Fragile X syndrome (FXS) is a neurodevelopmental disorder oftentimes associated with abnormal social behaviors and altered sensory responsiveness. It is hypothesized that the inappropriate filtering of sensory stimuli, including olfaction, can lead to aberrant social behavior in FXS. However, previous studies investigating olfaction in animal models of FXS have shown inconsistent results. Here, we found that Fmr1 knock-out (KO) mice, a mouse model of FXS, showed increased sniffing duration for non-social odors during their first exposure. Additionally, while wild-type (WT) males demonstrated differences in behavioral patterns between non-social odors while Fmr1 KO males did not show such distinction. We also showed that Fmr1 KO males spent significantly less time sniffing female urine odor compared to WT males. Moreover, we found an increased volume of the olfactory bulb in Fmr1 KO males. Overall, our findings suggest that the Fmr1 KO mice demonstrate atypical olfactory behaviors as well as structural changes in the olfactory bulb.

Department of Pathophysiology Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 76 323 00 Plzen Czech Republic

The Department of Cellular and Integrative Physiology The University of Texas Health Science Center at San Antonio San Antonio TX USA

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Verdura, E. et al. Heterogeneity in fragile X syndrome highlights the need for precision medicine-based treatments. Front. Psychiatry12, 722378. 10.3389/fpsyt.2021.722378 (2021). PubMed PMC

Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell66, 817–822. 10.1016/0092-8674(91)90125-i (1991). PubMed

McCary, L. M. & Roberts, J. E. Early identification of autism in fragile X syndrome: A review. J. Intellect. Disabil. Res.57, 803–814. 10.1111/j.1365-2788.2012.01609.x (2013). PubMed PMC

Roberts, J. E., McCary, L. M., Shinkareva, S. V. & Bailey, D. B. Jr. Infant development in fragile X syndrome: Cross-syndrome comparisons. J. Autism Dev. Disord.46, 2088–2099. 10.1007/s10803-016-2737-1 (2016). PubMed PMC

Miller, L. J., Reisman, J., McIntosh, D. N. & Simon, J. in Sensory integration and developmental disabilities (eds S. Roley, R. C. Schaaf, & E. Blanche) (Therapy Skill Builders, 2001).

Bodaleo, F., Tapia-Monsalves, C., Cea-Del Rio, C., Gonzalez-Billault, C. & Nunez-Parra, A. Structural and functional abnormalities in the olfactory system of fragile X syndrome models. Front. Mol. Neurosci.12, 135. 10.3389/fnmol.2019.00135 (2019). PubMed PMC

Tomchek, S. D. & Dunn, W. Sensory processing in children with and without autism: A comparative study using the short sensory profile. Am. J. Occup. Ther.61, 190–200. 10.5014/ajot.61.2.190 (2007). PubMed

Pritchard, W. S., Raz, N. & August, G. J. Visual augmenting/reducing and P300 in autistic children. J. Autism Dev. Disord.17, 231–242. 10.1007/BF01495058 (1987). PubMed

Tecchio, F. et al. Auditory sensory processing in autism: A magnetoencephalographic study. Biol. Psychiatry54, 647–654. 10.1016/s0006-3223(03)00295-6 (2003). PubMed

Soudry, Y., Lemogne, C., Malinvaud, D., Consoli, S. M. & Bonfils, P. Olfactory system and emotion: Common substrates. Eur. Ann. Otorhinolaryngol. Head Neck Dis.128, 18–23. 10.1016/j.anorl.2010.09.007 (2011). PubMed

Parma, V., Bulgheroni, M., Tirindelli, R. & Castiello, U. Body odors promote automatic imitation in autism. Biol. Psychiatry74, 220–226. 10.1016/j.biopsych.2013.01.010 (2013). PubMed

Semin, G. R. & Groot, J. H. The chemical bases of human sociality. Trends Cogn. Sci.17, 427–429. 10.1016/j.tics.2013.05.008 (2013). PubMed

Frumin, I. et al. A social chemosignaling function for human handshaking. Elife4, 5154. 10.7554/eLife.05154 (2015). PubMed PMC

