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Neuroscience Graduate Programme "Neurobiology of Emotion Dysfunctions"

Research Projects

Psychopathologies are amongst the leading causes of disease and disability worldwide. In particular, anxiety- and depression-related disorders, which are characterized not only by severe emotional, but also by social dysfunctions, are among the most common psychiatric illnesses with life time prevalence of about 30% and 19%, respectively. These numbers reflect a large socio-economic burden and emphasize the importance of developing specific, predictable and efficient treatment options based on increased understanding of underlying neurobiological mechanisms.

The GRK “Neurobiology of Emotion Dysfunction” aims to substantially bundle research efforts at UR to reveal important mechanisms at molecular, cellular (including neuronal and glial), neuroendocrine and behavioural levels, which are likely to contribute to psychopathologies with particular focus on dysfunctions in anxiety- and depression-related behaviour, social and non-social fear and associated social deficits.

P1: Plasticity of glia-neuron interactions in emotional dysfunctions

Dr. Barbara Di Benedetto / Prof. Dr. Inga Neumann

Understanding the plasticity of glia-neuron interactions in emotional dysfunctions

Alterations in synaptic plasticity characterize several emotion dysfunctions. Glia cells (astrocytes, GFAP labelled, and microglia cells) orchestrate molecular signals crucial for the development and maintenance of functional neuronal synapses (synaptophysin labelled) and could therefore represent ideal substrates of pharmacological treatments aimed at restoring a physiological synaptic communication. This project aims at i) understanding how the plasticity of glia-neuron interactions is affected in emotion dysfunctions and ii) identifying alternative targets to develop tailored therapeutic treatments for such dysfunctions.

Methods: pharmacogenetic manipulations in vitro and in vivo (primary cell culture, stereotactic surgery, adenoviral-mediated RNA interference, local pharmacological treatments) combined with behavioral studies and histological methods (immunofluorescent-histochemistry, western blots, qPCR, in situ hybridization, morphological examinations).

P2: Brain neuropeptides & partner loss-induced depressive-like behaviour

PD Dr. Oliver Bosch / Prof. Larry Young

Impact of brain neuropeptides on partner loss-induced depressive-like behaviour in prairie voles

Positive social relationships are vital for mental and physical health. Conversely, sudden disruption of such relationships is often followed by emotional distress, triggering severe physical and psychological sequelae, including depression. Therefore, elucidating the neural systems underlying social loss-induced depression is essential to understand and, consequently, develop strategies against the psychiatric consequences of these events. We aim to reach that goal by using the monogamous prairie vole model, and by applying a variety of techniques from shRNA, intracerebral microdialysis, acute or chronic application of receptor (ant-)agonists, and epigenetic approaches to electrophysiology. Parts of the project will be conducted in the lab of Prof. Larry Young at Emory University, Atlanta / US.

P3: Stress & Regulation of female aggression

Dr. Trynke de Jong / Prof. Dr. Veronica Egger

Unraveling the role of stress in the regulation of female aggression

What causes pathological aggression? Some individuals explode upon the mildest of provocations; others use violence as a manner of thrill seeking. This project aims to gain translational insight into the role of stress hyper- and hypo-responsiveness in pathological aggression, using female and male rats as models. Individual differences in both aggression and stress responsiveness are explored, and the serenic properties of pharmacogenetic interventions in the stress system are analyzed.

Methods: Detailed behavioural observations, neuroendocrine techniques (catheter placement, blood/microdialysate sampling, hormone measurements), stereotactic surgeries, targeted neuropharmacology and siRNA treatments, DREADD manipulations, neuroimaging (immunofluorescence, in situ hybridization, receptor autoradiography), neurogenetics (punching, qPCR).

