TOB is an effector of the hippocampus-mediated acute stress response

Abstract

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 lead to decreased stress resilience and pathological behavior. However, temporal modulation of molecular pathways underlying stress response remains poorly understood. Transducer of ErbB2.1, known as TOB, is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in psychological stress machinery at molecular, neural circuit, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress. At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity were dysregulated in Tob knockout (Tob-KO) mice. Electrophysiological recordings in hippocampal slices showed increased postsynaptic AMPAR-mediated neurotransmission, accompanied by decreased GABA neurotransmission and subsequently 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 changes in factors involved in stress response like decreased stress-induced LCN2 expression and ERK phosphorylation, as well as increased MKP-1 expression. This study introduces TOB as an important modulator in the hippocampal stress signaling machinery. In summary, we reveal a molecular pathway and neural circuit mechanism by which Tob deletion contributes to expression of pathological stress-related behavior.

The shared genetic architecture of suicidal behaviour and psychiatric disorders: A genomic structural equation modelling study

“…In neurons, the nonsense-mediated RNA decay (NMD) pathway serves as a regulatory mechanism to control mRNA, and mutations in the NMD genes have been associated with neurodevelopmental disorders, such as schizophrenia and neurodegenerative disorders, such as amyotrophic lateral sclerosis (Jaffrey and Wilkinson, 2018). TOB1, which codes for an antiproliferative protein that targets Frontiers in Genetics frontiersin.org mRNA deadenylation and decay (Hosoda et al, 2011), has previously been associated with neurodegenerative disorders (Weskamp and Barmada, 2018), such as multiple sclerosis (Gironi et al, 2016) and a TOB1 deletion has been associated with hippocampus-mediated acute stress response in animal models (Youssef et al, 2022). The primary role of the signal transduction pathway is to regulate overall growth and behaviour.…”

Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activation

“…In order to habituate awake mice to the MRI imaging protocol, an acclimation protocol was employed after the surgeries for head-fixation [16][17][18] . Male mice were fixed in a mock MRI environment and exposed to MRI imaging sounds and blue illumination for 2 h to habituate them to a leak of illumination during scanning (2.0 Hz).…”

“…A previous optogenetic fMRI experiment activated DRN serotonin neurons using the Pet1 promoter under anesthesia and showed widespread suppression of cortical activities [15]. We introduced an acclimation protocol to allow stable fMRI recording in awake mice [16–18] and found that DRN serotonin activation in an awake state induced increased brain-wide activity in both cortical and subcortical areas. In contrast, under anesthesia with isoflurane, DRN serotonin activation decreased activities in those areas, consistent with a previous study [15].…”