Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 24, 2020

Hexanal inhalation affects cognition and anxiety-like behavior in mice

Hiroshi Ueno, Atsumi Shimada, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yu Takahashi, Yosuke Matsumoto, Motoi Okamoto and Takeshi Ishihara


Hexanal is a 6-carbon aldehyde that smells like green leaves and urine to mammals. However, its physiological effects remain unclear. In particular, the effects of hexanal inhalation on the central nervous system have not been clarified. We investigated hexanal inhalation in mice and conducted a series of behavioral experiments to examine the neuropsychological effects of hexanal. After inhaling hexanal emissions for 30 min, mice were subjected to an open field test, a hot plate test, a grip strength test, an elevated plus maze test, a Y-maze test, a tail suspension test, and a forced swim test to examine the effects of hexanal odor on mouse behavior. Compared to controls, mice that inhaled hexanal exhibited reduced anxiety-like behavior in the elevated plus maze test. In addition, mice that inhaled hexanal displayed significantly improved spatial cognitive ability in the Y-maze test. However, in some behavioral experiments there was no significant difference between control mice and mice that inhaled hexanal. The results of this study suggest that hexanal inhalation causes anxiolytic effects and improves cognitive function in mice. These findings may have implications for safety management procedures and determining the effective use of household goods containing hexanal, though further work is required.

Corresponding author: Hiroshi Ueno, Ph.D., Department of Medical Technology, Kawasaki University of Medical Welfare, 288, Matsushima, Kurashiki, Okayama, 701-0193, Japan, E-mail:

Funding source: Yakumo Foundation for Environmental Science

Funding source: Towa Foundation for Food Science & Research;Kawasaki Medical School


We thank Kawasaki Medical School Central Research Institute for providing instruments to support this study. The authors would like to thank Editage ( for English language editing.

  1. Author contributions: All authors had full access to all study data and take full responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: H.U., A.S., and M.O. Data acquisition: H.U., S.S., and Y.T. Data analysis and interpretation: H.U., A.S., and S.S. Drafting of the manuscript: H.U., A.S., Y.T., and M.O. Critical revision of the manuscript for important intellectual content: A.S., S.M., N.K., K.W., Y.T., Y.M., M.O., and T.I. Statistical analyses: H.U and S.S. Study supervision: M.O. and T.I.

  2. Funding sources: This work is supported by a Grant Aid for the Yakumo Foundation for Environmental Science and the Towa Foundation for Food Science & Research.

  3. Data availability statement: All relevant data are within the manuscript.

  4. Conflict of interest: The authors declare that there are no conflicts of interest.


1. Sánchez-Vidaña, DI, Ngai, SP, He, W, Chow, JK, Lau, BW, Tsang, HW. The effectiveness of aromatherapy for depressive symptoms: a systematic review. Evid Based Complement Alternat Med 2017:5869315.10.1155/2017/5869315Search in Google Scholar PubMed PubMed Central

2. Koulivand, PH, Khaleghi Ghadiri, M, Gorji, A. Lavender and the nervous system. Evid Based Complement Alternat Med 2013:681304.10.1155/2013/681304Search in Google Scholar PubMed PubMed Central

3. de Sousa, DP, de Almeida Soares Hocayen, P, Andrade, LN, Andreatini, R. A systematic review of the anxiolytic-like effects of essential oils in animal models. Molecules 2015;20:18620–60. in Google Scholar

4. Cavanagh, HM, Wilkinson, JM. Biological activities of lavender essential oil. Phytother Res 2002;16:301–8. in Google Scholar

5. Lv, XN, Liu, ZJ, Zhang, HJ, Tzeng, CM. Aromatherapy and the central nerve system (CNS): therapeutic mechanism and its associated genes. Curr Drug Targets 2013;14:872–9. in Google Scholar

6. Lis-Balchin, M. Essential oils and ‘aromatherapy’: their modern role in healing. J R Soc Health 1997;117:324–9. in Google Scholar

7. Zhang, Y, Wu, Y, Chen, T, Yao, L, Liu, J, Pan, X, et al. Assessing the metabolic effects of aromatherapy in human volunteers. Evid Based Complement Alternat Med 2013:356381. in Google Scholar

8. Kim, SS, Gallaher, DD, Csallany, AS. Lipophilic aldehydes and related carbonyl compounds in rat and human urine. Lipids 1999;34:489–96. in Google Scholar

9. Shibata, Y, Matsui, K, Kajiwara, T, Hatanaka, A. Fatty acid hydroperoxide lyase is a heme protein. Biochem Biophys Res Commun 1995;207:438–43. in Google Scholar

10. Song, MK, Lee, HS, Ryu, JC. Integrated analysis of microRNA and mRNA expression profiles highlights aldehyde-induced inflammatory responses in cells relevant for lung toxicity. Toxicology 2015;334:111–21. in Google Scholar

11. Inagaki, H, Kiyokawa, Y, Tamogami, S, Watanabe, H, Takeuchi, Y, Mori, Y. Identification of a pheromone that increases anxiety in rats. Proc Natl Acad Sci U S A 2014;111:18751–6. in Google Scholar