P4: Spir/formin complex & emotional fear learning

Prof. Dr. Eugen Kerkhoff / Prof. Dr. Veronica Egger

Function of the Spir/formin actin nucleator complex in emotional fear learning

Neuronal plasticity is the basis of mammalian learning and memory, with the dynamic actin cytoskeleton and associated motor proteins as essential mediators of plastic change. Proteins such as Spir actin nucleators and formins cooperate in generating actin filaments at vesicle membranes, which serve as tracks for vesicle transport processes. Transgenic mouse models revealed a function of both Spir-1 and formin-2 actin nucleators in emotional fear learning. Molecular protein interaction studies at the Kerkhoff lab show that Spir actin nucleators interact with myosin V actin motor proteins, which function in postsynaptic AMPA receptor transport. By combining expertises on protein complexes and vesicle transport on the one side (Kerkhoff) and neuronal subcellular signaling on the other side (Egger) we aim to unravel a function of the Spir/formin actin nucleator complex in plasticity of neuronal signaling in the limbic system.

P5: OXT & microRNA & protein synthesis involved in anxiolysis

Prof. Dr. Gunter Meister / Prof. Dr. Inga Neumann

Oxytocin actions on neuronal microRNA expression and protein synthesis: Involvement in oxytocin-induced anxiolysis

Project: The neuropeptide oxytocin (OXT) exerts anxiolytic and pro-social effects which can last up to several hours suggesting long-lasting molecular alterations, for instance at the level of protein synthesis. In this project we test the hypothesis that OXT exerts long-term effects on socio-emotional behaviour via regulation of expression of microRNAs (miRNAs). miRNAs are non-coding, single-stranded RNAs which can bind to specific target mRNAs and regulate mRNA translation and stability. Specifically, the PhD student will assess the selected miRNA expression levels in adult or embryonic primary hypothalamic cells and in the hypothalamus following acute or chronic OXT treatment. The student will further study, whether these identified miRNAs are involved in OXT-induced anxiolysis and whether the previously identified intracellular signaling cascades (Jurek et al. 2015; van den Burg, 2015) coupled to the OXT receptor control the expression of these identified miRNAs.

Methods include: Deep Sequencing and RTqPCR for quantification of miRNA levels; primary embryonic and adult hypothalamic cells for in vitro studies; locked nucleic acids - a class of high-affinity RNA analogs for selective inhibition of specific miRNAs in vivo; behavioural tests (plusmaze, light-dark box) for assessment of anxiety-related behavior; TargetScan to map neuronal miRNA pathways, to identify target mRNAs; cross-linking immunoprecipitation (CLIP).

P6: Brain systems involved in cued and social fear conditioning

Prof. Dr. Andreas Mühlberger / Prof. Dr. Mark Greenlee

Brain systems involved in cued and social fear conditioning in humans

Main target of this part of the project is to characterize the neural processes that underlie social fear conditioning (SFC) in humans and to compare these with responses seen in cued fear conditioning (CFC). A behavioral neuroscience approach including pharmacological manipulation and genetic stratification will be realized to investigate the effects of intranasal OXT on different phases of SFC. Virtual Reality will be used for the ecological valid SFC paradigm and fMRI to assess neural processes of fear conditioning.

P7: Neuropeptides & neuro-glial plasticity in fear conditioning

Prof. Dr. Inga Neumann / Prof. Dr. Andreas Mühlberger

Neurobiological differences between cued and social fear conditioning in mice: impact of neuropeptides and neuro-glial plasticity

Project: We have recently shown that the neuropeptide oxytocin (OXT) and neuropeptide S (NPS) differentially affect the extinction of cued fear and social fear in mice (Toth et al., 2012; Zoicas et al., 2015; Slattery et al., 2015). In this project we aim to study the detailed cellular and molecular mechanisms of actions of OXT and NPS on social and cued fear extinction in selected brain regions such as the amygdala, lateral septum and hypothalamic paraventricular nucleus (PVN). Specifically, we aim to study whether these neuropeptide actions also involve epigenetic alterations of target genes, or effects on glia cells and on neuronal-glial plasticity. The PhD student will further study physiological situations, which are associated with an increased neuropeptide system activity (e.g. lactation, sexual activity) and the effects on cued and / or social fear conditioning and fear extinction.

