Effects of acute and chronic activation of oxytocin receptor on intraneuronal signaling cascades: implications for anxiety-like behaviour

• Applicants: Dr. Benjamin Jurek; Professorin Dr. Inga D. Neumann
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 338314427

The growing interest in the behavioral effects of the neuropeptide oxytocin (OXT) as treatment option for various psychopathologies including anxiety disorders creates the need for a deeper understanding of the molecular processes following acute, but especially chronic OXT receptor (OXTR) activation. Surprisingly, compared to the high number of behavioural studies in animals and humans, neuronal and molecular mechanisms underlying the OXT effects are rarely reported, especially in the context of chronically activated intracellular signaling cascades and their downstream target proteins and genes.Therefore, the present project aims to reveal OXTR-mediated intraneuronal effects in hypothalamic neurons after acute treatment, and to compare these effects with cytoplasmic or genetic alterations after chronic application of OXT in vivo and in vitro. We aim to identify signalling cascades and transcription factors that are essentially involved in the anxiolytic effect of OXT, i.e. we will study alterations in anxiety-related behavior following specific pharmacogenetic manipulation of selected factors using siRNA, CRISPR/cas9, and antagonists in male and female rats. Although some candidate signaling cascades and transcription factors have already been associated with the OXTR in myometrial or neuronal cells, the involvement of those cascades in the regulation of any behavior is unknown. This allowed us to narrow the focus of this application down to a selected set of 7 neuronal factors that are likely to be involved in the regulation of anxiety-like behavior (TRPV2, MEK1/2, ERK5, CaMKII, PKC, CREB, MEF-2). After identifying intraneuronal target factors regulated by acute (Aim 1) or chronic (Aim 2) OXT in vivo, we will assess the molecular details and prove causal links between cascades, transcription factors, and gene transcription in vitro. We hypothesize that the unique combination of signaling cascades causes OXT-specific effects, which are dependent on the dose and duration of treatment, sex, and tissue (brain or periphery, Aim 3). Overall, we aim to reveal detailed neuronal mechanisms of action of OXT essential for the design of an effective and specific therapeutic treatment, e.g. of patients suffering from anxiety disorders.

• DFG Programme: Research Grants