Bardet-Biedl Syndrome (BBS) is an autosomal recessive genetic disorder characterized by polydactyly, obesity, and vision loss. Some BBS patients experience developmental delay and difficulties in emotional regulation, but neurological features of this disorder are understudied. BBS mouse models have defects in fear conditioning and reduced anxiety-like behaviors in open field tests. The purpose of this study is to characterize the anxiety-like behavior in Bbs10 knockout mice prior to significant visual impairment using elevated plus maze. Bbs10-/- mice made significantly more entries into the open arms and traveled greater distances compared to littermate controls, suggestive of reduced anxiety-like behaviors.
","acknowledgements":"We gratefully acknowledge Dr. Hanna Stevens, Robert J. Taylor and Faith Fairbairn, University of Iowa.
","authors":[{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["dataCuration","formalAnalysis","investigation","validation","writing_reviewEditing","visualization","supervision"],"email":"mackenzie-bengen@uiowa.edu","firstName":"Mackenzie ","lastName":"Bengen","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":true,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","project","supervision","writing_originalDraft","writing_reviewEditing"],"email":"ying-hsu@uiowa.edu","firstName":"Ying","lastName":"Hsu","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":true,"WBId":null,"orcid":"0000-0002-0396-9680"},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"naim-chabaytah@uiowa.edu","firstName":"Naim","lastName":"Chabaytah","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"ethan-brandauer@uiowa.edu","firstName":"Ethan","lastName":"Brandauer ","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"sarah-giese@uiowa.edu","firstName":"Sarah","lastName":"Giese","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"tyler-rankin@uiowa.edu","firstName":"Tyler","lastName":"Rankin","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"joseph-laird@uiowa.edu","firstName":"Joseph","lastName":"Laird","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"neda-mokhberian@uiowa.edu","firstName":"Neda","lastName":"Mokhberian","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["fundingAcquisition","project","writing_reviewEditing"],"email":"arlene-drack@uiowa.edu","firstName":"Arlene","lastName":"Drack","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[{"awardId":"1K99EY036493-01A1","funderName":"National Eye Institute (United States)","awardRecipient":"Ying Hsu"},{"awardId":"PILOT grant award","funderName":"University of Iowa Intellectual and Developmental Disabilities Research Center","awardRecipient":"PI: Arlene Drack; Co-PIs: Ying Hsu, Hanna Stevens, Jacob Michaelson"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Supported by Ronald Keech Professorship (PI: Drack).
","image":{"url":"https://portal.micropublication.org/uploads/8e08d8ceed6123836146c87dec92a225.jpg"},"imageCaption":"The elevated plus maze apparatus (a). Time-to-platform in light-adapted functional vision test for Bbs10-/- mice and wild-type (WT) or heterozygous (HET) control littermates (b). Time-to-platform in dark-adapted functional vision test for controls and Bbs10-/- mice (c). Number of entries into open arms for controls and Bbs10-/- mice (d). Distance traveled in open arms for controls and Bbs10-/- mice (e). Number of entries into center square for controls and Bbs10-/- mice (f). Number of entries into closed arms for controls and Bbs10-/- mice (g). Distance traveled in closed arms for controls and Bbs10-/- mice (h). Trajectories in elevated plus maze test for a typical control and a Bbs10-/- mouse (i). Body weight of controls and Bbs10-/- mice at 22 - 24 days old (j).
","imageTitle":"Bbs10-/- mice show increased open arm exploration in elevated plus maze
","methods":"Animal husbandry and mouse model
This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All the animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocol #1041421 of the University of Iowa. The BBS10 mouse model was acquired from the KOMP2 Center at the Jackson Laboratory, and it is now distributed through the Mutant Mouse Resource and Research Centers (MMRRC) as C57BL/6N-Bbs10tm1.1(KOMP)Vlcg/JMmucd. This mouse model was generated from the embryonic stem cell line Bbs10tm1(KOMP)Vlcg (VG13389A-A11, MMRRC). The characterization of this mouse model was described in detail elsewhere (Mayer et al. 2022). Mice were crossed onto the 129S6 genetic background for at least 7 generations. Animals were housed according to IACUC recommendations. Both male and female mice were used in this study.
Elevated plus maze
Each side arm of the elevated plus maze apparatus measured 34.7 cm long, and the walls of the closed arms were 15 cm tall. The center square measured 5.6 cm wide, which was also the width of each of the side arms. The side arms had an elevation of 49.7 cm from the bottom of the apparatus, and the entire apparatus was positioned on a table that was 60.4 cm tall. The apparatus was made of dark, opaque plastic. Mice between 22-24 days old were placed in the intersection of the four arms of the elevated plus maze, designated the center, facing an open arm. Their behavior and movement were video recorded for 5 minutes. These mice were not tested in any other behavioral assays prior to this experiment. For each animal, it was their first exposure to the elevated plus maze test. Video recording and automatic video tracking of the animal’s body and time spent in each compartment were performed in ANYMAZE software version 6.32. The floor of the side arms were covered in white tape to increase contrast for automatic video tracking. An observer also manually marked number of times an animal placed 2 forepaws into the open arm compartment as an additional metric. The elevated plus maze test was performed under typical fluorescent ceiling light. The maze was cleaned by 70 % ethanol between animals to mask scent. Males and females were tested on separate days when possible. If they must be tested on the same day, all the male animals were tested first, the white tape was replaced in addition to cleaning, and then all the female animals were tested. At the conclusion of each day, 10 % bleach was used to clean the apparatus.
Visually-guided swim assay
The visually-guided swim assay, adapted from the Morris water maze, was performed as previously described (Hassan et al. 2023). Briefly, over four training days, a mouse was trained to identify and swim to a platform in a water maze for five trials a day. The location of the platform was randomized at every trial to prevent memorization. Following training, a mouse was tested over four testing days, for five trials a day, with randomized platform positions. After testing in lighted conditions, functional vision was measured under dark-adapted conditions under a dim red light. Under dark-adapted conditions, a mouse was trained over 2 training days, then tested over 4 testing days for 5 trials a day, with randomized platform positions. Time-to-platform metrics over 20 trials were independently averaged for light-adapted and dark-adapted conditions.
Statistical analysis
Scientific visualization was performed using GraphPad PRISM, and statistical analysis was performed using 2-tailed Welsh’s t-test with assumption of unequal standard deviation. Error bars in graphs and in manuscript text represent standard error of the mean. Grubbs' tests were performed and datapoints meeting criteria for outliers were excluded.
","reagents":"","patternDescription":"
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, vision loss, and behavioral/neurological traits. BBS genes code for proteins that jointly regulate trafficking in an organelle called the cilium (Nachury 2018). Mutations in at least 26 different BBS genes can independently cause BBS presenting with many shared clinical features (Dollfus et al. 2024; Forsyth and Gunay-Aygun 2003 [Updated 2023 Mar 23]). Mutations in BBS10 constitute the second most common cause of BBS among BBS genes, accounting for approximately 21 % of all BBS cases (Stoetzel et al. 2006). BBS10, together with BBS6 and BBS12, are chaperonin proteins responsible for assembly of the BBSome, a protein complex participating in ciliary trafficking (Seo et al. 2010). In children with BBS, night blindness is typically noted before onset of significant vision loss. Parents of children with BBS first noted night blindness in their children at an average age of 8.5 years, and their children were registered as “blind” at an average age of 15.5 years (Beales et al. 1999). Compared to trajectories of visual impairment, behavioral/neurological features are not as well understood. Clinical reports associate BBS with autism-spectrum disorder in some patients (Chatterjee et al. 2014; Jain et al. 2026). In mouse models of BBS, altered ciliary functions impact migration, differentiation, and proliferation of neurons in the brain, which could be associated with neurological phenotypes in patients (Carter et al. 2012). In one study, approximately 50% of the subjects with BBS experienced developmental delays, with development of speech being delayed by up to 2 years in 47% of the subjects (Beales et al. 1999). Additionally, this study also noted an inappropriate affect and a disinhibited demeaner in approximately half the enrolled patients (Beales et al. 1999).
In mouse models of BBS, including in Bbs1M390R/M390R mice and mice with postnatal deletion of Bbs8, long-term context-dependent fear conditioning was impaired, despite intact short-term context-dependent fear conditioning (Pak et al. 2021). In a study dissecting anxiety-related phenotypes of Bbs6-/- and Bbs8-/- mice, BBS6 being a member of the chaperonin complex and BBS8 being a member of the BBSome complex, Bbs8-/- mice exhibited increased latency to immobility in the forced swim test, and Bbs6-/- mice also showed a trend of increase in this trait (Rodig et al. 2022). In the open field test, Bbs6-/- mice traveled significantly greater distances compared to that in littermate controls, a trend also observed in Bbs8-/- mice compared to their littermates (Rodig et al. 2022). Together, these data showed that Bbs6-/- and Bbs8-/- mice had decreased anxiety-like phenotypes, at least in a non-social context.
