Influenza A virus infection causes alterations in expression of synaptic regulatory genes combined with changes in cognitive and emotional behaviors in mice
Abstract
Epidemiological studies have indicated a link between certain neuropsychiatric diseases and exposure to viral infections. In order to examine long-term effects on behavior and gene expression in the brain of one candidate virus, we have used a model involving olfactory bulb injection of the neuro-adapted influenza A virus strain, WSN/33, in C57Bl/6 mice. Following this olfactory route of invasion, the virus targets neurons in the medial habenular, midline thalamic and hypothalamic nuclei as well as monoaminergic neurons in the brainstem. The mice survive and the viral infection is cleared from the brain within 12 days. When tested 14-20 weeks after infection, the mice displayed decreased anxiety in the elevated plus-maze and impaired spatial learning in the Morris water maze test. Elevated transcriptional activity of two genes encoding synaptic regulatory proteins, regulator of G-protein signaling 4 and calcium/calmodulin-dependent protein kinase IIalpha, was found in the amygdala, hypothalamus and cerebellum. It is of particular interest that the gene encoding RGS4, which has been related to schizophrenia, showed the most pronounced alteration. This study indicates that a transient influenza virus infection can cause persistent changes in emotional and cognitive functions as well as alterations in the expression of genes involved in the regulation of synaptic activities.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Experimental studies show that injection of Influenza A virus in mice's olfactory bulb caused cognitive impairment 14-20 weeks after the infection.
“Experimental studies show that the injection of Influenza A virus in mice’s olfactory bulb caused cognitive impairment 14–20 weeks after the infection [112]”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [112]
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444 · see citing works
Place navigation impaired in rats with hippocampal lesions
Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O'Keefe, J. (1982) · Nature · doi:10.1038/297681a0 · Cited by 6,340 · see citing works
The neuroanatomical and neurochemical basis of conditioned fear
Fendt, M., & Fanselow, M. S. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(99)00016-0 · Cited by 1,092 · see citing works
Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A., & Levitt, P. (2000) · Neuron · doi:10.1016/s0896-6273(00)00085-4 · Cited by 882 · see citing works
A VIRUS OBTAINED FROM INFLUENZA PATIENTS
Smith, W., Andrewes, C. H., & Laidlaw, P. P. (1933) · The Lancet · doi:10.1016/s0140-6736(00)78541-2 · Cited by 867 · see citing works
Interaction with the NMDA receptor locks CaMKII in an active conformation
Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., & Schulman, H. (2001) · Nature · doi:10.1038/35081080 · Cited by 732 · see citing works
The olfactory bulbectomized rat as a model of depression: An update
Kelly, J. P., Wrynn, A. S., & Leonard, B. E. (1997) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(97)00004-1 · Cited by 662 · see citing works
Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia
Mirnics, K., Middleton, F. A., Stanwood, G. D., Lewis, D. A., & Levitt, P. (2001) · Molecular Psychiatry · doi:10.1038/sj.mp.4000866 · Cited by 446 · see citing works
Tobita, K., Sugiura, A., Enomoto, C., & Furuyama, M. (1975) · Medical Microbiology and Immunology · doi:10.1007/bf02123572 · Cited by 407 · see citing works
α-CaMKII-dependent plasticity in the cortex is required for permanent memory
Frankland, P. W., O'Brien, C., Ohno, M., Kirkwood, A., & Silva, A. J. (2001) · Nature · doi:10.1038/35077089 · Cited by 397 · see citing works
Association and linkage analyses of RGS4 polymorphisms in schizophrenia
Chowdari, K. V. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.12.1373 · Cited by 368 · see citing works
�gren, S. O., Hall, H., K�hler, C., Magnusson, O., & Sj�strand, S. E. (1986) · Psychopharmacology · doi:10.1007/bf00179179 · Cited by 217 · see citing works
Self-citationStimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula
Ellison, G. D. (1994) · Brain Research Reviews · doi:10.1016/0165-0173(94)90012-4 · Cited by 182 · see citing works
Cycling cells in the adult rat neocortex preferentially generate oligodendroglia
