Pharmacological Alk Inhibition to Mitigate Behavioral Changes and Cognitive Injury in Adolescent and Adult NF1 Mutant Mice
Abstract
Neurofibromatosis type 1 (NF1) is a genetically determined neurodevelopmental disorder and tumor syndrome with an incidence of approximately 1/3000 live births. In nutritionally-stressed fly larvae Jeb and Alk protect neurogenesis from growth restriction. Concordantly, NF1 loss is associated with increased neurogenesis, an enhanced behavioral response to subchronic doses of antidepressants, and spontaneous anti-depressive-like behaviors. It is, therefore, important to assess the effects of prolonged pharmacologic Alk inhibition on sleep, hippocampal neurogenesis, depressive and anxiety-like behaviors. We test the hypothesis that the pharmacologic inhibition of Alk will have short and long-term effects on behavioral performance, including measures of anxiety, depressive like behaviors, and circadian activity, cognitive performance, and neurogenesis, in heterozygous NF1 mutant mice treated in adulthood. The Specific Aims are: 1) To determine the optimal timing and dose of pharmacologic Alk inhibition to achieve maximal cognitive performance in heterozygous NF1 mutant mice; 2) To evaluate the potential benefit of Alk inhibition on altered circadian activity levels, a non-cognitive behavioral alteration associated with NF1 that may contribute to the cognitive disabilities; and 3) To assess potential adverse behavioral and cognitive effects of Alk inhibition in wild-type and NF1 heterozygous mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2021
- Accession Number
- AD1180338
Entities
People
- Jacob Raber
Organizations
- Oregon Health & Science University