The goal of this study is to determine whether Bbs10-null mice (Bbs10-/-) have anxiety-like phenotype using the elevated plus maze behavior test. The elevated plus maze test is a well-validated behavioral assay using a plus-shaped apparatus, with two of the four arms “closed” (surrounded by opaque walls) and the other two arms “open” (Figure 1a). Rodents naturally prefer dark, enclosed spaces, and this innate preference drives them towards the closed arms. They also have an innate fear for height and for lighted areas, hence the natural tendency to avoid open arms. The preference of the mice to explore the closed versus the open arms in elevated plus maze informs the degree of their anxiety-like behavior (or lack thereof) (Walf and Frye 2007). The BBS10 mouse model, on the 129S6/SvEvTac incipient genetic background, harbors a deletion encompassing parts of exon 1 and 2 of the Bbs10 gene, and mice that are null for Bbs10 recapitulate phenotypes seen in humans including vision loss and obesity (Mayer et al. 2022). However, their behavioral phenotypes have not been fully characterized.
In this study, the anxiety-like phenotype of Bbs10-/- mice and wild-type (WT) or heterozygous (HET) control littermates was examined when they were between postnatal day 22 and 24, prior to significant loss of light-adapted vision. To ascertain their functional vision in light-adapted conditions, vision was assessed using a visually-guided swim assay between ages of 34 days to 60 days old, shortly after they completed the elevated plus maze tests. The time it took for Bbs10-/- mice to locate a platform in lighted conditions was not significantly different than that of their control littermates (Figure 1b), indicating that light-adapted functional vision was not yet severely impaired. It is worth noting that Bbs10-/- mice had impairment in dark-adapted functional vision in the swim assay at this age (Figure 1c; time-to-platform for Bbs10-/-: 20.877 s; time-to-platform for control: 8.497 s; p< 0.05). Impairment in dark-adapted vision prior to light-adapted vision recapitulates the phenotype in humans. In elevated plus maze, 22 - 24 days old Bbs10-/- mice made 3 times as many entries into the open arms of the elevated plus maze compared to those made by their control littermates (Figure 1d, Bbs10-/-: 7.6 ± 1.956 entries; control: 2.5 ±0.560 entries; p < 0.05). In addition, Bbs10-/- mice traveled 5 times greater distances in the open arms of the elevated plus maze compared to distances traveled by their control littermates (Figure 1e; Bbs10-/-: 0.616 ± 0.215 m; control: 0.122 ± 0.048 m; p < 0.05). Bbs10-/- mice also tend to spend more time on the open arms, even though this observation is not statistically significant (Bbs10-/-: 19.263 ± 6.523; control: 6.940 ± 2.001; p = 0.107). Correspondingly, Bbs10-/- mice made significantly greater number of entries into the center zone compared to littermate controls (Figure 1f), even though the number of entries into the closed arm was not significantly different compared to littermate controls (Figure 1g). The total distance traveled in the closed arms was 1.6 times greater in Bbs10-/- mice compared to controls (Figure 1h, Bbs10-/-: 10.713 ± 0.855 m; control 6.659 ± 0.512 m; p <0.005). The number of open arm entries between males and females was not significantly different in the controls (male control: 1.25 ± 0.366; female control: 3.182 ± 0.893; p = 0.0663) nor in the Bbs10-/- group (male Bbs10-/-: 7.8 ± 3.441; female Bbs10-/-: 7.4 ± 2.315; p = 0.9259). The number of center zone entries between males and females was not significantly different in the controls (male control: 20.556 ± 3.444; female control: 18.455 ± 2.129; p = 0.6122) nor in the Bbs10-/- group (male Bbs10-/-: 30.0 ± 6.096; female Bbs10-/-: 28.6 ± 3.868; p = 0.8535). Typical trajectories of a control and a Bbs10-/- mouse in the elevated plus maze test are shown (both females) (Figure 1i). At 22 – 24 days old, Bbs10-/- mice have significantly reduced bodyweights (Figure 1j, Bbs10-/-: 6.083 ± 0.338; controls: 12.518 ± 0.243; p <0.0001). Together, these data show that mice lacking the Bbs10 gene demonstrate increased exploration of the open arms in the elevated plus maze test, pointing to decreased anxiety. Furthermore, Bbs10-/- mice traveled 5-fold greater distances in the open arms and 1.6 times greater distances in the closed arms compared to control littermates. These phenotypes, present prior to severe impairment in light-adapted vision and prior to onset of obesity, likely represent intrinsic neurological features of Bbs10-/- mice.The lower degrees of anxiety in BBS mouse models could be plausibly associated with the disinhibited affect observed in BBS patients, although a direct link has not been established and more studies are needed.
","references":[{"reference":"Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. 1999. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36(6): 437-46.
","pubmedId":"10874630","doi":""},{"reference":"Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, et al., Sheffield VC. 2012. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18(12): 1797-804.
","pubmedId":"23160237","doi":""},{"reference":"Chatterjee SS, Guha P, Talukdar A, Dasgupta G. 2014. Autism: a rare presentation of Bardet-Biedl syndrome. BMJ Case Rep 2014: pii: bcr2014203882. 10.1136/bcr-2014-203882.
","pubmedId":"24899006","doi":""},{"reference":"Dollfus H, Lilien MR, Maffei P, Verloes A, Muller J, Bacci GM, et al., Valverde D. 2024. Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations. Eur J Hum Genet 32(11): 1347-1360.
","pubmedId":"39085583","doi":""},{"reference":"Forsyth R, Gunay-Aygun M. 2003 [Updated 2023 Mar 23] Bardet-biedl syndrome overview. In: Adam MP BS, Mirzaa GM, et al., editor. Genereviews® [internet]. University of Washington, Seattle, Seattle (WA).
","pubmedId":"","doi":""},{"reference":"Hassan S, Hsu Y, Mayer SK, Thomas J, Kothapalli A, Helms M, et al., Drack AV. 2023. A visually guided swim assay for mouse models of human retinal disease recapitulates the multi-luminance mobility test in humans. Saudi J Ophthalmol 37(4): 313-320.
","pubmedId":"38155679","doi":""},{"reference":"Jain D, Koparde V, Chate SS. 2026. A distinct autism-like phenotype in bardet-biedl syndrome case report. J Indian Assoc Child. 22. doi:10.1177/09731342261442659
","pubmedId":"","doi":""},{"reference":"Mayer SK, Thomas J, Helms M, Kothapalli A, Cherascu I, Salesevic A, et al., Drack AV. 2022. Progressive retinal degeneration of rods and cones in a Bardet-Biedl syndrome type 10 mouse model. Dis Model Mech 15(9): 10.1242/dmm.049473.
","pubmedId":"36125046","doi":""},{"reference":"Nachury MV. 2018. The molecular machines that traffic signaling receptors into and out of cilia. Curr Opin Cell Biol 51: 124-131.
","pubmedId":"29579578","doi":""},{"reference":"Pak TK, Carter CS, Zhang Q, Huang SC, Searby C, Hsu Y, et al., Sheffield VC. 2021. A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment. PLoS Genet 17(4): e1009484.
","pubmedId":"33886537","doi":""},{"reference":"Rödig N, Sellmann K, Dos Santos Guilherme M, Nguyen VTT, Cleppien D, Stroh A, May-Simera HL, Endres K. 2022. Behavioral Phenotyping of Bbs6 and Bbs8 Knockout Mice Reveals Major Alterations in Communication and Anxiety. Int J Mol Sci 23(23): 10.3390/ijms232314506.
","pubmedId":"36498834","doi":""},{"reference":"Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, Sheffield VC. 2010. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107(4): 1488-93.
","pubmedId":"20080638","doi":""},{"reference":"Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, et al., Dollfus H. 2006. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38(5): 521-4.
","pubmedId":"16582908","doi":""},{"reference":"Walf AA, Frye CA. 2007. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2): 322-8.
","pubmedId":"17406592","doi":""}],"title":"Bardet-Biedl Syndrome Type 10 Mice Display Reduced Anxiety-like Behavior
","reviews":[{"reviewer":{"displayName":"Kristina Endres"},"openAcknowledgement":true,"status":{"submitted":true}}],"curatorReviews":[]},{"id":"45e8a5a7-3df2-4643-b748-cf96892c6089","decision":"accept","abstract":"Bardet-Biedl Syndrome (BBS) is an autosomal recessive genetic disorder characterized by polydactyly, obesity, and vision loss. Some BBS patients experience developmental delay and difficulties in emotional regulation, but neurological features of this disorder are understudied. BBS mouse models have defects in fear conditioning and reduced anxiety-like behaviors in open field tests. The purpose of this study is to characterize the anxiety-like behavior in Bbs10 knockout mice prior to severe visual impairment using elevated plus maze. Bbs10-/- mice made significantly more entries into the open arms and traveled greater distances compared to littermate controls, suggestive of reduced anxiety-like behaviors.
","acknowledgements":"We gratefully acknowledge Dr. Hanna Stevens, Robert J. Taylor and Faith Fairbairn, University of Iowa.
