[PhD Thesis Public Presentation_Zoom] ‐ Mohieldin Youssef– “Role of TOB in the Brain: An Insight into Stress Coping Machinery”
Presenter: Mohieldin Youssef
Supervisor: Prof. Tadashi Yamamoto
Unit: Cell Signal Unit
Zoom URL: to be available 48 hours prior to the examination
Title: Role of TOB in the Brain: An Insight into Stress Coping Machinery
Stress affects behavior and involves critical dynamic changes at multiple levels ranging from molecular pathways to neural circuits and behavior. Abnormalities at any of these levels leads to decreased stress resilience and pathological behavior. However, temporal modulation of molecular pathways remains poorly understood. Transducer of ErbB2.1, known as TOB, (TOB1) is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in the brain’s stress machinery at molecular, neural circuit, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress paradigms. At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity was dysregulated in Tob knockout (Tob-KO) mice. Electrophysiological recordings in hippocampal slices showed increased postsynaptic AMPAR-mediated neurotransmission, accompanied by decreased GABA neurotransmission and subsequent altered Excitatory/Inhibitory balance after Tob deletion. At the behavioral level, Tob-KO mice show abnormal, hippocampus-dependent, contextual fear conditioning and extinction, and depression-like behaviors. On the other hand, increased anxiety observed in Tob-KO mice is hippocampus-independent. At the molecular level, we observed decreased stress-induced LCN2 expression and ERK phosphorylation, as well as increased MKP-1 expression. This study proposes that TOB serves as an important modulator in the hippocampal stress signaling machinery. Herein, we show a molecular pathway and neural circuit mechanism by which TOB contributes to expression of pathological stress-related behavior.