Supervisors: dr hab. Anna Błasiak (anna.blasiak@uj.edu.pl)

Institute of Zoology and Biomedical Research

Background information:

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can develop in individuals who have experienced or witnessed a traumatic event, such as accident, natural disaster, domestic violence, combat, or sexual assault. It is widely accepted that dysfunction within the interconnected circuitry of context processing, stress and anxiety control - involving the hippocampus, prefrontal cortex, thalamus, and amygdala - play a central role in the pathophysiology of PTSD1. Moreover, impaired memory related processes as well as pattern separation – has been shown to be a phenotypic marker of PTSD.

The functional dynamics of the DG remains under control of oxytocin (OXT), a neuropeptide synthesized mainly in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Notably, OXT has been implicated in the pathophysiology of PTSD and growing number of studies indicate possible use of OXT in the therapeutic interventions targeting PTSD. OXT system is under tight control of relaxin-3 (RLN3) signaling2, and it was shown, that DG express receptors for both OXT and RLN3 (OXTR and RXFP3, respectively).

The main question to be addressed in the project:

Despite numerous studies conducted on the neuronal mechanisms underlying PTSD, the involvement of OXT and RLN3 and their receptors systems in the pathophysiology of PTSD remains incompletely understood. Therefore, the primary aims of the proposed research are to investigate at the level of individual cells, neuronal networks and behaviour, the impact of RXFP3 and OXTR receptor activation on DG neuronal activity, long term potentiation (LTP) and depression (LTD) as well as social interactions in control animals and those exhibiting PTSD symptoms. An important aspect of the planned research is to explore intracellular signaling pathways and ion channels activated as a result of RXFP3 and OXTR receptor stimulation.

Information on the methods/description of work:

Planned experiments will involve both control animals (rats) and those subjected to contextual fear conditioning and PTSD induction. In the study aimed at elucidating the influence of OXT and RLN3 on DG neurons activity at the single-cell level, whole-cell patch clamp recordings are planned. Electrophysiological patch clamp recordings will be utilized to characterize the molecular mechanisms underlying the effects of OXTR and RXFP3 activation as well as the involvement of these neuropeptides in LTP and LTD in DG. Multiplex in situ hybridization will be used to characterize potential PTSD-related changes in the expression of mRNA for the neurotransmitters and receptors in DG neurons. Finally, behavioral experiments in rats will be performed to verify the impact of chemogenetic activation of RLN3 and OXT neurons on the progression of PTSD in experimental animals.

Additional information (e.g Special requirements from the student):

Candidates with previous experience in electrophysiological ex vivo patch clamp, analysis of electrophysiological data, preparation of tissues for subsequent anatomical studies, in situ hybridization and immunohistochemical techniques, as well as in behavioral testing on rodents and the rodent neurosurgery.

Place/name of potential foreign collaborator:

Florey Institute of Neuroscience and Mental Health, Melbourne, Australia/Professor Andrew Gundlach

References:

[1]. Liberzon I, Abelson JL. Context Processing and the Neurobiology of Post-Traumatic Stress Disorder. Neuron. 2016 Oct 5;92(1):14-30. doi: 10.1016/j.neuron.2016.09.039. PMID: 27710783; PMCID: PMC5113735. [2.] Kania A, Szlaga A, Sambak P, Gugula A, Blasiak E, Micioni Di Bonaventura MV, Hossain MA, Cifani C, Hess G, Gundlach AL, Blasiak A. RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior. J Neurosci. 2020 Jul 8;40(28):5362-5375. doi: 10.1523/JNEUROSCI.2895-19.2020. Epub 2020 Jun 12. PMID: 32532885; PMCID: PMC7343322.