","authors":[{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["dataCuration","formalAnalysis","investigation","validation","writing_reviewEditing","visualization","supervision"],"email":"mackenzie-bengen@uiowa.edu","firstName":"Mackenzie ","lastName":"Bengen","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":true,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","project","supervision","writing_originalDraft","writing_reviewEditing"],"email":"ying-hsu@uiowa.edu","firstName":"Ying","lastName":"Hsu","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":true,"WBId":null,"orcid":"0000-0002-0396-9680"},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"naim-chabaytah@uiowa.edu","firstName":"Naim","lastName":"Chabaytah","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"ethan-brandauer@uiowa.edu","firstName":"Ethan","lastName":"Brandauer ","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"sarah-giese@uiowa.edu","firstName":"Sarah","lastName":"Giese","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"tyler-rankin@uiowa.edu","firstName":"Tyler","lastName":"Rankin","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"joseph-laird@uiowa.edu","firstName":"Joseph","lastName":"Laird","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"neda-mokhberian@uiowa.edu","firstName":"Neda","lastName":"Mokhberian","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["fundingAcquisition","project","writing_reviewEditing"],"email":"arlene-drack@uiowa.edu","firstName":"Arlene","lastName":"Drack","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[{"awardId":"1K99EY036493-01A1","funderName":"National Eye Institute (United States)","awardRecipient":"Ying Hsu"},{"awardId":"PILOT grant award","funderName":"University of Iowa Intellectual and Developmental Disabilities Research Center","awardRecipient":"PI: Arlene Drack; Co-PIs: Ying Hsu, Hanna Stevens, Jacob Michaelson"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"The study was funded by a PILOT award from the University of Iowa Intellectual and Developmental Disability Research Center (PI: Drack), Ronald Keech Professorship (PI: Drack) and National Institutes of Health National Eye Institute (NEI) K99 1K99EY036493-01A1 (PI: Hsu).
","image":{"url":"https://portal.micropublication.org/uploads/8f872b8dd330206ba26a588ac7bdd36c.jpg"},"imageCaption":"The elevated plus maze apparatus (a). Time-to-platform in light-adapted functional vision test for Bbs10-/- mice and wild-type (WT) or heterozygous (HET) control littermates (b). Time-to-platform in dark-adapted functional vision test for controls and Bbs10-/- mice (c). Number of entries into open arms for controls and Bbs10-/- mice (d). Time spent in open arms for controls and Bbs10-/- mice (e). Distance traveled in open arms for controls and Bbs10-/- mice (f). Locomotion speed in open arms for controls and Bbs10-/- mice (g). Number of entries into closed arms for controls and Bbs10-/- mice (h). Time spent in closed arms for controls and Bbs10-/- mice (i). Distance traveled in closed arms for controls and Bbs10-/- mice (j). Locomotion speed in closed arms for controls and Bbs10-/- mice (k). Number of entries into center square for controls and Bbs10-/- mice (l). Trajectories in elevated plus maze test for a typical control mouse and a Bbs10-/- mouse (m).
","imageTitle":"Bbs10-/- mice show increased open arm exploration in elevated plus maze
","methods":"Animal husbandry and mouse model
This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocol #4031421 of the University of Iowa. The BBS10 mouse model was acquired from the KOMP2 Center at the Jackson Laboratory, and it is now distributed through the Mutant Mouse Resource and Research Centers (MMRRC) as C57BL/6N-Bbs10tm1.1(KOMP)Vlcg/JMmucd. This mouse model was generated from the embryonic stem cell line Bbs10tm1(KOMP)Vlcg (VG13389A-A11, MMRRC). The characterization of this mouse model and genotyping procedures were described in detail elsewhere (Mayer et al. 2022). Mice were crossed onto the 129S6 genetic background for at least 7 generations. Animals were housed according to IACUC recommendations. Both male and female mice were used in this study.
Elevated plus maze
Each side arm of the elevated plus maze apparatus measured 34.7 cm long, and the walls of the closed arms were 15 cm tall. The center square measured 5.6 cm wide, which was also the width of each of the side arms. The side arms had an elevation of 49.7 cm from the bottom of the apparatus, and the entire apparatus was positioned on a table that was 60.4 cm tall. The apparatus was made of dark, opaque plastic. Mice between 22-24 days old were placed in the intersection of the four arms of the elevated plus maze, designated the center, facing an open arm. Their behavior and movement were video recorded for 5 minutes. These mice were not tested in any other behavioral assays prior to this experiment. For each animal, it was their first exposure to the elevated plus maze test. Video recording and automatic video tracking of the animal’s body and time spent in each compartment were performed in ANYMAZE software version 6.32. The floor of the side arms were covered in white tape to increase contrast for automatic video tracking. An observer also manually marked the number of times an animal placed 2 forepaws into the open arm compartment as an additional metric. The elevated plus maze test was performed under typical fluorescent ceiling light, between 12 to 5 pm. The maze was cleaned by 70 % ethanol between animals to mask scent. Males and females were tested on separate days when possible. If they must be tested on the same day, all the male animals were tested first, the white tape was replaced in addition to cleaning, and then all the female animals were tested. At the conclusion of each day, 10 % bleach was used to clean the apparatus.
Visually-guided swim assay
The visually-guided swim assay, adapted from the Morris water maze, was performed as previously described (Hassan et al. 2023). Briefly, over four training days, a mouse was trained to identify and swim to a platform in a water maze for five trials per day. The location of the platform was randomized at every trial to prevent memorization. Following training, a mouse was tested over four testing days, for five trials per day, with randomized platform positions. After testing in lighted conditions, functional vision was measured under dark-adapted conditions under a dim red light. Under dark-adapted conditions, a mouse was trained over 2 training days, then tested over 4 testing days for 5 trials per day, with randomized platform positions. Time-to-platform metrics over 20 trials were independently averaged for light-adapted and dark-adapted conditions. Occasionally, a test mouse has been found to prefer swimming or to repeatedly float with no desire to reach the platform. The following criteria for exclusion were used. All data from a mouse (light and dark) will be discarded if during the test phase a mouse’s mean swim time is greater than one standard deviation from their genotype’s median and subjective evidence of swimming preference (i.e., consistent floating, that is floating more than three times over four test days or more than three corrections of floating per test episode, escaping the researcher by jumping into the water from the platform) is also present (Hassan et al. 2023). For swim assays, each animal is considered a biological datapoint and standard error of the mean was calculated using the averaged time-to-platform of each animal.
Statistical analysis
Scientific visualization was performed using GraphPad PRISM 11.0.2, and statistical analysis was performed using 2-tailed Welsh’s t-test with assumption of unequal standard deviation. Error bars in graphs and in manuscript text represent standard error of the mean. Grubbs' tests were performed and datapoints meeting criteria for outliers (alpha < 0.05) were excluded.
","reagents":"","patternDescription":"
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, vision loss, and behavioral/neurological traits. BBS genes encode proteins that jointly regulate trafficking in an organelle called the primary cilium (Nachury 2018). Mutations in at least 26 different BBS genes can independently cause BBS with overlapping clinical features (Dollfus et al. 2024; Forsyth and Gunay-Aygun 2003 [Updated 2023 Mar 23]). Many BBS genes, including BBS1, 2, 4, 5, 7, 8, 9, 18, encode proteins that form a complex - the BBSome (Loktev et al. 2008; Nachury et al. 2007). The BBSome is a cargo adaptor to the ciliary trafficking machinery. BBS10, BBS6 and BBS12 encode chaperonin proteins responsible for assembly of the BBSome (Seo et al. 2010). Mutations in BBS10 constitute the second most common cause of BBS among BBS genes, accounting for approximately 21 % of all BBS cases (Stoetzel et al. 2006). In children with BBS, night blindness is typically noted before onset of significant vision loss. Parents of children with BBS first noted night blindness in their children at an average age of 8.5 years, and their children were registered as “blind” at an average age of 15.5 years (Beales et al. 1999). Behavioral/neurological features are not as well understood. Clinical reports associate BBS with autism-spectrum disorder in some patients (Chatterjee et al. 2014; Jain et al. 2026). In mouse models of BBS, altered ciliary functions impact migration, differentiation, and proliferation of neurons in the brain, which could be associated with neurological phenotypes in patients (Carter et al. 2012). In one study, approximately 50% of subjects with BBS experienced developmental delays, with development of speech being delayed by up to 2 years in 47% of the subjects (Beales et al. 1999). This study also noted an inappropriate affect and a disinhibited demeanor in approximately half of the enrolled patients (Beales et al. 1999). Neurological features of BBS merits further study.
In mouse models of BBS, including Bbs1M390R/M390R mice and mice with postnatal deletion of Bbs8, long-term context-dependent fear conditioning was impaired, despite intact short-term context-dependent fear conditioning (Pak et al. 2021). In a study dissecting anxiety-related phenotypes of Bbs6-/- and Bbs8-/- mice, Bbs8-/- mice exhibited increased latency to immobility in the forced swim test, and a trend was also seen in Bbs6-/- mice (Rodig et al. 2022). BBS mice may be more resistant to depression compared to littermates. BBS8 is a member of the BBSome complex and BBS6 is a member of the chaperonin complex (Seo et al. 2010). In the open field test, Bbs6-/- mice traveled significantly greater distances compared to that in littermate controls, a trend also observed in Bbs8-/- mice compared to their littermates (Rodig et al. 2022). Additionally, Bbs8-/- mice spent significantly less time in the corners of the open field arenas, a tendency also seen in Bbs6-/- mice. Together, these data showed that Bbs6-/- and Bbs8-/- mice had decreased anxiety-like phenotypes, at least in a non-social context.
