¹Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

Correspondence: Professor SO Ögren, Department of Neuroscience, Retzius väg 8, Karolinska Institutet, Stockholm SE-171 77, Sweden. E-mail: Sven.Ove.Ogren@neuro.ki.se

Received 17 March 2004; Revised 24 May 2004; Accepted 25 May 2004; Published online 6 July 2004.

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 II, 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.