)

Change of behavior and transcriptome in tamed miceA new paper "Combined Change of Behavioral Traits for Domestication and Gene-Networks in Mice Selectively Bred for Active Tameness" has been published in Genes, Brain and Behavior.  2020 December 13 DOI:10.1111/gbb.12721
Tameness can be divided into two components: active tameness and passive tameness. We conducted selective breeding for higher scores of active tameness using a wild-derived heterogeneous stock. In the analyses of nine behavioral traits related to tameness, we found that five traits showed changes in the selective groups compared to the control groups through the generations. We conducted cluster analyses to evaluate the relationship among the nine traits and RNA-Seq analysis to characterize the molecular network related to tameness. The results suggested that active tameness was hidden in the control groups but became apparent in the selected populations by selective breeding (Fig 4), potentially driven by changes in gene expression networks. (22 December 2020)

A new "Behind the paper" article in Nature Research Ecology & Evolution CommunityNew BEHIND THE PAPER article "Reexamining the a of Mouse Genetics A to Z" has been posted in Nature Research Ecology & Evolution. We wrote about more story of finding a root cause of nonagouti and historical origin of the mutation. (22 August 2019)

Nested retrotransposition is a root cause of the classical black coat colorNested retrotransposition in the East Asian mouse genome causes the classical nonagouti mutation. Communications Biology 2: 283, 2019. doi: 10.1038/s42003-019-0539-7
Black coat color (nonagouti) is one of the widespread classical mutation in laboratory mouse strains including a standard strain C57BL/6 (B6). Endogenous retrovirus VL30 inserted in the nonagouti (a) allele has been considered as the cause of the nonagouti phenotype. Here, we revealed true mutation in the a allele. We found that β4, an endogenous retrovirus nested within the VL30, interrupts the agouti expression by the abnormal splicing. To demonstrate the normal agouti gene expression even with VL30, we used CRISPR/Cas9 to delete the β4 element completely. The β4-deleted mice restored agouti gene expression and agouti coat color. In partial deletion of β4 except for a single LTR, the mutant allele mimicked the black-and-tan (at) allele and the coat color. Phylogenetic analyses indicate that the a allele and the β4 retrovirus originated from an East Asian mouse linage that is most likely related to Japanese fancy mice, JF1. Structural variation in the agouti gene among mouse strains reveals that the VL30 insertion is derived from a natural mutation in East Asian wild mice. We propose that the a allele was derived from step-by-step insertional mutation events of VL30 followed by β4 retrovirus into an intact agouti allele. (15 August 2019)

Social hierarchy affects depression-like behavior and gene expression in mouse brainHierarchy in the home cage affects behaviour and gene expression in group-housed C57BL/6 male mice. Scientific Reports 7: 6991, 2017. doi:10.1038/s41598-017-07233-5
Social stress is one of the major causes of depression in humans. It is therefore important that the effects of social stress on behaviour and gene expression in the brain are studied. We performed experiments using male mice to analyse social hierarchy in groups of mice in cages and investigated emotional behaviour and hippocampal gene expression in the mice. We found significantly different emotional behaviour and expression of genes associated with the serotonergic system in dominant and subordinate mice. Treating the mice with a selective serotonin reuptake inhibitor antidepressant restored gene expression in subordinate mice and caused the emotional behaviour of the subordinate mice to be recovered, suggesting that alterations to the serotonergic system are key factors in phenotypic changes caused by the social ranks of subordinate mice. We believe that the results of this study are important because they improve our understanding of how social stress induces mental health problems in humans. (7 August 2017)

What makes domestic animals such as mice and dogs tameSelective breeding and selection mapping using a novel wild-derived heterogeneous stock of mice revealed two closely-linked loci for tameness. Scientific Reports 7: 4607, 2017. doi:10.1038/s41598-017-04869-1
During the process of domestication, the phenotype of tameness has often been selected, but the genetic factors actually associated with tameness remain unclear. To understand the genetic basis associated with active tameness, we developed a new mouse resource, wild-derived heterogeneous stock (WHS), made by crossing eight wild strains. Given that this WHS contains a mixed genome of wild strains, we might expect a high genetic diversity with a high variation of active tameness in the WHS population. We then conducted selective breeding for active tameness using the WHS. By so doing, we successfully developed WHS populations that exhibit higher active tameness than the control groups. Further genetic analysis of genome-wide SNPs revealed two loci, which were significantly selected during selective breeding. Given that dog is a highly domesticated animal with an extreme level of active tameness, we compared our results with the genomic information of dogs. As a result, we found two loci that could be related to active tameness in mouse and dog. (12 July 2017)