The goal of this study is to determine whether Bbs10-null mice (Bbs10-/-) have an anxiety-like phenotype using the elevated plus maze behavior test. The elevated plus maze test is a well-validated behavioral assay using a plus-shaped apparatus, with two of the four arms “closed” (surrounded by opaque walls) and the other two arms “open” (Figure 1a). Rodents naturally prefer dark, enclosed spaces, and this innate preference drives them towards the closed arms. They also have an innate fear for height and for lighted areas, hence the natural tendency to avoid open arms. The preference of the mice to explore closed versus open arms in elevated plus maze informs the degree of their anxiety-like behavior (or lack thereof) (Walf and Frye 2007). The BBS10 mouse model, on the 129S6/SvEvTac incipient genetic background, harbors a deletion encompassing parts of exon 1 and 2 of the Bbs10 gene. Mice that are null for Bbs10 (Bbs10-/-) recapitulate phenotypes seen in humans, including vision loss and obesity (Mayer et al. 2022). However, their behavioral phenotypes have not been fully characterized.
In this study, the anxiety-like phenotype of Bbs10-/- mice and control littermates was examined when they were between postnatal day 22 and 24, an age when impairment in functional day vision of Bbs10-/- mice is mild. Both wild-type (WT) littermates and littermates heterozygous (HET) for the Bbs10-null allele were used as controls due to the recessive nature of BBS. To ascertain their functional vision in light-adapted conditions, a visually-guided swim assay was performed between the ages of 34 days to 60 days old, shortly after they completed the elevated plus maze tests. In this vision test, each mouse was trained to locate a platform in a water maze, then underwent 20 different platform-finding trials, with the platform position randomly placed for each trial. For this experiment, a datapoint is the averaged time-to-platform metric of 20 trials of the test mouse in a given lighting condition. In these and in subsequent bar graphs, male mice are shown as circles, and female mice are shown as triangles to enable the visualization of sex compositions of the groups. Due to sample size limitations, this study was not powered to investigate sex differences in behavioral traits, and males and females were combined for analysis. The averaged time it took for Bbs10-/- mice to locate a platform in lighted conditions was 12.7 ± 2.9 s (n = 4), compared to the averaged time it took for control littermates, which was 6.6 ± 1.3 s (n = 6). Even though the time-to-platform metrics were not significantly different between groups (p = 0.125), Bbs10-/- mice tended to take longer to find the platform, indicating onset of a mild visual impairment in the light (Figure 1b). At this age, Bbs10-/- mice had statistically significant impairment in dark-adapted functional vision in the swim assay (Figure 1c; Bbs10-/-: 24.139 ± 2.5 s; control: 10.374 ± 1.1 s; p= 0.006). In the elevated plus maze, 22 - 24 days old Bbs10-/- mice made twice as many entries into the open arms compared to those made by their control littermates (Figure 1d, Bbs10-/-: 6.92 ± 1.658 entries; control: 2.957 ± 0.611 entries; p = 0.040), and Bbs10-/- mice tended to spend more time in the open arms compared to controls (Figure 1e; Bbs10-/-: 15.967 ± 5.064; control: 7.159 ± 1.897; p = 0.125). Bbs10-/- mice traveled on average 3.7 times greater distances in the open arms of the elevated plus maze compared to distances traveled by their littermate controls (Figure 1f; Bbs10-/-: 0.606 ± 0.196 m; control: 0.155 ± 0.057 m; p = 0.0462). Locomotion speed in the open arms was not significantly different between Bbs10-/- and controls (Bbs10-/-: 0.018 ± 0.004 m/s; control: 0.013 ± 0.004 m/s; p = 0.346; Figure 1g).
Number of entries into the closed arms was not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 19.308 ± 2.080; control: 18.043 ± 1.572; p = 0.632; Figure 1h). Time spent in the closed arms was also not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 227.085 ± 12.412; control: 246.859 ± 6.665; p = 0.177; Figure 1i). However, Bbs10-/- mice travelled significantly greater distances in the closed arms despite not spending significantly more time there (Bbs10-/-: 10.658 ± 0.886 m; control: 6.690 ± 0.488 m; p = 0.0003; Figure 1j). Bbs10-/- mice had significantly greater locomotion speed in the closed arms of the elevated plus maze compared to littermate controls (Bbs10-/-: 0.047 ± 0.006 m/s; control: 0.026 ± 0.003 m/s; p = 0.0068; Figure 1k). The number of entries into the center zone was not different between Bbs10-/- mice compared to littermate controls (Figure 1l). Typical trajectories of a wild-type control and a Bbs10-/- mouse (both females) on the elevated plus maze test are shown in Figure 1m. In Figure 1m, the starting position of the animal is shown as a blue dot, and the position of the animal at the end of the test is shown as a red dot.
BBS mice are runty during postnatal development but develop obesity in adulthood (Mayer et al. 2022). To determine whether bodyweights were a confounding factor in locomotion and behavior, weights were recorded. At 22 – 24 days old, juvenile Bbs10-/- mice have significantly reduced bodyweights and have not yet developed obesity (Bbs10-/-: 6.083 ± 0.338 g; controls: 12.518 ± 0.243 g; p <0.0001).
Together, these data show that mice lacking the Bbs10 gene make an increased number of entries into the open arms of the elevated plus maze, a finding typically interpreted as a decreased level of anxiety and/or fear experienced by the animals. Hypermobility was also detected in these juvenile Bbs10-/- mice, at least prior to onset of obesity. Since these experiments were performed in juvenile mice prior to severe vision loss, these phenotypes likely reflect intrinsic behavioral features of Bbs10-/- mice.These observations in Bbs10-/- echo findings made in Bbs6-/- and Bbs8-/- mice.Future studies could be performed in mice with brain-specific deletion of BBS genes to completely remove visual impairment as a confounding factor in behavior. The lower degrees of anxiety in BBS mouse models could be plausibly associated with the disinhibited affect observed in BBS patients, although a direct link has not been established and more studies are needed. These behavioral differences could also reflect a greater drive for exploration and/or a greater sense of curiosity.
","references":[{"reference":"Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. 1999. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36(6): 437-46.
","pubmedId":"10874630","doi":""},{"reference":"Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, et al., Sheffield VC. 2012. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18(12): 1797-804.
","pubmedId":"23160237","doi":""},{"reference":"Chatterjee SS, Guha P, Talukdar A, Dasgupta G. 2014. Autism: a rare presentation of Bardet-Biedl syndrome. BMJ Case Rep 2014: pii: bcr2014203882. 10.1136/bcr-2014-203882.
","pubmedId":"24899006","doi":""},{"reference":"Dollfus H, Lilien MR, Maffei P, Verloes A, Muller J, Bacci GM, et al., Valverde D. 2024. Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations. Eur J Hum Genet 32(11): 1347-1360.
","pubmedId":"39085583","doi":""},{"reference":"Forsyth R, Gunay-Aygun M. 2003 [Updated 2023 Mar 23] Bardet-biedl syndrome overview. In: Adam MP BS, Mirzaa GM, et al., editor. Genereviews® [internet]. University of Washington, Seattle, Seattle (WA).
","pubmedId":"","doi":""},{"reference":"Hassan S, Hsu Y, Mayer SK, Thomas J, Kothapalli A, Helms M, et al., Drack AV. 2023. A visually guided swim assay for mouse models of human retinal disease recapitulates the multi-luminance mobility test in humans. Saudi J Ophthalmol 37(4): 313-320.
","pubmedId":"38155679","doi":""},{"reference":"Jain D, Koparde V, Chate SS. 2026. A distinct autism-like phenotype in bardet-biedl syndrome case report. J Indian Assoc Child. 22. doi:10.1177/09731342261442659
","pubmedId":"","doi":""},{"reference":"Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, et al., Nachury MV. 2008. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15(6): 854-65.
","pubmedId":"19081074","doi":""},{"reference":"Mayer SK, Thomas J, Helms M, Kothapalli A, Cherascu I, Salesevic A, et al., Drack AV. 2022. Progressive retinal degeneration of rods and cones in a Bardet-Biedl syndrome type 10 mouse model. Dis Model Mech 15(9): 10.1242/dmm.049473.
","pubmedId":"36125046","doi":""},{"reference":"Nachury MV. 2018. The molecular machines that traffic signaling receptors into and out of cilia. Curr Opin Cell Biol 51: 124-131.
","pubmedId":"29579578","doi":""},{"reference":"Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peränen J, Merdes A, et al., Jackson PK. 2007. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129(6): 1201-13.
","pubmedId":"17574030","doi":""},{"reference":"Pak TK, Carter CS, Zhang Q, Huang SC, Searby C, Hsu Y, et al., Sheffield VC. 2021. A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment. PLoS Genet 17(4): e1009484.
","pubmedId":"33886537","doi":""},{"reference":"Rödig N, Sellmann K, Dos Santos Guilherme M, Nguyen VTT, Cleppien D, Stroh A, May-Simera HL, Endres K. 2022. Behavioral Phenotyping of Bbs6 and Bbs8 Knockout Mice Reveals Major Alterations in Communication and Anxiety. Int J Mol Sci 23(23): 10.3390/ijms232314506.
","pubmedId":"36498834","doi":""},{"reference":"Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, Sheffield VC. 2010. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107(4): 1488-93.
","pubmedId":"20080638","doi":""},{"reference":"Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, et al., Dollfus H. 2006. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38(5): 521-4.
","pubmedId":"16582908","doi":""},{"reference":"Walf AA, Frye CA. 2007. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2): 322-8.
