We hypothesize that many acquired neuropsychiatric syndromes are caused by protective anti-microbial antibodies that cross-react with neuronal antigens and damage neurons or alter their function. Usually, these antibodies circulate in the blood and in many tissues throughout the body, but cannot gain access to the brain because of the blood-brain barrier which prevents molecules from leaving the cerebral blood vessels. Epinephrine, one of the hormones activated by fear and traumatic stress, opens the blood-brain barrier and allows substances in the circulation to have access to the brain, most particularly to the amygdala. We propose to test the model that acquired neuropsychiatric dysfunction can occur in mice immunized with microbial antigens, pneumococcus, streptococcus and B anthracis, and then exposed directly to epinephrine or to traumatic stress. We will examine the brains of these mice and their behavior to determine if there is antibody-mediated damage with ensuing alterations in cognition or emotional responses. We will additionally determine whether similar pathology occurs in mice given human anti-pneumococcal or anti-streptococcal antibodies and exposed to pharmacologic or physiologic stress. This proposal represents an interdisciplinary approach to address a novel hypothesis regarding the relationship between infection and neuropsychiatric syndromes. Expertise in immunology, neurology and neuroscience are all critical to this proposal. If this model can be validated, novel approaches to preventing neuropsychiatric symptoms that occur following trauma could be explored.
|Diamond, B; Bloom, O; Al Abed, Y et al. (2011) Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med 269:36-44|
|Diamond, Betty (2010) Antibodies and the Brain: Lessons from Lupus. J Immunol 185:2637-2640|
|Prabhakaran, Jaya; Majo, Vattoly J; Milak, Matthew S et al. (2010) Synthesis, in vitro and in vivo evaluation of [11C]MMTP: a potential PET ligand for mGluR1 receptors. Bioorg Med Chem Lett 20:3499-501|
|Diamond, Betty; Huerta, Patricio T; Mina-Osorio, Paola et al. (2009) Losing your nerves? Maybe it's the antibodies. Nat Rev Immunol 9:449-56|