Junior Career Research Stipend

 


This 6-months stipend will be provided to support meritorious medical students over the period of their MD thesis with interest particularly in pain research. We can also support master’s students for the period of their  thesis. The students will have the opportunity to work in an international scientific environment providing support for developing their career.

 

How to apply:

The interested candidate has to write a research proposal (maximally 2-pages) and may contact the PI of the project for additional information. The candidate can apply only for 1 project. The application material should include the proposal, CV including grades from key exams (e.g. Abitur and Physikum for MD students). Please send the application material to

Project overview:

Project 1 Acuna: Generation and analysis of a m-opiod receptor polymorphism associated with impaired pain sensitivity and drug tolerance in human neurons in vitro

Project 2 Kuner: Delineation of cellular mechanisms underlying distinct sensory modalities in the cingulate, somatosensory and insular cortices

Project 3 Grinevich: Can anxiolytic neuropeptide oxytocin facilitate fear?

Project 4 Groh/Mease: Deep-learning characterization of behaviors in freely moving mice 

Project 5 Hertle/Bading: In vivo optogenetic modulation of astrocytic PKA signaling

Project 6 Monyer: Establish a behavioral paradigm to test sustained attention in mice 

Project 7 Mauceri: Epigenetic control of structural and functional plasticity in spinal circuits

Project 8 Pham: MR-Imaging of neurovascular coupling of CNS and PNS

 

 

 

Detailed descriptoins:

Generation and analysis of a mu-opiod receptor polymorphism associated with impaired pain sensitivity and drug tolerance in human neurons in vitro 

Dr. Claudio Acuna ()

AG Acuna, Chica and Heinz Schaller Foundation

Institute of Anatomy and Cell Biology

Heidelberg University

______________________________________

We are newly established lab in Heidelberg, interested in the use of stem cell technologies to generate in vitro models of brain disease, ranging from autism to pain. We are looking for an enthusiastic MD or MS student to carry out an exciting project at the interface of stem-cell biology and pain research.

It is widely accepted that genetic polymorphisms may explain, at least in part, individual differences in pain sensitivity and in pain drug tolerance. Despite of its obvious significance, however, the most fundamental cellular mechanisms by which such genetic variants may impact neuronal function and thereby pain sensitivity and drug tolerance are largely unknown. In this project, we will focus on a single-nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G, which is strongly and significantly associated with reduced expression of the OPRM1 gene, hypersensitivity to pain, and an increased consumption of analgesics for clinical pain. Specifically, this project aims:

  1. 1. To develop and validate a genetic model of the A118G polymorphism using CRISPR/Cas9 in human pluripotent stem cells.
  2. 2. To differentiate these genetically-engineered pluripotent stem cells into functional cortical-like human neural networks
  3. 3. To assess the impact of the A118G polymorphism on neuronal structure, synaptic transmission and plasticity, and transcriptional profile of human neural networks using next generation sequencing technologies.

We expect this project will provide crucial insight into the neural and genetic mechanisms impacted by the A118G polymorphism, which may in turn account at least in part for the changes in pain sensitivity and pain drug tolerance, commonly observed in carriers of this genetic variant.

______________________________________

 

Delineation of cellular mechanisms underlying distinct sensory modalities in the cingulate, somatosensory and insular cortices. 

Contact: Prof. Dr. Rohini Kuner

Email: 

______________________________________

This project seeks to address how cellular selectivity for various sensory modalities (e.g. mechanical, heat, cold) is generated in the cortex and how this selectivity is altered in chronic pain conditions. In particular, clinical imaging studies have implicated functional changes in the cingulate, somatosensory and insular cortices in chronic pain patients, however the specificity of cellular activities generating different somatosensory percepts remain unknown. Moreover, it remains unclear if firstly there are distinct activity ensembles in these cortical regions that differentially encode mechanical or thermal processing and secondly, if changes in their activity patterns drive pain chronicity.  