","pubmedId":"17406592","doi":""}],"title":"Bardet-Biedl Syndrome Type 10 Mice Display Reduced Anxiety-like Behavior
","reviews":[],"curatorReviews":[]},{"id":"b7a2a15a-befe-4e57-ae87-e7a3a95e983c","decision":"edit","abstract":"Bardet-Biedl Syndrome (BBS) is an autosomal recessive genetic disorder characterized by polydactyly, obesity, and vision loss. Some BBS patients experience developmental delay and difficulties in emotional regulation, but neurological features of this disorder are understudied. BBS mouse models have defects in fear conditioning and reduced anxiety-like behaviors in open field tests. The purpose of this study is to characterize the anxiety-like behavior in Bbs10 knockout mice prior to severe visual impairment using elevated plus maze. Bbs10-/- mice made significantly more entries into the open arms and traveled greater distances compared to littermate controls, suggestive of reduced anxiety-like behaviors.
","acknowledgements":"We gratefully acknowledge Dr. Hanna Stevens, Robert J. Taylor and Faith Fairbairn, University of Iowa.
","authors":[{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["dataCuration","formalAnalysis","investigation","validation","writing_reviewEditing","visualization","supervision"],"email":"mackenzie-bengen@uiowa.edu","firstName":"Mackenzie ","lastName":"Bengen","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":true,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","project","supervision","writing_originalDraft","writing_reviewEditing"],"email":"ying-hsu@uiowa.edu","firstName":"Ying","lastName":"Hsu","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":true,"WBId":null,"orcid":"0000-0002-0396-9680"},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"naim-chabaytah@uiowa.edu","firstName":"Naim","lastName":"Chabaytah","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"ethan-brandauer@uiowa.edu","firstName":"Ethan","lastName":"Brandauer ","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"sarah-giese@uiowa.edu","firstName":"Sarah","lastName":"Giese","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"tyler-rankin@uiowa.edu","firstName":"Tyler","lastName":"Rankin","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"joseph-laird@uiowa.edu","firstName":"Joseph","lastName":"Laird","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"neda-mokhberian@uiowa.edu","firstName":"Neda","lastName":"Mokhberian","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["fundingAcquisition","project","writing_reviewEditing"],"email":"arlene-drack@uiowa.edu","firstName":"Arlene","lastName":"Drack","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[{"awardId":"1K99EY036493-01A1","funderName":"National Eye Institute (United States)","awardRecipient":"Ying Hsu"},{"awardId":"PILOT grant award","funderName":"University of Iowa Intellectual and Developmental Disabilities Research Center","awardRecipient":"PI: Arlene Drack; Co-PIs: Ying Hsu, Hanna Stevens, Jacob Michaelson"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"The study was funded by a PILOT award from the University of Iowa Intellectual and Developmental Disability Research Center (PI: Drack), Ronald Keech Professorship (PI: Drack) and National Institutes of Health National Eye Institute (NEI) K99 1K99EY036493 (PI: Hsu). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
","image":{"url":"https://portal.micropublication.org/uploads/8f872b8dd330206ba26a588ac7bdd36c.jpg"},"imageCaption":"The elevated plus maze apparatus (a). Time-to-platform in light-adapted functional vision test for Bbs10-/- mice and wild-type (WT) or heterozygous (HET) control littermates (b). Time-to-platform in dark-adapted functional vision test for controls and Bbs10-/- mice (c). Number of entries into open arms for controls and Bbs10-/- mice (d). Time spent in open arms for controls and Bbs10-/- mice (e). Distance traveled in open arms for controls and Bbs10-/- mice (f). Locomotion speed in open arms for controls and Bbs10-/- mice (g). Number of entries into closed arms for controls and Bbs10-/- mice (h). Time spent in closed arms for controls and Bbs10-/- mice (i). Distance traveled in closed arms for controls and Bbs10-/- mice (j). Locomotion speed in closed arms for controls and Bbs10-/- mice (k). Number of entries into center square for controls and Bbs10-/- mice (l). Trajectories in elevated plus maze test for a typical control mouse and a Bbs10-/- mouse (m).
","imageTitle":"Bbs10-/- mice show increased open arm exploration in the elevated plus maze
","methods":"Animal husbandry and mouse model
This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocol #4031421 of the University of Iowa. The BBS10 mouse model was acquired from the KOMP2 Center at the Jackson Laboratory, and it is now distributed through the Mutant Mouse Resource and Research Centers (MMRRC) as C57BL/6N-Bbs10tm1.1(KOMP)Vlcg/JMmucd. This mouse model was generated from the embryonic stem cell line Bbs10tm1(KOMP)Vlcg (VG13389A-A11, MMRRC). The characterization of this mouse model and genotyping procedures were described in detail elsewhere (Mayer et al. 2022). Mice were crossed onto the 129S6 genetic background for at least 7 generations. Animals were housed according to IACUC recommendations. Both male and female mice were used in this study.
Elevated plus maze
Each side arm of the elevated plus maze apparatus measured 34.7 cm long, and the walls of the closed arms were 15 cm tall. The center square measured 5.6 cm wide, which was also the width of each of the side arms. The side arms had an elevation of 49.7 cm from the bottom of the apparatus, and the entire apparatus was positioned on a table that was 60.4 cm tall. The apparatus was made of dark, opaque plastic. Mice between 22-24 days old were placed in the intersection of the four arms of the elevated plus maze, designated the center, facing an open arm. Their behavior and movement were video recorded for 5 minutes. These mice were not tested in any other behavioral assays prior to this experiment. For each animal, it was their first exposure to the elevated plus maze test. Video recording and automatic video tracking of the animal’s body and time spent in each compartment were performed in ANYMAZE software version 6.32. The floor of the side arms were covered in white tape to increase contrast for automatic video tracking. An observer also manually marked the number of times an animal placed 2 forepaws into the open arm compartment as an additional metric. The elevated plus maze test was performed under typical fluorescent ceiling light, between 12 to 5 pm. The maze was cleaned by 70 % ethanol between animals to mask scent. Males and females were tested on separate days when possible. If they must be tested on the same day, all the male animals were tested first, the white tape was replaced in addition to cleaning, and then all the female animals were tested. At the conclusion of each day, 10 % bleach was used to clean the apparatus.
Visually-guided swim assay
The visually-guided swim assay, adapted from the Morris water maze, was performed as previously described (Hassan et al. 2023). Briefly, over four training days, a mouse was trained to identify and swim to a platform in a water maze for five trials per day. The location of the platform was randomized at every trial to prevent memorization. Following training, a mouse was tested over four testing days, for five trials per day, with randomized platform positions. After testing in lighted conditions, functional vision was measured under dark-adapted conditions under a dim red light. Under dark-adapted conditions, a mouse was trained over 2 training days, then tested over 4 testing days for 5 trials per day, with randomized platform positions. Time-to-platform metrics over 20 trials were independently averaged for light-adapted and dark-adapted conditions. Occasionally, a test mouse has been found to prefer swimming or to repeatedly float with no desire to reach the platform. The following criteria for exclusion were used. All data from a mouse (light and dark) will be discarded if during the test phase a mouse’s mean swim time is greater than one standard deviation from their genotype’s median and subjective evidence of swimming preference (i.e., consistent floating, that is floating more than three times over four test days or more than three corrections of floating per test episode, escaping the researcher by jumping into the water from the platform) is also present (Hassan et al. 2023). For swim assays, each animal is considered a biological datapoint and standard error of the mean was calculated using the averaged time-to-platform of each animal.
Statistical analysis
Scientific visualization was performed using GraphPad PRISM 11.0.2, and statistical analysis was performed using 2-tailed Welsh’s t-test with assumption of unequal standard deviation. Error bars in graphs and in manuscript text represent standard error of the mean. Grubbs' tests were performed and datapoints meeting criteria for outliers (alpha < 0.05) were excluded.
","reagents":"","patternDescription":"
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, vision loss, and behavioral/neurological traits. BBS genes encode proteins that jointly regulate trafficking in an organelle called the primary cilium (Nachury 2018). Mutations in at least 26 different BBS genes can independently cause BBS with overlapping clinical features (Dollfus et al. 2024; Forsyth and Gunay-Aygun 2003 [Updated 2023 Mar 23]). Many BBS genes, including BBS1, 2, 4, 5, 7, 8, 9 and 18, encode proteins that form a complex - the BBSome (Loktev et al. 2008; Nachury et al. 2007). The BBSome is a cargo adaptor to the ciliary trafficking machinery. BBS10, BBS6 and BBS12 encode chaperonin proteins responsible for assembly of the BBSome (Seo et al. 2010). Mutations in BBS10 constitute the second most common cause of BBS among BBS genes, accounting for approximately 21 % of all BBS cases (Stoetzel et al. 2006). In children with BBS, night blindness is typically noted before onset of significant vision loss. Parents of children with BBS first noted night blindness in their children at an average age of 8.5 years, and their children were registered as “blind” at an average age of 15.5 years (Beales et al. 1999). Behavioral/neurological features are not as well understood. Clinical reports associate BBS with autism-spectrum disorder in some patients (Chatterjee et al. 2014; Jain et al. 2026). In mouse models of BBS, altered ciliary functions impact migration, differentiation, and proliferation of neurons in the brain, which could be associated with neurological phenotypes in patients (Carter et al. 2012). In one study, approximately 50% of subjects with BBS experienced developmental delays, with development of speech being delayed by up to 2 years in 47% of the subjects (Beales et al. 1999). This study also noted an inappropriate affect and a disinhibited demeanor in approximately half of the enrolled patients (Beales et al. 1999). Neurological features of BBS merits further study.