Levison, S. W., Young, G. M., & Goldman, J. E. (1999) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19990815)57:4 · Cited by 172 · see citing works
Olfactory bulbectomy as a model for agitated hyposerotonergic depression
Lumia, A. R., Teicher, M. H., Salchli, F., Ayers, E., & Possidente, B. P. (1992) · Brain Research · doi:10.1016/0006-8993(92)90995-l · Cited by 171 · see citing works
Park, C. H., Ishinaka, M., Takada, A., Kida, H., Kimura, T., Ochiai, K., & Umemura, T. (2002) · Archives of Virology · doi:10.1007/s00705-001-0750-x · Cited by 164 · see citing works
A fixed sequence Bonferroni procedure for testing multiple endpoints
Wiens, B. L. (2003) · Pharmaceutical Statistics · doi:10.1002/pst.64 · Cited by 156 · see citing works
EXCRETION OF PLATINUM INTO BREAST MILK
de Vries, E. G. E., van der Zee, A. G. J., Uges, D. R. A., & Sleijfer, D. T. (1989) · The Lancet · doi:10.1016/s0140-6736(89)91396-2 · Cited by 145 · see citing works
Confirming <i>RGS4</i> as a susceptibility gene for schizophrenia
Morris, D. W., Rodgers, A., McGhee, K. A., Schwaiger, S., Scully, P., Quinn, J., Meagher, D., Waddington, J. L., Gill, M., & Corvin, A. P. (2004) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.20109 · Cited by 137 · see citing works
Swiergiel, A. H., Smagin, G. N., Johnson, L. J., & Dunn, A. J. (1997) · Brain Research · doi:10.1016/s0006-8993(97)01009-3 · Cited by 130 · see citing works
Cytokines and the acute phase response to influenza virus in mice
Conn, C. A., McClellan, J. L., Maassab, H. F., Smitka, C. W., Majde, J. A., & Kluger, M. J. (1995) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1995.268.1.r78 · Cited by 129 · see citing works
A NEUROTROPIC STRAIN OF HUMAN INFLUENZA VIRUS
Stuart-Harris, C. H. (1939) · The Lancet · doi:10.1016/s0140-6736(00)74067-0 · Cited by 122 · see citing works
The substantia nigra is a major target for neurovirulent influenza A virus.
Takahashi, M., Yamada, T., Nakajima, S., Nakajima, K., Yamamoto, T., & Okada, H. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.6.2161 · Cited by 120 · see citing works
Siderovski, D. P., Heximer, S. P., & Forsdyke, D. R. (1994) · DNA and Cell Biology · doi:10.1089/dna.1994.13.125 · Cited by 116 · see citing works
Ögren, S. O., Pramanik, A. B., & Schött, P. A. (1996) · Neuroscience · doi:10.1016/0306-4522(96)00215-1 · Cited by 113 · see citing works
Self-citationA STUDY OF THE NEUROTROPIC TENDENCY IN STRAINS OF THE VIRUS OF EPIDEMIC INFLUENZA
Francis, T., & Moore, A. E. (1940) · The Journal of Experimental Medicine · doi:10.1084/jem.72.6.717 · Cited by 105 · see citing works
Jordan, I., & Lipkin, W. I. (2001) · Reviews in Medical Virology · doi:10.1002/rmv.300 · Cited by 96 · see citing works
Bejar, R. L., Yasuda, R., Krugers, H. J., Hood, K. L., & Mayford, M. R. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05719.2002 · Cited by 95 · see citing works
Reinacher, M., Bonin, J., Narayan, O., & Scholtissek, C. (1983) · PubMed · Cited by 94 · see citing works
Isolation and characterization of a novel B cell activation gene
Hong, J., Wilson, G. L., Fox, C. H., et al. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.9.3895 · Cited by 92 · see citing works
Rubin, S. A., Sylves, P., Vogel, M. W., Pletnikov, M., Moran, T. H., Schwartz, G. J., & Carbone, K. M. (1999) · Brain Research Bulletin · doi:10.1016/s0361-9230(98)00133-6 · Cited by 83 · see citing works
Manual and Semiautomated Measurement of Cerebellar Subregions on MR Images
Pierson, R. K., Corson, P. W., Sears, L. L., Alicata, D., Magnotta, V. A., OʼLeary, D. S., & Andreasen, N. C. (2002) · NeuroImage · doi:10.1006/nimg.2002.1207 · Cited by 75 · see citing works
Influenza Viral Infections Enhance Sleep in Mice
Fang, J., Sanborn, C., Renegar, K. B., Majde, J. A., & Krueger, J. M. (1995) · Experimental Biology and Medicine · doi:10.3181/00379727-210-43945 · Cited by 74 · see citing works
Misane, I. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(99)00109-8 · Cited by 62 · see citing works
Invasion and Persistence of the Neuroadapted Influenza Virus A/WSN/33 in the Mouse Olfactory System
Aronsson, F. S., Robertson, B. J., Ljunggren, H., et al. (2003) · Viral Immunology · doi:10.1089/088282403322396208 · Cited by 57 · see citing works
Self-citationMolnar, M., Potkin, S. G., Bunney, W. E., & Jones, E. G. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01456-7 · Cited by 56 · see citing works
Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice.
