Biology subjects

Doszyn, O.

Publications and source records attributed to Doszyn, O..

2 recordsLinked to original sources

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2022

mTORC1 hyperactivation causes sensory integration deficits due to habenula impairment

Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for proper brain development. Hyperactivation of mTORC1 is found in many developmental diseases, including autism spectrum disorder (ASD). Atypical reactivity to sensory stimuli is often found in patients with ASD. The most frequent hereditary cause of ASD is Tuberous Sclerosis Complex (TSC), in which inactivating mutations in the TSC1 or TSC2 genes result in hyperactivation of the mTORC1 pathway. We have discovered that the zebrafish model of TSC, tsc2vu242/vu242 mutants lack light preference, a behavior requiring integration of multiple sensory inputs. Here, we show that the lack of light preference in tsc2vu242/vu242 zebrafish is caused by aberrant sensory integration of light stimuli in the left dorsal habenula. Single-cell calcium imaging analysis revealed that tsc2vu242/vu242 fish showed impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli resulting in atypical response to light. Lack of light-preference behavior and abnormal neuronal activity in the left dorsal habenula were rescued by rapamycin, indicating that hyperactive mTorC1 causes aberrant habenula function and impaired sensory integration resulting in lack of light preference. Our results link sensory integration deficits seen in TSC patients suffering from ASD with hyperactive mTORC1 and suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.

neuroscience↗