In mouse models of BBS, including Bbs1M390R/M390R mice and mice with postnatal deletion of Bbs8, long-term context-dependent fear conditioning was impaired, despite intact short-term context-dependent fear conditioning (Pak et al. 2021). In a study dissecting anxiety-related phenotypes of Bbs6-/- and Bbs8-/- mice, Bbs8-/- mice exhibited increased latency to immobility in the forced swim test, and a trend was also seen in Bbs6-/- mice (Rodig et al. 2022). BBS mice may be more resistant to depression compared to littermates. BBS8 is a member of the BBSome complex and BBS6 is a member of the chaperonin complex (Seo et al. 2010). In the open field test, Bbs6-/- mice traveled significantly greater distances compared to that in littermate controls, a trend also observed in Bbs8-/- mice compared to their littermates (Rodig et al. 2022). Additionally, Bbs8-/- mice spent significantly less time in the corners of the open field arenas, a tendency also seen in Bbs6-/- mice. Together, these data showed that Bbs6-/- and Bbs8-/- mice had decreased anxiety-like phenotypes, at least in a non-social context.
The goal of this study is to determine whether Bbs10-null mice (Bbs10-/-) have an anxiety-like phenotype using the elevated plus maze behavior test. The elevated plus maze test is a well-validated behavioral assay using a plus-shaped apparatus, with two of the four arms “closed” (surrounded by opaque walls) and the other two arms “open” (Figure 1a). Rodents naturally prefer dark, enclosed spaces, and this innate preference drives them towards the closed arms. They also have an innate fear for height and for lighted areas, hence the natural tendency to avoid open arms. The preference of the mice to explore closed versus open arms in elevated plus maze informs the degree of their anxiety-like behavior (or lack thereof) (Walf and Frye 2007). The BBS10 mouse model, on the 129S6/SvEvTac incipient genetic background, harbors a deletion encompassing parts of exon 1 and 2 of the Bbs10 gene. Mice that are null for Bbs10 (Bbs10-/-) recapitulate phenotypes seen in humans, including vision loss and obesity (Mayer et al. 2022). However, their behavioral phenotypes have not been fully characterized.
In this study, the anxiety-like phenotype of Bbs10-/- mice and control littermates was examined when they were between postnatal day 22 and 24, an age when impairment in functional day vision of Bbs10-/- mice is mild. Both wild-type (WT) littermates and littermates heterozygous (HET) for the Bbs10-null allele were used as controls due to the recessive nature of BBS. To ascertain their functional vision in light-adapted conditions, a visually-guided swim assay was performed between the ages of 34 days to 60 days old, shortly after they completed the elevated plus maze tests. In this vision test, each mouse was trained to locate a platform in a water maze, then underwent 20 different platform-finding trials, with the platform position randomly placed for each trial. For this experiment, a datapoint is the averaged time-to-platform metric of 20 trials of the test mouse in a given lighting condition. In these and in subsequent bar graphs, male mice are shown as circles, and female mice are shown as triangles to enable the visualization of sex compositions of the groups. Due to sample size limitations, this study was not powered to investigate sex differences in behavioral traits, and males and females were combined for analysis. The averaged time it took for Bbs10-/- mice to locate a platform in lighted conditions was 12.7 ± 2.9 s (n = 4), compared to the averaged time it took for control littermates, which was 6.6 ± 1.3 s (n = 6). Even though the time-to-platform metrics were not significantly different between groups (p = 0.125), Bbs10-/- mice tended to take longer to find the platform, indicating onset of a mild visual impairment in the light (Figure 1b). At this age, Bbs10-/- mice had statistically significant impairment in dark-adapted functional vision in the swim assay (Figure 1c; Bbs10-/-: 24.139 ± 2.5 s; control: 10.374 ± 1.1 s; p= 0.006). In the elevated plus maze, 22 - 24 days old Bbs10-/- mice made twice as many entries into the open arms compared to those made by their control littermates (Figure 1d, Bbs10-/-: 6.92 ± 1.658 entries; control: 2.957 ± 0.611 entries; p = 0.040), and Bbs10-/- mice tended to spend more time in the open arms compared to controls (Figure 1e; Bbs10-/-: 15.967 ± 5.064; control: 7.159 ± 1.897; p = 0.125). Bbs10-/- mice traveled on average 3.7 times greater distances in the open arms of the elevated plus maze compared to distances traveled by their littermate controls (Figure 1f; Bbs10-/-: 0.606 ± 0.196 m; control: 0.155 ± 0.057 m; p = 0.0462). Locomotion speed in the open arms was not significantly different between Bbs10-/- and controls (Bbs10-/-: 0.018 ± 0.004 m/s; control: 0.013 ± 0.004 m/s; p = 0.346; Figure 1g).
Number of entries into the closed arms was not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 19.308 ± 2.080; control: 18.043 ± 1.572; p = 0.632; Figure 1h). Time spent in the closed arms was also not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 227.085 ± 12.412; control: 246.859 ± 6.665; p = 0.177; Figure 1i). However, Bbs10-/- mice travelled significantly greater distances in the closed arms despite not spending significantly more time there (Bbs10-/-: 10.658 ± 0.886 m; control: 6.690 ± 0.488 m; p = 0.0003; Figure 1j). Bbs10-/- mice had significantly greater locomotion speed in the closed arms of the elevated plus maze compared to littermate controls (Bbs10-/-: 0.047 ± 0.006 m/s; control: 0.026 ± 0.003 m/s; p = 0.0068; Figure 1k). The number of entries into the center zone was not different between Bbs10-/- mice compared to littermate controls (Figure 1l). Typical trajectories of a wild-type control and a Bbs10-/- mouse (both females) on the elevated plus maze test are shown in Figure 1m. In Figure 1m, the starting position of the animal is shown as a blue dot, and the position of the animal at the end of the test is shown as a red dot.
BBS mice are runty during postnatal development but develop obesity in adulthood (Mayer et al. 2022). To determine whether bodyweights were a confounding factor in locomotion and behavior, weights were recorded. At 22 – 24 days old, juvenile Bbs10-/- mice have significantly reduced bodyweights and have not yet developed obesity (Bbs10-/-: 6.083 ± 0.338 g; controls: 12.518 ± 0.243 g; p <0.0001).
Together, these data show that mice lacking the Bbs10 gene make an increased number of entries into the open arms of the elevated plus maze, a finding typically interpreted as a decreased level of anxiety and/or fear experienced by the animals. Hypermobility was also detected in these juvenile Bbs10-/- mice, at least prior to onset of obesity. Since these experiments were performed in juvenile mice prior to severe vision loss, these phenotypes likely reflect intrinsic behavioral features of Bbs10-/- mice.These observations in Bbs10-/- echo findings made in Bbs6-/- and Bbs8-/- mice.Future studies could be performed in mice with brain-specific deletion of BBS genes to completely remove visual impairment as a confounding factor in behavior. The lower degrees of anxiety in BBS mouse models could be plausibly associated with the disinhibited affect observed in BBS patients, although a direct link has not been established and more studies are needed. These behavioral differences could also reflect a greater drive for exploration and/or a greater sense of curiosity.
","references":[{"reference":"Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. 1999. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36(6): 437-46.
","pubmedId":"10874630","doi":""},{"reference":"Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, et al., Sheffield VC. 2012. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18(12): 1797-804.
","pubmedId":"23160237","doi":""},{"reference":"Chatterjee SS, Guha P, Talukdar A, Dasgupta G. 2014. Autism: a rare presentation of Bardet-Biedl syndrome. BMJ Case Rep 2014: pii: bcr2014203882. 10.1136/bcr-2014-203882.
","pubmedId":"24899006","doi":""},{"reference":"Dollfus H, Lilien MR, Maffei P, Verloes A, Muller J, Bacci GM, et al., Valverde D. 2024. Bardet-Biedl syndrome improved diagnosis criteria and management: Inter European Reference Networks consensus statement and recommendations. Eur J Hum Genet 32(11): 1347-1360.
","pubmedId":"39085583","doi":""},{"reference":"Forsyth R, Gunay-Aygun M. 2003 [Updated 2023 Mar 23] Bardet-biedl syndrome overview. In: Adam MP BS, Mirzaa GM, et al., editor. Genereviews® [internet]. University of Washington, Seattle, Seattle (WA).
","pubmedId":"","doi":""},{"reference":"Hassan S, Hsu Y, Mayer SK, Thomas J, Kothapalli A, Helms M, et al., Drack AV. 2023. A visually guided swim assay for mouse models of human retinal disease recapitulates the multi-luminance mobility test in humans. Saudi J Ophthalmol 37(4): 313-320.
","pubmedId":"38155679","doi":""},{"reference":"Jain D, Koparde V, Chate SS. 2026. A distinct autism-like phenotype in bardet-biedl syndrome case report. J Indian Assoc Child. 22. doi:10.1177/09731342261442659
","pubmedId":"","doi":""},{"reference":"Loktev AV, Zhang Q, Beck JS, Searby CC, Scheetz TE, Bazan JF, et al., Nachury MV. 2008. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15(6): 854-65.
","pubmedId":"19081074","doi":""},{"reference":"Mayer SK, Thomas J, Helms M, Kothapalli A, Cherascu I, Salesevic A, et al., Drack AV. 2022. Progressive retinal degeneration of rods and cones in a Bardet-Biedl syndrome type 10 mouse model. Dis Model Mech 15(9): 10.1242/dmm.049473.
