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Item Guanabenz Reduces Hyperactivity and Neuroinflammation Caused by Latent Toxoplasmosis in Mice(2020-02) Martynowicz, Jennifer Marie; Sullivan, William J.; Arrizabalaga, Gustavo; Boehm II, Stephen L.; Gilk, Stacey D.; Spinola, Stanley M.Toxoplasma gondii is an intracellular parasite that causes persistent, lifelong infection in one-third of humans worldwide. The parasite converts from a lytic, actively replicating form (tachyzoite) into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. While acute infection can be life threatening to immunosuppressed individuals, chronic infection has been linked to behavioral changes in rodents and neurological disease in humans. Notably, chronic infection in mice leads to hyperactivity in an open field. Whether these behavioral changes are due to parasite manipulation of the host or the host response to infection remains an outstanding question. We have previously shown that the anti-hypertensive drug guanabenz reduces Toxoplasma cyst burden in the brains of BALB/c mice, providing a means to examine whether brain cyst depletion reverses behavioral changes. We used two mouse strains (BALB/c and C57BL/6) differing in their susceptibility to infection. Following drug treatment of chronically infected mice, locomotor activity in an open field was assessed. In both mouse strains, the increased hyperactivity seen during chronic infection returned to normal levels following guanabenz treatment. Guanabenz reduced brain cyst burden ~70% in BALB/c mice as expected, but it increased cyst burden 49% in C57BL/6 mice. Examination of the brains showed that guanabenz decreased inflammation and perivascular cuffing in both infected mouse strains. Our study shows for the first time that it is possible to reverse a key behavioral change associated with chronic Toxoplasma infection. Surprisingly, the rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation instead of cyst counts, suggesting that some behavioral changes arise from host responses to infection rather than a parasite-driven process.Item Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model(BMC, 2020-01-15) Lukkes, J. L.; Drozd, H. P.; Fitz, S. D.; Molosh, A. I.; Clapp, D. W.; Shekhar, A.; Psychiatry, School of MedicineBACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a mutation in one copy of the neurofibromin gene (NF1+/-). Even though approximately 40-60% of children with NF1 meet the criteria for attention deficit hyperactivity disorder (ADHD), very few preclinical studies, if any, have investigated alterations in impulsivity and risk-taking behavior. Mice with deletion of a single NF1 gene (Nf1+/-) recapitulate many of the phenotypes of NF1 patients. METHODS: We compared wild-type (WT) and Nf1+/- mouse strains to investigate differences in impulsivity and hyperactivity using the delay discounting task (DDT), cliff avoidance reaction (CAR) test, and open field. We also investigated whether treatment with the clinically effective alpha-2A adrenergic receptor agonist, guanfacine (0.3 mg/kg, i.p.), would reverse deficits observed in behavioral inhibition. RESULTS: Nf1+/- mice chose a higher percentage of smaller rewards when both 10- and 20-s delays were administered compared to WT mice, suggesting Nf1+/- mice are more impulsive. When treated with guanfacine (0.3 mg/kg, i.p.), Nf1+/- mice exhibited decreased impulsive choice by waiting for the larger, delayed reward. Nf1+/- mice also exhibited deficits in behavioral inhibition compared to WT mice in the CAR test by repetitively entering the outer edge of the platform where they risk falling. Treatment with guanfacine ameliorated these deficits. In addition, Nf1+/- mice exhibited hyperactivity as increased distance was traveled compared to WT controls in the open field. This hyperactivity in Nf1+/- mice was reduced with guanfacine pre-treatment. CONCLUSIONS: Overall, our study confirms that Nf1+/- mice exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD, and can be used as a model system to identify alterations in neural circuitry associated with symptoms of ADHD in children with NF1.