Supervisors: dr hab. Tomasz Błasiak, prof. UJ (tomasz.blasiak@uj.edu.pl)

Institute of Zoology and Biomedical Research

Background information:

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired attention, increased impulsivity, and hyperactivity. Our current knowledge, both about the symptoms and the neurobiological basis of ADHD, is largely based on clinical and basic research conducted on males. However, there is a growing body of evidence suggesting that both the occurrence and the intensity of some disease symptoms are gender-dependent 1. Moreover, recent research has highlighted a bias in ADHD diagnostic criteria, predominantly derived from male-centric studies, that potentially leads to overlooking the occurrence of diverse symptoms in females. Consequently, women are frequently underdiagnosed, misdiagnosed, or diagnosed later in life.

Unfortunately, the scarcity of neurobiological and behavioural studies conducted on female animal models of ADHD makes it impossible to ascertain whether intersex differences in symptoms are also present in species other than humans. Furthermore, since we do not have knowledge about the neurobiological basis of this disorder in females, it is impossible to compare it with the phenomena observed in males, let alone explain what could be the basis for potential differences in symptoms. One of the significant etiological bases of ADHD, described in males of various species, is the disturbance of neuronal activity control in the prefrontal cortex, especially the right hemisphere of the brain, by catecholaminergic systems: dopaminergic and noradrenergic. The prefrontal cortex plays a key role in attention processes, decision-making, action planning, and emotion control, with the right hemisphere strongly specializing in behavioural inhibition.

Interference in the development of catecholaminergic systems in the neonatal period, involving intracerebroventricular administration of 6-hydroxydopamine, is an animal model of ADHD, although its detailed characterization and thorough validation has been largely conducted on rat and mice males2. The 6‐OHDA animals exhibited the major ADHD‐like symptoms mentioned above, as well as numerous co-existing symptoms including elevated anxiety, antisocial behaviours, and impaired cognitive functions. At the same time, a decrease in amount of catecholamines and structural changes in cortical areas were observed in the animals studied. Furthermore, it was found that most symptoms disappeared under the influence of methylphenidate - a treatment effectively used in humans with ADHD. All of the above has been shown on several species of animals, but mainly on males...

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.