Evolutionary Perspectives on Anxiety: Telencephalic Circuitry and the Anxiogenic Role of TrkB Signaling in Tuberous Sclerosis Complex

Abstract

Tuberous Sclerosis Complex (TSC) is a genetic disease which manifests as a range of neurological symptoms, including benign brain tumors, epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Among the latter, according to recent reports, anxiety and mood disorders affect over 50% of patients. We have previously demonstrated anxiety-like behavioral symptoms in the zebrafish model of TSC, which were rescued by treatment with the TrkB antagonist ANA-12. Here, we aimed to investigate the mechanism of how ANA-12 regulates behavior by analyzing brain activity in the telencephalon of TSC zebrafish larvae, and we identified the affected regions as corresponding to the known mammalian circuitry involved in anxiety processing. Due to differences in development, the identification of telencephalic territories that are homologous between zebrafish and mammals remains challenging, particularly at early, dynamic stages of development. However, we were able to identify populations of neurons in the zebrafish habenula and ventral subpallium whose involvement in anxiety parallels that of mammals. Those regions were dysregulated in the TSC mutant. This dysregulation correlated with aberrant anxiety behavior and was rescued by treatment with ANA-12. Our results suggest that hyperactivation of TrkB in those regions is a major contributor to anxiety-like behavior as seen in TSC fish, and that those mechanisms could be evolutionarily conserved between zebrafish and mammals.