Endevelt-Shapira, Y. et al. Altered responses to social chemosignals in autism spectrum disorder. Nat. Neurosci.21, 111–119. 10.1038/s41593-017-0024-x (2018). PubMed

Rozenkrantz, L. et al. A mechanistic link between olfaction and autism spectrum disorder. Curr. Biol.25, 1904–1910. 10.1016/j.cub.2015.05.048 (2015). PubMed PMC

Rogers, S. J., Hepburn, S. & Wehner, E. Parent reports of sensory symptoms in toddlers with autism and those with other developmental disorders. J. Autism Dev. Disord.33, 631–642. 10.1023/b:jadd.0000006000.38991.a7 (2003). PubMed

Xu, M., Minagawa, Y., Kumazaki, H., Okada, K. I. & Naoi, N. Prefrontal responses to odors in individuals with autism spectrum disorders: Functional nirs measurement combined with a fragrance pulse ejection system. Front. Hum. Neurosci.14, 523456. 10.3389/fnhum.2020.523456 (2020). PubMed PMC

Kumar, A. et al. A brain region-specific predictive gene map for autism derived by profiling a reference gene set. PLoS One6, e28431. 10.1371/journal.pone.0028431 (2011). PubMed PMC

Musumeci, S. A. et al. Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome. Epilepsia41, 19–23. 10.1111/j.1528-1157.2000.tb01499.x (2000). PubMed

Chen, L. & Toth, M. Fragile X mice develop sensory hyperreactivity to auditory stimuli. Neuroscience103, 1043–1050. 10.1016/s0306-4522(01)00036-7 (2001). PubMed

Levenga, J. et al. AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol. Dis.42, 311–317. 10.1016/j.nbd.2011.01.022 (2011). PubMed

Felgerolle, C. et al. Visual behavior impairments as an aberrant sensory processing in the mouse model of fragile X syndrome. Front. Behav. Neurosci.13, 228. 10.3389/fnbeh.2019.00228 (2019). PubMed PMC

Franco, L. M., Okray, Z., Linneweber, G. A., Hassan, B. A. & Yaksi, E. Reduced lateral inhibition impairs olfactory computations and behaviors in a drosophila model of fragile X syndrome. Curr. Biol.27, 1111–1123. 10.1016/j.cub.2017.02.065 (2017). PubMed PMC

Larson, J., Kim, D., Patel, R. C. & Floreani, C. Olfactory discrimination learning in mice lacking the fragile X mental retardation protein. Neurobiol. Learn. Mem.90, 90–102. 10.1016/j.nlm.2008.01.002 (2008). PubMed PMC

Schilit Nitenson, A. et al. Fragile X mental retardation protein regulates olfactory sensitivity but not odorant discrimination. Chem. Sens40, 345–350. 10.1093/chemse/bjv019 (2015). PubMed PMC

Mazal, P. P., Haehner, A. & Hummel, T. Relation of the volume of the olfactory bulb to psychophysical measures of olfactory function. Eur. Arch. Otorhinolaryngol.273, 1–7. 10.1007/s00405-014-3325-7 (2016). PubMed

Buschhuter, D. et al. Correlation between olfactory bulb volume and olfactory function. Neuroimage42, 498–502. 10.1016/j.neuroimage.2008.05.004 (2008). PubMed

Takahashi, H., Yoshihara, S. & Tsuboi, A. The functional role of olfactory bulb granule cell subtypes derived from embryonic and postnatal neurogenesis. Front. Mol. Neurosci.11, 229. 10.3389/fnmol.2018.00229 (2018). PubMed PMC

Fujiwara, N. & Cave, J. W. Partial conservation between mice and humans in olfactory bulb interneuron transcription factor codes. Front. Neurosci.10, 337. 10.3389/fnins.2016.00337 (2016). PubMed PMC

Lledo, P. M., Merkle, F. T. & Alvarez-Buylla, A. Origin and function of olfactory bulb interneuron diversity. Trends Neurosci.31, 392–400. 10.1016/j.tins.2008.05.006 (2008). PubMed PMC

Luo, Y. et al. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genet.6, e1000898. 10.1371/journal.pgen.1000898 (2010). PubMed PMC

Scotto-Lomassese, S. et al. Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb. J. Neurosci.31, 2205–2215. 10.1523/JNEUROSCI.5514-10.2011 (2011). PubMed PMC