Low motor learning during the early phase of the accelerated rotarod task in Caspr3-KO miceCaspr3-deficient mice exhibit low motor learning during the early phase of the accelerated rotarod task. PLoS ONE 11(1):e0147887. 2016. doi: 10.1371/journal.pone.0147887.
Contactin-associated protein-like 3 (Caspr3, also known as Cntnap3) is a neural cell adhesion molecule belonging to the Caspr family, which comprises five members: Caspr, Caspr2, Caspr3, Caspr4, and Caspr5. Although the roles of Caspr, Caspr2, and Caspr4 have been reported previously in studies using knockout mice, the function of Caspr3 remains to be revealed. In this study, we conducted systematic analyses of behavioral phenotypes using a wide range of behavioral tests on Caspr3-knockout mice and their wild-type littermates. The results show that Caspr3-knockout mice specifically exhibited reduced motor learning in the rotarod test. Analyses of c-Fos expression in brains following the motor learning test suggested that the activities of neural cells in Caspr3-knockout mice were reduced in the dorsal striatum compared with those of wild-type mice. These results show that Caspr3 plays an important role in controlling motor learning in mice.

Glutamate Input in the Dorsal Raphe Nucleus As a Determinant of Escalated Aggression in Male MiceGlutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice. The Journal of Neuroscience 22 April 2015, 35(16): 6452-6463, 2015.doi: 10.1523/JNEUROSCI.2450-14.2015
We have been investigating neural mechanism in which escalated agression is regulated in male mice. In this study, we observed that microinjection of L-glutamate into the DRN escalated attack bites toward an intruder dose-dependently. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. We also found that, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase was not observed when animals were engaged in species-typical aggression. We concluded that glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons. (23 April 2015)

Different genetic factors affect different aspects of aggression in Japanese wild strain MSMGenetic mapping of escalated aggression in wild-derived mouse strain MSM/Ms: association with serotonin-related genes. Frontiers in Neuroscience Volume8, Article156. 11 June 2014. doi: 10.1038/hdy.2014.42.
The Japanese wild-derived mouse strain MSM/Ms (MSM) exhibits high levels of aggression than the standard laboratory strain C57BL/6J. We identified two chromosomes, Chr 4 and Chr 15, which were involved in the heightened aggression observed in MSM. These chromosomes had different effects on aggression: whereas MSM Chr 15 increased agitation and initiation of aggressive events, MSM Chr 4 induced a maladaptive level of aggressive behavior. Expression analysis of mRNAs of serotonin related genes indicated that the expression of Tph2, an enzyme involved in serotonin synthesis, in the midbrain was increased in the Chr 4 consomic strain, as well as in MSM, and that there was a strong positive genetic correlation between aggressive behavior and Tph2 expression at the mRNA level. (13 June 2014)

A cluster of four QTLs for behavior segregated by new method using a statistical regression modelSegregation of a QTL cluster for home-cage activity using a new mapping method based on regression analysis of congenic mouse strains. Heredity Advance online publication 30 April 2014. doi: 10.1038/hdy.2014.42.
We collaborated with Drs. Shogo Kato and Satoshi Kuriki in the Institute of Statistical Mathematics and established a new method for mapping multiple QTLs using data from a series of congenic strains by applying a regression model for the analysis of total home-cage activity in mice. The results of the analysis identified four significant QTLs in a 14.5 Mb genomic region. Among these, three have negative effects but one has a positive effect on total home-cage activity. In further analysis of recombinants obtained from the congenic strains, we confirmed the existence of the QTL that has a positive effect on the activity as well as another QTL that suppresses the effect of this positive QTL. These results clarify for the first time the association of a complex genetic mechanism in the QTL cluster on chromosome 6 with the regulation of home-cage activity. (7 May 2014)

Development of a freeware that enables automatic characterization of social behavior in miceA male-specific QTL for social interaction behavior in mice mapped with automated pattern detection by a hidden Markov model incorporated into newly developed freeware
Toshiya Arakawa*, Akira Tanave*, Shiho Ikeuchi, Aki Takahashi, Satoshi Kakihara, Shingo Kimura, Hiroki Sugimoto, Nobuhiko Asada, Toshihiko Shiroishi, Kazuya Tomihara, Takashi Tsuchiya, Tsuyoshi Koide.  * equally contributed.
Journal of Neuroscience Methods Available online 21 April 2014 doi:10.1016/j.jneumeth.2014.04.012
Notwithstanding the importance of effective approaches to analyze social interaction between animals in experimental settings, the methods that are currently available to do this rely predominantly on human observation. This makes large-scale studies of social interaction behavior difficult. In this paper, we report the development of freeware, called DuoMouse, that enables video recording to track the movements of two mice from a movie file, analysis of behavioral states using a hidden Markov model (HMM), and visualization of the results. The freeware developed in the present study is very useful for large-scale genetic and pharmacological studies of social behavior in mice.