Methods include: established mouse models of cued and social fear conditioning; in-situ hybridization, mopuse primary cell culture, immunohistochemistry, immunocytochemistry, standard molecular techniques, pharmaco-genetic manipulation of OXT or NPS system activity in vivo (e.g. Hdac1 inhibitors, siRNA, chromatin immunoprecipitation, methylation analysis by bisulfite sequencing, DREADD, receptor antagonists).

P8: TSPO & human stress regulation

PD Dr. CarolinE Nothdurfter / Prof. Dr. Andreas Mühlberger

Functional role of translocator protein (TSPO) in human stress regulation

TSPO is supposed to play an important role in different mitochondrial functions. Dysregulation of such mitochondrial functions is involved in the pathophysiology of several psychiatric disorders, such as depression and anxiety disorders. However, little is known about these TSPO functions in stress, which in turn can contribute to the development of these diseases, and about the specific contribution to processes of fear and/or anxiety. The aim of this project is to investigate the functional role of TSPO in stress regulation by means of a clinical volunteer study, which also includes the evaluation of pharmacological intervention with TSPO ligands. Probands will be exposed to different acute stress paradigms in reality and in virtual reality. During these tests, physiological and self-report measures as well as behavioral responses and TSPO associated parameters in blood will be assessed.

P9: Behavioural relevance of glial OXT receptor signalling

Dr. Benjamin Jurek / Prof. Dr. Christian Wetzel

Oxytocin receptor (OXTR)-coupled intra-glial signalling cascades and their behavioural relevance

Despite the interest in the multiple effects of oxytocin (OXT) in humans and rodents, there is a lack of detailed molecular studies that reveal possible side-effects and identify the exact cellular mechanisms that underlie the behavioural outcomes of OXT. OXT is likely to exert a barrage of molecular effects in neuronal, but also glial cells, via a plethora of signalling cascades that are coupled to the OXT receptor (OXTR), such as the MEK1/2, p38, ERK5, CaMKII, or the transient receptor potential (TRP) ion channels. However, most studies focus on isolated neuronal responses to OXT, ignoring the impact of OXT-induced glial signalling and their behavioural relevance. The aim of this project is to understand the molecular OXTR-coupled mechanisms that underlie the behavioural effects of OXT, in particular its anxiolytic and anti-stress effects. To this end, the PhD student will analyse the intra-glial pathways that signal from the OXTR and alter cellular excitability, morphology, or gene expression in primary glial cell culture and in rats.
To study the OXTR-coupled signalling cascades the student will make use of genetic (CRISPR/cas9 or siRNA) or pharmacological (specific kinase inhibitors) silencing of target genes/proteins, primary glial culture, plasmid transfection of glia cells, FRET, calcium imaging, RT-qPCR, Western Blot, ELISA, IHC, and Chromatin-IP.

P10: Mitochondria & emotional dysfunction

Prof. Dr. Christian Wetzel / PD Dr. caroline Nothdurfter

Involvement of impaired mitochondrial function in emotional dysfunction

Mitochondria are the energy-providing organelles of the cell. In addition to ATP synthesis, they play a critical role in regulation of cellular metabolism, steroid synthesis, Ca2+ homeostasis, proliferation and programmed cell death (apoptosis). It has already been shown that mitochondrial dysfunction leads to the impairment of fundamental physiological processes such as neurogenesis and synaptic transmission, thus contributing to the development of neurological and neuropsychiatric disorders. Mitochondrial function is dependent on a multimeric protein complex consisting of transporters/carriers, ion channel forming proteins and various enzymes (VDAC, TSPO, ANT, Hexokinase, GSK3), spanning the inner and outer mitochondrial membranes. This multimeric complex mediates the exchange of ions and metabolites between the cytosol and the mitochondrial matrix. The function and pathophysiology of this complex as well as its role in emotional dysfunction is in the focus of this project.