Castren, M. et al. Altered differentiation of neural stem cells in fragile X syndrome. Proc. Natl. Acad. Sci. U. S. A.102, 17834–17839. 10.1073/pnas.0508995102 (2005). PubMed PMC

The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: A model to study fragile X mental retardation. Cell78, 23–33 (1994). PubMed

Percie du Sert, N. et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol.18, e3000410. 10.1371/journal.pbio.3000410 (2020). PubMed PMC

Zou, J., Wang, W., Pan, Y. W., Lu, S. & Xia, Z. Methods to measure olfactory behavior in mice. Curr. Protoc. Toxicol.63, 11–18. 10.1002/0471140856.tx1118s63 (2015). PubMed PMC

Arbuckle, E. P., Smith, G. D., Gomez, M. C. & Lugo, J. N. Testing for odor discrimination and habituation in mice. J. Vis. Exp.99, e52615. 10.3791/52615 (2015). PubMed PMC

Yang, M. & Crawley, J. N. Simple behavioral assessment of mouse olfaction. Curr. Protoc. Neurosci.8, 24. 10.1002/0471142301.ns0824s48 (2009). PubMed PMC

Wersinger, S. R. et al. Social motivation is reduced in vasopressin 1b receptor null mice despite normal performance in an olfactory discrimination task. Horm. Behav.46, 638–645. 10.1016/j.yhbeh.2004.07.004 (2004). PubMed

Achiraman, S. & Archunan, G. 1-Iodo-2methylundecane, a putative estrus-specific urinary chemo-signal of female mouse (Mus musculus). Theriogenology66, 1913–1920. 10.1016/j.theriogenology.2006.05.010 (2006). PubMed

Yamazaki, K., Beauchamp, G. K., Singer, A., Bard, J. & Boyse, E. A. Odortypes: Their origin and composition. Proc. Natl. Acad. Sci. U. S. A.96, 1522–1525. 10.1073/pnas.96.4.1522 (1999). PubMed PMC

Schaefer, M. L., Young, D. A. & Restrepo, D. Olfactory fingerprints for major histocompatibility complex-determined body Odors. J. Neurosci.21, 2481–2487 (2001). PubMed PMC

Rodrigues, L. S. et al. Olfactory impairment in the rotenone model of Parkinson’s disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation. Front. Cell Neurosci.8, 383. 10.3389/fncel.2014.00383 (2014). PubMed PMC

Cora, M. C., Kooistra, L. & Travlos, G. Vaginal cytology of the laboratory rat and mouse: Review and criteria for the staging of the Estrous cycle using stained vaginal smears. Toxicol. Pathol.43, 776–793. 10.1177/0192623315570339 (2015). PubMed PMC

Pawluski, J. L., Brummelte, S., Barha, C. K., Crozier, T. M. & Galea, L. A. Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front. Neuroendocrinol.30, 343–357. 10.1016/j.yfrne.2009.03.007 (2009). PubMed

Merzin, M. Applying stereological method in radiology. Volume measurement, University of Tartu, (2008).

Mouton, Peter. Unbiased stereology (Johns Hopkins University Press, 2011). 10.56021/9780801899843.

Gundersen, H. J. & Jensen, E. B. The efficiency of systematic sampling in stereology and its prediction. J. Microsc.147, 229–263 (1987). PubMed

Latchney, S. E. et al. The effect of spaceflight on mouse olfactory bulb volume, neurogenesis, and cell death indicates the protective effect of novel environment. . Appl. Physiol.1985(116), 1593–1604. 10.1152/japplphysiol.01174.2013 (2014). PubMed PMC

Benson, T. E., Ryugo, D. K. & Hinds, J. W. Effects of sensory deprivation on the developing mouse olfactory system: A light and electron microscopic, morphometric analysis. J. Neurosci.4, 638–653. 10.1523/JNEUROSCI.04-03-00638.1984 (1984). PubMed PMC

Prosser, H. M., Bradley, A. & Caldwell, M. A. Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. Eur. J. Neurosci.26, 3339–3344. 10.1111/j.1460-9568.2007.05958.x (2007). PubMed PMC