","pubmedId":"36125046","doi":""},{"reference":"Nachury MV. 2018. The molecular machines that traffic signaling receptors into and out of cilia. Curr Opin Cell Biol 51: 124-131.
","pubmedId":"29579578","doi":""},{"reference":"Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peränen J, Merdes A, et al., Jackson PK. 2007. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129(6): 1201-13.
","pubmedId":"17574030","doi":""},{"reference":"Pak TK, Carter CS, Zhang Q, Huang SC, Searby C, Hsu Y, et al., Sheffield VC. 2021. A mouse model of Bardet-Biedl Syndrome has impaired fear memory, which is rescued by lithium treatment. PLoS Genet 17(4): e1009484.
","pubmedId":"33886537","doi":""},{"reference":"Rödig N, Sellmann K, Dos Santos Guilherme M, Nguyen VTT, Cleppien D, Stroh A, May-Simera HL, Endres K. 2022. Behavioral Phenotyping of Bbs6 and Bbs8 Knockout Mice Reveals Major Alterations in Communication and Anxiety. Int J Mol Sci 23(23): 10.3390/ijms232314506.
","pubmedId":"36498834","doi":""},{"reference":"Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, Sheffield VC. 2010. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107(4): 1488-93.
","pubmedId":"20080638","doi":""},{"reference":"Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, et al., Dollfus H. 2006. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38(5): 521-4.
","pubmedId":"16582908","doi":""},{"reference":"Walf AA, Frye CA. 2007. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2): 322-8.
","pubmedId":"17406592","doi":""}],"title":"Bardet-Biedl Syndrome Type 10 Mice Display Reduced Anxiety-like Behavior
","reviews":[],"curatorReviews":[]},{"id":"971b04f2-b40a-4bbd-903d-d14874ad1a4a","decision":"publish","abstract":"Bardet-Biedl Syndrome (BBS) is an autosomal recessive genetic disorder characterized by polydactyly, obesity, and vision loss. Some BBS patients experience developmental delay and difficulties in emotional regulation, but neurological features of this disorder are understudied. BBS mouse models have defects in fear conditioning and reduced anxiety-like behaviors in open field tests. The purpose of this study is to characterize the anxiety-like behavior in Bbs10 knockout mice prior to severe visual impairment using elevated plus maze. Bbs10-/- mice made significantly more entries into the open arms and traveled greater distances compared to littermate controls, suggestive of reduced anxiety-like behaviors.
","acknowledgements":"We gratefully acknowledge Dr. Hanna Stevens, Robert J. Taylor and Faith Fairbairn, University of Iowa.
","authors":[{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["dataCuration","formalAnalysis","investigation","validation","writing_reviewEditing","visualization","supervision"],"email":"mackenzie-bengen@uiowa.edu","firstName":"Mackenzie ","lastName":"Bengen","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":true,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","project","supervision","writing_originalDraft","writing_reviewEditing"],"email":"ying-hsu@uiowa.edu","firstName":"Ying","lastName":"Hsu","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":true,"WBId":null,"orcid":"0000-0002-0396-9680"},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"naim-chabaytah@uiowa.edu","firstName":"Naim","lastName":"Chabaytah","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"ethan-brandauer@uiowa.edu","firstName":"Ethan","lastName":"Brandauer ","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"sarah-giese@uiowa.edu","firstName":"Sarah","lastName":"Giese","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"tyler-rankin@uiowa.edu","firstName":"Tyler","lastName":"Rankin","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"joseph-laird@uiowa.edu","firstName":"Joseph","lastName":"Laird","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["investigation"],"email":"neda-mokhberian@uiowa.edu","firstName":"Neda","lastName":"Mokhberian","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["University of Iowa, Iowa City, IA, United States"],"departments":[""],"credit":["fundingAcquisition","project","writing_reviewEditing"],"email":"arlene-drack@uiowa.edu","firstName":"Arlene","lastName":"Drack","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[{"awardId":"1K99EY036493-01A1","funderName":"National Eye Institute (United States)","awardRecipient":"Ying Hsu"},{"awardId":"PILOT grant award","funderName":"University of Iowa Intellectual and Developmental Disabilities Research Center","awardRecipient":"PI: Arlene Drack; Co-PIs: Ying Hsu, Hanna Stevens, Jacob Michaelson"}],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"The study was funded by a PILOT award from the University of Iowa Intellectual and Developmental Disability Research Center (PI: Drack), Ronald Keech Professorship (PI: Drack) and National Institutes of Health National Eye Institute (NEI) K99 1K99EY036493 (PI: Hsu). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
","image":{"url":"https://portal.micropublication.org/uploads/8f872b8dd330206ba26a588ac7bdd36c.jpg"},"imageCaption":"The elevated plus maze apparatus (a). Time-to-platform in light-adapted functional vision test for Bbs10-/- mice and wild-type (WT) or heterozygous (HET) control littermates (b). Time-to-platform in dark-adapted functional vision test for controls and Bbs10-/- mice (c). Number of entries into open arms for controls and Bbs10-/- mice (d). Time spent in open arms for controls and Bbs10-/- mice (e). Distance traveled in open arms for controls and Bbs10-/- mice (f). Locomotion speed in open arms for controls and Bbs10-/- mice (g). Number of entries into closed arms for controls and Bbs10-/- mice (h). Time spent in closed arms for controls and Bbs10-/- mice (i). Distance traveled in closed arms for controls and Bbs10-/- mice (j). Locomotion speed in closed arms for controls and Bbs10-/- mice (k). Number of entries into center square for controls and Bbs10-/- mice (l). Trajectories in elevated plus maze test for a typical control mouse and a Bbs10-/- mouse (m).
","imageTitle":"Bbs10-/- mice show increased open arm exploration in the elevated plus maze
","methods":"Animal husbandry and mouse model
This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocol #4031421 of the University of Iowa. The BBS10 mouse model was acquired from the KOMP2 Center at the Jackson Laboratory, and it is now distributed through the Mutant Mouse Resource and Research Centers (MMRRC) as C57BL/6N-Bbs10tm1.1(KOMP)Vlcg/JMmucd. This mouse model was generated from the embryonic stem cell line Bbs10tm1(KOMP)Vlcg (VG13389A-A11, MMRRC). The characterization of this mouse model and genotyping procedures were described in detail elsewhere (Mayer et al. 2022). Mice were crossed onto the 129S6 genetic background for at least 7 generations. Animals were housed according to IACUC recommendations. Both male and female mice were used in this study.
Elevated plus maze
Each side arm of the elevated plus maze apparatus measured 34.7 cm long, and the walls of the closed arms were 15 cm tall. The center square measured 5.6 cm wide, which was also the width of each of the side arms. The side arms had an elevation of 49.7 cm from the bottom of the apparatus, and the entire apparatus was positioned on a table that was 60.4 cm tall. The apparatus was made of dark, opaque plastic. Mice between 22-24 days old were placed in the intersection of the four arms of the elevated plus maze, designated the center, facing an open arm. Their behavior and movement were video recorded for 5 minutes. These mice were not tested in any other behavioral assays prior to this experiment. For each animal, it was their first exposure to the elevated plus maze test. Video recording and automatic video tracking of the animal’s body and time spent in each compartment were performed in ANYMAZE software version 6.32. The floor of the side arms were covered in white tape to increase contrast for automatic video tracking. An observer also manually marked the number of times an animal placed 2 forepaws into the open arm compartment as an additional metric. The elevated plus maze test was performed under typical fluorescent ceiling light, between 12 to 5 pm. The maze was cleaned by 70 % ethanol between animals to mask scent. Males and females were tested on separate days when possible. If they must be tested on the same day, all the male animals were tested first, the white tape was replaced in addition to cleaning, and then all the female animals were tested. At the conclusion of each day, 10 % bleach was used to clean the apparatus.
Visually-guided swim assay
The visually-guided swim assay, adapted from the Morris water maze, was performed as previously described (Hassan et al. 2023). Briefly, over four training days, a mouse was trained to identify and swim to a platform in a water maze for five trials per day. The location of the platform was randomized at every trial to prevent memorization. Following training, a mouse was tested over four testing days, for five trials per day, with randomized platform positions. After testing in lighted conditions, functional vision was measured under dark-adapted conditions under a dim red light. Under dark-adapted conditions, a mouse was trained over 2 training days, then tested over 4 testing days for 5 trials per day, with randomized platform positions. Time-to-platform metrics over 20 trials were independently averaged for light-adapted and dark-adapted conditions. Occasionally, a test mouse has been found to prefer swimming or to repeatedly float with no desire to reach the platform. The following criteria for exclusion were used. All data from a mouse (light and dark) will be discarded if during the test phase a mouse’s mean swim time is greater than one standard deviation from their genotype’s median and subjective evidence of swimming preference (i.e., consistent floating, that is floating more than three times over four test days or more than three corrections of floating per test episode, escaping the researcher by jumping into the water from the platform) is also present (Hassan et al. 2023). For swim assays, each animal is considered a biological datapoint and standard error of the mean was calculated using the averaged time-to-platform of each animal.
Statistical analysis
Scientific visualization was performed using GraphPad PRISM 11.0.2, and statistical analysis was performed using 2-tailed Welsh’s t-test with assumption of unequal standard deviation. Error bars in graphs and in manuscript text represent standard error of the mean. Grubbs' tests were performed and datapoints meeting criteria for outliers (alpha < 0.05) were excluded.