Kuzmin, A., Sandin, J., Terenius, L. Y., & Ögren, S. O. (2000) · PubMed · Cited by 56 · see citing works
Self-citationExpression of RGS2, RGS4 and RGS7 in the developing postnatal brain
Ingi, T., & 青木弥恵子 (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.01925.x · Cited by 52 · see citing works
Genetics of Schizophrenia and Affective Disorders
Maier, W., Zobel, A. W., & Rietschel, M. (2003) · Pharmacopsychiatry · doi:10.1055/s-2003-45130 · Cited by 48 · see citing works
Selective olfactory bulb lesions: Reactivity changes and avoidance learning in rats
Sieck, M. H., & Gordon, B. L. (1972) · Physiology & Behavior · doi:10.1016/0031-9384(72)90010-8 · Cited by 46 · see citing works
Role of Aversively Motivated Behavior in the Olfactory Bulbectomy Syndrome
Primeaux, S. D., & Holmes, P. V. (1999) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00027-x · Cited by 46 · see citing works
Mori, I., Diehl, A. D., Chauhan, A., Ljunggren, H., & Kristensson, K. (1999) · Journal of NeuroVirology · doi:10.3109/13550289909029476 · Cited by 46 · see citing works
Self-citationEngel, J., Zhang, J., Bergström, T. B., CONRADI, N. G., Forkstam, C., Liljeroth, A., & Svensson, L. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02149-1 · Cited by 45 · see citing works
Viruses and Behavioural Changes: A Review of Clinical and Experimental Findings
Mohammed, A. H. S., Norrby, E., & Kristensson, K. (1993) · Reviews in the Neurosciences · doi:10.1515/revneuro.1993.4.3.267 · Cited by 41 · see citing works
Self-citationMurphy, J. J., & Norton, J. D. (1990) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/0167-4781(90)90096-k · Cited by 39 · see citing works
Persistence of the influenza A/WSN/33 virus RNA at midbrain levels of immunodefective mice
Aronsson, F. S. (2001) · Journal of NeuroVirology · doi:10.1080/13550280152058771 · Cited by 33 · see citing works
Self-citationBrot, M. D., Rail, G. F., Oldstone, M. B. A., et al. (1997) · Journal of NeuroVirology · doi:10.3109/13550289709029467 · Cited by 27 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dubé, M., & Talbot, P. J. (2019) · Viruses · doi:10.3390/v12010014 · Cited by 1,048 · see citing works
Assessment of cognitive function in patients after COVID-19 infection
Becker, J. H., Lin, J. J., Doernberg, M., Stone, K., Navis, A., Festa, J. R., & Wisnivesky, J. P. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.30645 · Cited by 367 · see citing works
Damiano, R. F., Guedes, B. F., de Rocca, C. C., de Pádua Serafim, A., Castro, L. H. M., Munhoz, C. D., Nitrini, R., Filho, G. B., Miguel, E. C., Lucchetti, G., et al. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01286-4 · Cited by 98 · see citing works
Johansson, J. U., Ericsson, J., Janson, J., Beraki, S., Stanić, D., Mandic, S. A., Wikström, M. A., Hökfelt, T., Ögren, S. O., Rozell, B., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000278 · Cited by 83 · see citing works
Self-citationAsp, L., Beraki, S., Kristensson, K., Ögren, S. O., & Karlsson, H. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.04.004 · Cited by 33 · see citing works
Self-citationKhalil, O. S., Forrest, C. M., Pisar, M., Smith, R. A., Darlington, L. G., & Stone, T. W. (2013) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2013.828745 · Cited by 14 · see citing works
- Authors
- Beraki, S., Aronsson, F., Karlsson, H., Ögren, S. O., & Kristensson, K.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Ögren, S O
- Venue
- Molecular Psychiatry
- Published
- 2004-07-06
- Volume
- 10
- Issue
- 3
- Pages
- 299-308
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1980164431
- Cited by
- 67
- References
- 48
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 5 · 2014: 6 · 2013: 2 · 2012: 4
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- influenza A virus, anxiety, spatial learning impairment, RGS4, CaMKIIα, synaptic gene expression, amygdala, hypothalamus, cerebellum, schizophrenia, emotional behavior, cognitive function
- MeSH terms
- Animals, Cognition, Cognition Disorders, Emotions, Gene Expression Regulation, Limbic System, Male, Mice, Inbred C57BL, Motor Activity, Orthomyxoviridae Infections, Influenza A virus, Space Perception, Synapses, Transcription, Genetic, Neurotransmitter Agents, Maze Learning, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review