Fazzari, P., Mortimer, N., Yabut, O., Vogt, D. & Pla, R. Cortical distribution of GABAergic interneurons is determined by migration time and brain size. Development147, 185033. 10.1242/dev.185033 (2020). PubMed PMC

Chao, O. Y. et al. Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism. Mol. Brain.13, 111. 10.1186/s13041-020-00649-7 (2020). PubMed PMC

Rais, M., Binder, D. K., Razak, K. A. & Ethell, I. M. Sensory processing phenotypes in fragile X syndrome. ASN Neuro10, 1759091418801092. 10.1177/1759091418801092 (2018). PubMed PMC

Zorio, D. A., Jackson, C. M., Liu, Y., Rubel, E. W. & Wang, Y. Cellular distribution of the fragile X mental retardation protein in the mouse brain. J. Comp. Neurol.525, 818–849. 10.1002/cne.24100 (2017). PubMed PMC

Jennings, L., Williams, E., Avlas, M. & Dewan, A. The behavioral sensitivity of mice to acetate esters. Chem. Senses47, 17. 10.1093/chemse/bjac017 (2022). PubMed PMC

Ogawa, K., Tashima, A., Sadakata, M. & Morinaga, O. Appetite-enhancing effects of vanilla flavours such as vanillin. J. Nat. Med.72, 798–802. 10.1007/s11418-018-1206-x (2018). PubMed

Root, C. M., Denny, C. A., Hen, R. & Axel, R. The participation of cortical amygdala in innate, odour-driven behaviour. Nature515, 269–273. 10.1038/nature13897 (2014). PubMed PMC

Lin, D. Y., Zhang, S. Z., Block, E. & Katz, L. C. Encoding social signals in the mouse main olfactory bulb. Nature434, 470–477. 10.1038/nature03414 (2005). PubMed

Harvey, S., Jemiolo, B. & Novotny, M. Pattern of volatile compounds in dominant and subordinate male mouse urine. J. Chem. Ecol.15, 2061–2072. 10.1007/BF01207438 (1989). PubMed

Jemiolo, B., Xie, T. M., Andreolini, F., Baker, A. E. & Novotny, M. Thet complex of the mouse: Chemical characterization by urinary volatile profiles. J. Chem. Ecol.17, 353–367. 10.1007/BF00994338 (1991). PubMed

Lehmann, M. L., Geddes, C. E., Lee, J. L. & Herkenham, M. Urine scent marking (USM): A novel test for depressive-like behavior and a predictor of stress resiliency in mice. PLoS One8, e69822. 10.1371/journal.pone.0069822 (2013). PubMed PMC

Kleitz-Nelson, H. K., Dominguez, J. M. & Ball, G. F. Dopamine release in the medial preoptic area is related to hormonal action and sexual motivation. Behav. Neurosci.124, 773–779. 10.1037/a0021490 (2010). PubMed PMC

Capsoni, S., Fogli Iseppe, A., Casciano, F. & Pignatelli, A. Unraveling the role of dopaminergic and calretinin interneurons in the olfactory bulb. Front. Neural. Circ.15, 718221. 10.3389/fncir.2021.718221 (2021). PubMed PMC

Wei, C. J., Linster, C. & Cleland, T. A. Dopamine D(2) receptor activation modulates perceived odor intensity. Behav. Neurosci.120, 393–400. 10.1037/0735-7044.120.2.393 (2006). PubMed

Fish, E. W. et al. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome. PLoS One8, e77896. 10.1371/journal.pone.0077896 (2013). PubMed PMC

Paul, K., Venkitaramani, D. V. & Cox, C. L. Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice. J. Physiol.591, 1133–1143. 10.1113/jphysiol.2012.241067 (2013). PubMed PMC

Fulks, J. L. et al. Dopamine release and uptake impairments and behavioral alterations observed in mice that model fragile X mental retardation syndrome. ACS Chem. Neurosci.1, 679–690. 10.1021/cn100032f (2010). PubMed PMC

Wang, H. et al. FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron59, 634–647. 10.1016/j.neuron.2008.06.027 (2008). PubMed

