Viral infections of the human fetus and newborn produce pathological behavior in the neonatal period and beyond. Childhood psychiatric illnesses such as autism may follow perinatal viral infections in the CNS. in this application a multidisciplinary group of virologists, behavioral scientists and neuroanatomists propose to study a model of encephalitis virus infection in the neonate, Borna disease virus (BDV). BDV is a neurotropic virus which persistently infects limbic system neurons and produces behavioral and anatomical abnormalities in the neonatal rat (persistent infection/newborn or PI/NB). Unlike most encephalitis viruses perinatal infection with BDV produces no inflammation in the CNS. PI/NB rats appear grossly normal but have increased motor activity, retarded learning abilities and diminished pain avoidance learning. We propose to study the pathogenesis of behavioral developmental abnormalities produced by perinatal infection with a persistent virus.
Specific Aims : 1. In the PI/NB rat which neuroanatomical regions contain neurons infected with BDV? Hypothesis: BDV infects selective neuronal groups in neonatal rats. BDV infected neurons will be identified by immunohistochemical stains for BDV proteins and in situ hybridization for BDV nucleic acids. BDV spreads in cell processes throughout the nervous system; we will chart the dissemination of virus as neural pathways develop. 2. Are characteristic abnormalities in behavior associated with BDV infection of specific neurons in the PI/NB rat? Hypothesis: BDV infection of specific neuron groups in the neonatal rat disrupts normal neurological functions, resulting in characteristic abnormalities in behavior. Using the results from Aim 1, behavior abnormalities related to the dysfunction of the infected neurons will be identified including: social interactions of mother and pup, taste reactivity, learned taste aversion and locomotor activity. Behavioral analyses will be performed on rats inoculated with BDV at sequential timepoints shortly after birth to assess the effects of perinatal infection on the development of these behaviors. 3. Are neurotransmitter distribution and levels affected by neonatal infection with BDV? Hypothesis: Neurochemical development is disturbed by neonatal infection with BDV. Alterations in anatomical distribution and qualitative levels of various neurotransmitters will be characterized immunohistochemically. If regional or global abnormalities are noted, pertinent neurotransmitter levels will be quantitated. 4. What neural cell feature confers specificity for infection with BDV? Hypothesis: BDV binds to a phylogenetically conserved neural cell molecule for entry into the cell, explaining the virus tropism for the nervous system in a wide variety of virus structure will be used to identify and characterize binding sites on susceptible neurons.
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