","reagents":"","patternDescription":"
Bardet-Biedl Syndrome (BBS) is a rare, autosomal recessive disorder characterized by obesity, vision loss, and behavioral/neurological traits. BBS genes encode proteins that jointly regulate trafficking in an organelle called the primary cilium (Nachury 2018). Mutations in at least 26 different BBS genes can independently cause BBS with overlapping clinical features (Dollfus et al. 2024; Forsyth and Gunay-Aygun 2003 [Updated 2023 Mar 23]). Many BBS genes, including BBS1, 2, 4, 5, 7, 8, 9 and 18, encode proteins that form a complex - the BBSome (Loktev et al. 2008; Nachury et al. 2007). The BBSome is a cargo adaptor to the ciliary trafficking machinery. BBS10, BBS6 and BBS12 encode chaperonin proteins responsible for assembly of the BBSome (Seo et al. 2010). Mutations in BBS10 constitute the second most common cause of BBS among BBS genes, accounting for approximately 21 % of all BBS cases (Stoetzel et al. 2006). In children with BBS, night blindness is typically noted before onset of significant vision loss. Parents of children with BBS first noted night blindness in their children at an average age of 8.5 years, and their children were registered as “blind” at an average age of 15.5 years (Beales et al. 1999). Behavioral/neurological features are not as well understood. Clinical reports associate BBS with autism-spectrum disorder in some patients (Chatterjee et al. 2014; Jain et al. 2026). In mouse models of BBS, altered ciliary functions impact migration, differentiation, and proliferation of neurons in the brain, which could be associated with neurological phenotypes in patients (Carter et al. 2012). In one study, approximately 50% of subjects with BBS experienced developmental delays, with development of speech being delayed by up to 2 years in 47% of the subjects (Beales et al. 1999). This study also noted an inappropriate affect and a disinhibited demeanor in approximately half of the enrolled patients (Beales et al. 1999). Neurological features of BBS merits further study.
In mouse models of BBS, including Bbs1M390R/M390R mice and mice with postnatal deletion of Bbs8, long-term context-dependent fear conditioning was impaired, despite intact short-term context-dependent fear conditioning (Pak et al. 2021). In a study dissecting anxiety-related phenotypes of Bbs6-/- and Bbs8-/- mice, Bbs8-/- mice exhibited increased latency to immobility in the forced swim test, and a trend was also seen in Bbs6-/- mice (Rodig et al. 2022). BBS mice may be more resistant to depression compared to littermates. BBS8 is a member of the BBSome complex and BBS6 is a member of the chaperonin complex (Seo et al. 2010). In the open field test, Bbs6-/- mice traveled significantly greater distances compared to that in littermate controls, a trend also observed in Bbs8-/- mice compared to their littermates (Rodig et al. 2022). Additionally, Bbs8-/- mice spent significantly less time in the corners of the open field arenas, a tendency also seen in Bbs6-/- mice. Together, these data showed that Bbs6-/- and Bbs8-/- mice had decreased anxiety-like phenotypes, at least in a non-social context.
The goal of this study is to determine whether Bbs10-null mice (Bbs10-/-) have an anxiety-like phenotype using the elevated plus maze behavior test. The elevated plus maze test is a well-validated behavioral assay using a plus-shaped apparatus, with two of the four arms “closed” (surrounded by opaque walls) and the other two arms “open” (Figure 1a). Rodents naturally prefer dark, enclosed spaces, and this innate preference drives them towards the closed arms. They also have an innate fear for height and for lighted areas, hence the natural tendency to avoid open arms. The preference of the mice to explore closed versus open arms in elevated plus maze informs the degree of their anxiety-like behavior (or lack thereof) (Walf and Frye 2007). The BBS10 mouse model, on the 129S6/SvEvTac incipient genetic background, harbors a deletion encompassing parts of exon 1 and 2 of the Bbs10 gene. Mice that are null for Bbs10 (Bbs10-/-) recapitulate phenotypes seen in humans, including vision loss and obesity (Mayer et al. 2022). However, their behavioral phenotypes have not been fully characterized.
In this study, the anxiety-like phenotype of Bbs10-/- mice and control littermates was examined when they were between postnatal day 22 and 24, an age when impairment in functional day vision of Bbs10-/- mice is mild. Both wild-type (WT) littermates and littermates heterozygous (HET) for the Bbs10-null allele were used as controls due to the recessive nature of BBS. To ascertain their functional vision in light-adapted conditions, a visually-guided swim assay was performed between the ages of 34 days to 60 days old, shortly after they completed the elevated plus maze tests. In this vision test, each mouse was trained to locate a platform in a water maze, then underwent 20 different platform-finding trials, with the platform position randomly placed for each trial. For this experiment, a datapoint is the averaged time-to-platform metric of 20 trials of the test mouse in a given lighting condition. In these and in subsequent bar graphs, male mice are shown as circles, and female mice are shown as triangles to enable the visualization of sex compositions of the groups. Due to sample size limitations, this study was not powered to investigate sex differences in behavioral traits, and males and females were combined for analysis. The averaged time it took for Bbs10-/- mice to locate a platform in lighted conditions was 12.7 ± 2.9 s (n = 4), compared to the averaged time it took for control littermates, which was 6.6 ± 1.3 s (n = 6). Even though the time-to-platform metrics were not significantly different between groups (p = 0.125), Bbs10-/- mice tended to take longer to find the platform, indicating onset of a mild visual impairment in the light (Figure 1b). At this age, Bbs10-/- mice had statistically significant impairment in dark-adapted functional vision in the swim assay (Figure 1c; Bbs10-/-: 24.139 ± 2.5 s; control: 10.374 ± 1.1 s; p= 0.006). In the elevated plus maze, 22 - 24 days old Bbs10-/- mice made twice as many entries into the open arms compared to those made by their control littermates (Figure 1d, Bbs10-/-: 6.92 ± 1.658 entries; control: 2.957 ± 0.611 entries; p = 0.040), and Bbs10-/- mice tended to spend more time in the open arms compared to controls (Figure 1e; Bbs10-/-: 15.967 ± 5.064; control: 7.159 ± 1.897; p = 0.125). Bbs10-/- mice traveled on average 3.7 times greater distances in the open arms of the elevated plus maze compared to distances traveled by their littermate controls (Figure 1f; Bbs10-/-: 0.606 ± 0.196 m; control: 0.155 ± 0.057 m; p = 0.0462). Locomotion speed in the open arms was not significantly different between Bbs10-/- and controls (Bbs10-/-: 0.018 ± 0.004 m/s; control: 0.013 ± 0.004 m/s; p = 0.346; Figure 1g).
Number of entries into the closed arms was not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 19.308 ± 2.080; control: 18.043 ± 1.572; p = 0.632; Figure 1h). Time spent in the closed arms was also not significantly different between Bbs10-/- and littermate controls (Bbs10-/-: 227.085 ± 12.412; control: 246.859 ± 6.665; p = 0.177; Figure 1i). However, Bbs10-/- mice travelled significantly greater distances in the closed arms despite not spending significantly more time there (Bbs10-/-: 10.658 ± 0.886 m; control: 6.690 ± 0.488 m; p = 0.0003; Figure 1j). Bbs10-/- mice had significantly greater locomotion speed in the closed arms of the elevated plus maze compared to littermate controls (Bbs10-/-: 0.047 ± 0.006 m/s; control: 0.026 ± 0.003 m/s; p = 0.0068; Figure 1k). The number of entries into the center zone was not different between Bbs10-/- mice compared to littermate controls (Figure 1l). Typical trajectories of a wild-type control and a Bbs10-/- mouse (both females) on the elevated plus maze test are shown in Figure 1m. In Figure 1m, the starting position of the animal is shown as a blue dot, and the position of the animal at the end of the test is shown as a red dot.
BBS mice are runty during postnatal development but develop obesity in adulthood (Mayer et al. 2022). To determine whether bodyweights were a confounding factor in locomotion and behavior, weights were recorded. At 22 – 24 days old, juvenile Bbs10-/- mice have significantly reduced bodyweights and have not yet developed obesity (Bbs10-/-: 6.083 ± 0.338 g; controls: 12.518 ± 0.243 g; p <0.0001).
Together, these data show that mice lacking the Bbs10 gene make an increased number of entries into the open arms of the elevated plus maze, a finding typically interpreted as a decreased level of anxiety and/or fear experienced by the animals. Hypermobility was also detected in these juvenile Bbs10-/- mice, at least prior to onset of obesity. Since these experiments were performed in juvenile mice prior to severe vision loss, these phenotypes likely reflect intrinsic behavioral features of Bbs10-/- mice.These observations in Bbs10-/- echo findings made in Bbs6-/- and Bbs8-/- mice.Future studies could be performed in mice with brain-specific deletion of BBS genes to completely remove visual impairment as a confounding factor in behavior. The lower degrees of anxiety in BBS mouse models could be plausibly associated with the disinhibited affect observed in BBS patients, although a direct link has not been established and more studies are needed. These behavioral differences could also reflect a greater drive for exploration and/or a greater sense of curiosity.
","references":[{"reference":"Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. 1999. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36(6): 437-46.
","pubmedId":"10874630","doi":""},{"reference":"Carter CS, Vogel TW, Zhang Q, Seo S, Swiderski RE, Moninger TO, et al., Sheffield VC. 2012. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med 18(12): 1797-804.
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