Galvez, R., Smith, R. L. & Greenough, W. T. Olfactory bulb mitral cell dendritic pruning abnormalities in a mouse model of the Fragile-X mental retardation syndrome: Further support for FMRP’s involvement in dendritic development. Brain. Res. Dev. Brain. Res.157, 214–216. 10.1016/j.devbrainres.2005.03.010 (2005). PubMed

Lai, J. K., Lerch, J. P., Doering, L. C., Foster, J. A. & Ellegood, J. Regional brain volumes changes in adult male FMR1-KO mouse on the FVB strain. Neuroscience318, 12–21. 10.1016/j.neuroscience.2016.01.021 (2016). PubMed

Ellegood, J., Pacey, L. K., Hampson, D. R., Lerch, J. P. & Henkelman, R. M. Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging. Neuroimage53, 1023–1029. 10.1016/j.neuroimage.2010.03.038 (2010). PubMed

Golden, C. E. M. et al. Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1. Transl Psychiatry10, 280. 10.1038/s41398-020-00943-x (2020). PubMed PMC

Igarashi, K. M. et al. Parallel mitral and tufted cell pathways route distinct odor information to different targets in the olfactory cortex. J. Neurosci.32, 7970–7985. 10.1523/JNEUROSCI.0154-12.2012 (2012). PubMed PMC

Chen, F. et al. Cholecystokinin-expressing superficial tufted cells modulate odour representation in the olfactory bulb and olfactory behaviours. J. Physiol.602, 3519–3543. 10.1113/JP285837 (2024). PubMed

Sun, X., Liu, X., Starr, E. R. & Liu, S. CCKergic tufted cells differentially drive two anatomically segregated inhibitory circuits in the mouse olfactory bulb. J. Neurosci.40, 6189–6206. 10.1523/JNEUROSCI.0769-20.2020 (2020). PubMed PMC

Tonacci, A. et al. Olfaction in autism spectrum disorders: A systematic review. Child. Neuropsychol.23, 1–25. 10.1080/09297049.2015.1081678 (2017). PubMed

Friston, K. Prediction, perception and agency. Int. J. Psychophysiol.83, 248–252. 10.1016/j.ijpsycho.2011.11.014 (2012). PubMed PMC

Limongi, R., Tomio, A. & Ibanez, A. Dynamical predictions of insular hubs for social cognition and their application to stroke. Front. Behav. Neurosci.8, 380. 10.3389/fnbeh.2014.00380 (2014). PubMed PMC

Gonzalez-Gadea, M. L. et al. Predictive coding in autism spectrum disorder and attention deficit hyperactivity disorder. J. Neurophysiol.114, 2625–2636. 10.1152/jn.00543.2015 (2015). PubMed PMC

Bolis, D. & Schilbach, L. Observing and participating in social interactions: Action perception and action control across the autistic spectrum. Dev. Cogn. Neurosci.29, 168–175. 10.1016/j.dcn.2017.01.009 (2018). PubMed PMC

Thye, M. D., Bednarz, H. M., Herringshaw, A. J., Sartin, E. B. & Kana, R. K. The impact of atypical sensory processing on social impairments in autism spectrum disorder. Dev. Cogn. Neurosci.29, 151–167. 10.1016/j.dcn.2017.04.010 (2018). PubMed PMC

Brang, D. & Ramachandran, V. S. Olfactory bulb dysgenesis, mirror neuron system dysfunction, and autonomic dysregulation as the neural basis for autism. Med. Hypotheses74, 919–921. 10.1016/j.mehy.2008.11.048 (2010). PubMed

Bandini, L. G. et al. Food selectivity in children with autism spectrum disorders and typically developing children. J. Pediatr.157, 259–264. 10.1016/j.jpeds.2010.02.013 (2010). PubMed PMC

Raspa, M., Bailey, D. B., Bishop, E., Holiday, D. & Olmsted, M. Obesity, food selectivity, and physical activity in individuals with fragile X syndrome. Am. J. Intellect. Dev. Disabil115, 482–495. 10.1352/1944-7558-115.6.482 (2010). PubMed

Cermak, S. A., Curtin, C. & Bandini, L. G. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J. Am. Diet. Assoc.110, 238–246. 10.1016/j.jada.2009.10.032 (2010). PubMed PMC