Aki Takahashi characterized inhibitory role of the medial prefrontal cortex on aggressive behavior using optogenetics techniqueControl of Intermale Aggression by Medial Prefrontal Cortex Activation in the Mouse. Aki Takahashi, Kazuki Nagayasu, Naoya Nishitani, Shuji Kaneko, Tsuyoshi Koide. PLoS ONE April 16, 2014 doi:10.1371/journal.pone.0094657
In general, aggressive behavior in social animals is regulated within a range of adaptive level. However, the neural mechanisms associate with the regulation of aggressive behavior still needs to be studied. She found inhibitory role of the medial prefrontal cortex on aggressive behavior using optogenetics method which enable her to regulate activity of neural cells in vivo. April 16, 2014.

Koide attended Gordon Research Conference to present recent progress on our researchTK attended Gordon Research Conference entitled "Genes and Behavior" which was held in February 2014 in Galveston, TX to give a oral presentation. This was a excellent meeting and had a stimulating time.

A way of making tamed animals from wild miceSelection for reluctance to avoid humans during the domestication of mice. Goto T, Tanave A, Moriwaki K, Shiroishi T, Koide T. Genes Brain and Behavior 2013. DOI: 10.1111/gbb.12088
Humans have developed many domestic animals for various purposes. Tameness is a behavioral characteristic that is changed during domestication process of wild ancestors. However, it is still need to be clarified how tameness change the behavior of animals. In order to address this point, we developed three behavioral tests to measure the level of two different classes of tameness in mice. We characterized tame behavior using 17 inbred mouse strains: ten wild strains, one Japanese fancy-mouse strain, and six laboratory strains. The results suggest that domesticated strains were predominantly selected for reluctance to avoid humans over the course of their domestication history.

Identification of both copy number variation-type and constant-type core elements in a large segmental duplication region of the mouse genomeUmemori J, Mori A, Ichiyanagi K, Uno T, and Koide T. BMC Genomics 14: 455, 2013
One type of genomic structural variation, copy number variations (CNVs), reside frequently in clusters and form CNV regions (CNVRs). CNVRs are associated tightly with segmental duplications (SDs), but the processes by which such structures arise remain unclear. In this study, we conducted self-plot analysis of all mouse chromosomes and identified various types of large SD on eight chromosomes. Subsequently, we focused on one SD on Chr 13, and identified 60 core elements within the repetitive structure. Our analysis showed that there are two types, CNV-type and constant-type, in this SD. This study may provide useful information for understanding mechainism related evolution and function of this SD.

A book for beginners of mouse research (Japanese book)TK edited a Japanese book entitled "A basic Primer of Mouse Research 2nd edition"

An Introductory book for Behavior Genetics (Japanese book)TK edited a Japanese book entitled "Introductory Behavior Genetics"

Bitter taste (Sucrose Octaacetate) aversion in mice caused by multigenic factors.Ishii A., Koide T., Takahashi A., Shiroishi T., Hettinger T.P., Frank M.E., Savoy L.D., Formaker B.K., Yertutanol S., ALionikas A. and Blizard D.A. B6-MSM consomic mouse strains reveal multiple loci for genetic variation in sucrose octaacetate aversion. Behavior Genetics (in press).  In this paper, we showed that Soa locus on distal Chr 6 that code for bitter taste receptors Tas2r strongly associate with SOA aversion. Our results also showed that Tas2r genes on Chr 2 and 15, as well as to genes not coding for bitter receptors (Chr 4), contribute to SOA aversion.

Genetic analysis of social behavior (Paper in Behavior Genetics: Takahashi et al.) Online open MSM/Ms (MSM), a Japanese wild mouse derived strain, exhibit higher social interaction but also show increased inter-male aggression comparing to C57BL/6J (B6). In order to understand genetic basis of difference in social behavior between MSM and B6, we analyzed a panel of MSM-B6 consomic strains using social interaction test. PDF

National Institute of Genetics    | | ©2005 Tsuyoshi Koide    Last update 2021 May