12. Bethany Brookshire. The scent of a worry (unabridged); 2015.Search in Google Scholar

13. Srinivas, A, Rao, PJ, Selvam, G, Murthy, PB, Reddy, PN. Acute inhalation toxicity of cerium oxide nanoparticles in rats. Toxicol Lett 2011;205:105–15. in Google Scholar

14. Ueno, H, Shimada, A, Suemitsu, S, Murakami, S, Kitamura, N, Wani, K, et al. Anti-depressive-like effect of 2-phenylethanol inhalation in mice. Biomed Pharmacother 2019;111:1499–506. in Google Scholar

15. Vogel, HG, Maas, J, Gebauer, A. Drug discovery and evaluation: methods in clinical pharmacology 2011th edition. Springer; 2011.10.1007/978-3-540-89891-7Search in Google Scholar

16. Hagihara, H, Horikawa, T, Nakamura, HK, Umemori, J, Shoji, H, Kamitani, Y, et al. Circadian gene circuitry predicts hyperactive behavior in a mood disorder mouse model. Cell Rep 2016;14:2784–96. in Google Scholar

17. Ohashi, R, Takao, K, Miyakawa, T, Shiina, N. Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: reduced social interaction and attenuated response to novelty. Sci Rep 2016;6:20775. in Google Scholar

18. Hamaguchi-Hamada, K, Hamada, S, Yagi, T. Exposure to hexanal odor induces extraordinary Fos expression in the medial preoptic area and amygdala of Fyn tyrosine kinase-deficient mice. Brain Res Mol Brain Res 2004;130:187–90. in Google Scholar

19. Seibenhener, ML, Wooten, MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 2015;6:e52434. in Google Scholar

20. Bourin, M, Hascoët, M. The mouse light/dark box test. Eur J Pharmacol 2003;463:55–5. in Google Scholar

21. Kako, H, Kobayashi, Y, Yokogoshi, H. Effects of n-hexanal on dopamine release in the striatum of living rats. Eur J Pharmacol 2011;651:77–2. in Google Scholar

22. Huang, GB, Zhao, T, Muna, SS, Bagalkot, TR, Jin, HM, Chae, HJ, et al. Effects of chronic social defeat stress on behaviour, endoplasmic reticulum proteins and choline acetyltransferase in adolescent mice. Int J Neuropsychopharmacol 2013;16:1635–47. in Google Scholar

23. Zhao, T, Huang, GB, Muna, SS, Bagalkot, TR, Jin, HM, Chae, HJ, et al. Effects of chronic social defeat stress on behavior and choline acetyltransferase, 78-kDa glucose-regulated protein, and CCAAT/enhancer-binding protein (C/EBP) homologous protein in adult mice. Psychopharmacology (Berl) 2013;228:217–30. in Google Scholar

24. Bagalkot, TR, Jin, HM, Prabhu, VV, Muna, SS, Cui, Y, Yadav, BK, et al. Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice. Neuroscience 2015;311:444–52. in Google Scholar

25. Jin, HM, Shrestha Muna, S, Bagalkot, TR, Cui, Y, Yadav, BK, Chung, YC. The effects of social defeat on behavior and dopaminergic markers in mice. Neuroscience 2015;288:167–77. in Google Scholar

26. Prabhu, VV, Nguyen, TB, Cui, Y, Oh, YE, Piao, YH, Baek, HM, et al. Metabolite signature associated with stress susceptibility in socially defeated mice. Brain Res 2019;1708:171–80. in Google Scholar

27. Grippo, AJ, Lamb, DG, Carter, CS, Porges, SW. Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors. Biol Psychiatry 2007;62:1162–70. in Google Scholar

28. Djordjevic, J, Djordjevic, A, Adzic, M, Radojcic, MB. Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers. Neuropsychobiology 2012;66:112–9. in Google Scholar

29. Ueno, H, Suemitsu, S, Murakami, S, Kitamura, N, Wani, K, Okamoto, M, et al. Region-specific impairments in parvalbumin interneurons in social isolation-reared mice. Neuroscience 2017;359:196–208. in Google Scholar

30. Matthews, K, Robbins, TW. Early experience as a determinant of adult behavioural responses to reward: the effects of repeated maternal separation in the rat. Neurosci Biobehav Rev 2003;27:45–55. in Google Scholar

31. Vetulani, J. Early maternal separation: a rodent model of depression and a prevailing human condition. Pharmacol Rep 2013;65:1451–61. in Google Scholar

32. Spengler, JD, Sexton, K. Indoor air pollution: a public health perspective. Science 1983;221:9–7. in Google Scholar

33. Soleimani, E, Moghadam, RH, Ranjbar, A. Occupational exposure to chemicals and oxidative toxic stress. Toxicol Environ Health Sci 2015;7:1–4. in Google Scholar

34. O’Brien, PJ, Siraki, AG, Shangari, N. Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 2005;35:609–62. in Google Scholar

35. Song, MK, Lee, HS, Choi, HS, Shin, CY, Kim, YJ, Park, YK, et al. Octanal-induced inflammatory responses in cells relevant for lung toxicity: expression and release of cytokines in A549 human alveolar cells. Hum Exp Toxicol 2014;33:710–21. in Google Scholar

Received: 2019-12-02
Revised: 2020-02-18
Accepted: 2020-05-26
Published Online: 2020-06-24
Published in Print: 2020-11-26

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow