Although there are animal models of hyperactivity, they involve destruction of parts of the brain but do not provide any hypotheses about the cause of this destruction in the naturally occurring syndrome. In this proposal, we pursue the hypothesis that some of the specific behavioral problems of childhood, such as hyperactivity, might be caused by infection with neurotropic viruses early in life. We have shown that neonatal infection of mice with a host-range mutant herpes simplex type 1 virus produces hyperactive behavior in the open field. In this project, we will determine whether the behavioral effects of the virus are similar to the behavioral characteristics of the human hyperactivity (attention deficit disorder) syndrome. We will test the ability of the mice to inhibit behavior using both aversively and appetatively motivated tasks, determine whether they are more distractible than normal and we will explore learning deficits. Activity will be studied in a variety of testing situations and the development of control of activity will be explored. A second set of studies will ask how the virus has its effect upon behavior. A major question is whether the virus has a tropism for systems controlling activity or, alternatively, affects these systems because they are developing and thus vulnerable during the time that the virus is growing in the brain. To do this, we will infect older animals, using high doses of the virus, immunosuppression, anti-lymphocyte serum, or a more virulent revertant of the virus in order to produde levels of infection equivalent to that we have been in neonates. If the virus effect is due to tropism for neural systems controlling activity, infection in adults should alter activity. The tissues targeted by the virus will be identified using either immunocytochemicallabeling of antibody to viral proteins or in situ DNA hybridization with radiolabeled probes. Routine histology of the affected areas will be used to determine whether cell damage has occurred. Dissection of affected brain areas for analysis of neurotransmitter changes will be used to determine useful psychopharmacologic manipulations to explore. We will determine whether latent virus remains in the brain after the infection resolves. This project is unique in that it involves close collaboration between a psychobiologist and a virologist and it postulates a cause for a common behavioral syndrome of childhood.
| Crnic, L S; Pizer, L I (1988) Behavioral effects of neonatal herpes simplex type 1 infection of mice. Neurotoxicol Teratol 10:381-6 |