Methods:

To test for specific participation of neurons in the processing of distinct sensory modalities, we will use a dual viral system using c-Fos promoter-based activity mapping to label cellular ensembles in freely-moving, behaving mice. This system utilizes the expression of the tetracycline-controlled transactivator (tTA) under the control of the activity-induced immediate early gene, c-fos, which in turns acts on a tTA regulated element (TRE; minimal promoter) to drive the expression of proteins placed downstream of TRE in a manner sensitive to Doxycycline, a CNS-penetrant tetracycline (Reijmers et al. 2007). Labeling of activated neurons in the cortex is achieved by stereotactic brain injections of two transgenic constructs delivered by adeno-associated viral vectors (rAAV). Mice that have incorporated both elements are raised on food or water that contains doxycycline. Under this condition, neuronal activation which leads to expression of tTA through c-fos-promoter activation will not trigger labeling, because doxycycline blocks activation of the TRE-promoter (Reijmers et al. 2007; Zhang et al. 2015). Taking the mice off doxycycline opens a particular time window to express mCherry or other proteins of interest specifically in cells that are activated in response to that particular stimulus applied within that time window. Mice are placed on doxycycline again to close the window and the cells that are activated by exposing the mice to the second test stimulus of choice can be identified via Fos immunohistochemistry.

This labelling approach allows us to study whether same or distinct cortical cells are activated in conditions of noxious or non-noxious mechanical versus thermal stimuli applied to the hind paws. Following this, we can then study whether or how this delineation is altered in inflamed or neuropathic animals. Finally, the functional relevance of these specific participating cells can be subsequently manipulated in vivo using optogenetic or chemogenetic tools to test their contributions in sensory and emotional affective behavioral phenotypes in acute and chronic pain states.  

Reijmers LG, Perkins BL, Matsuo N, Mayford M (2007) Localization of a stable neural correlate of associative memory. Science 317(5842):1230-1233.

Zhang Z, Ferretti V, Güntan İ, Moro A, Steinberg EA, Ye Z, Zecharia AY, Yu X, Vyssotski AL, Brickley SG, Yustos R, Pillidge ZE, Harding EC, Wisden W, Franks NP (2015) Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists. Nature Neuroscience 18(4):553-561.

______________________________________

Can anxiolytic neuropeptide oxytocin facilitate fear?

Prof. Dr. Valery Grinevich ()

ZI Mannheim

______________________________________

Oxytocin is a neurohormone produced in the hypothalamus of all mammals. Mainly known for its involvement in uterine contraction during labor and milk ejection reflex, we now know that it also acts as a neurotransmitter in the brain. Our group has shown that release of oxytocin in the amygdala reduces fear expression in rats. However controversial results have been found in humans in which oxytocin sometime seems to increase fear.

To investigate the neural basis of this counter intuitive effect, we focus on the paraventricular nucleus of the thalamus, a region strongly innervated by oxytocin fibers and that has been found to be a necessary input to the amygdala to produce fear expression. Thus, we hypothesize that oxytocin will exert opposite effects in this region as compared to inside the amygdala (i.e., increase fear expression), and we will also study other behaviors that are modulated by oxytocin and that could be influenced by its action in the paraventricular thalamus (e.g., pain and social behavior).

To do so, we use viral techniques to selectively target oxytocin neurons with optogenetic, DREADDs and calcium imaging tools. The student will learn to perform surgeries, behavioral testing, optogenetic, pharmacogenetic and behavioral testing in rats, as well as post-mortem analysis of their brain. We are looking for a motivated student who is willing to work in living rats.

Publications:

Knobloch et al. 2012 Evoked Axonal Oxytocin Release in the Central Amygdala Attenuates Fear Response. Neuron doi: 10.1016/j.neuron.2011.11.030.

Eliava et al 2016 A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing. Neuron doi: 10.1016/j.neuron.2016.01.041.

Hasan et al 2019 A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System Neuron doi: 10.1016/j.neuron.2019.04.029

 

______________________________________

 

Deep-learning characterization of behaviors in freely moving mice

Alexander Groh, Rebecca Mease (, )

Physiology, Uni Heidelberg

______________________________________

Recently developed software (DeepLabCut) uses deep-learning approaches to track animal movement. This transformative technology offers the opportunity to relate neural signals and behavior at an unprecedented level of precision. We seek a highly motivated and adventurous Master’s or MD student to establish use of this tool in freely moving mice performing during different behaviors (sensory threshold assessments, nociception assays, learning paradigms), and use the motor output data to characterize behavioral state. The successful applicant will be supported by a six month Junior Career Stipend from SFB 1158. 

Publications:

  • Multiplexed spike coding and adaptation in the thalamus. R.A. Mease, T. Kuner, A.L. Fairhall, and A. Groh. Cell Reports. (2017).

    Corticothalamic spike transfer via the L5B-POm pathway in vivo. R.A. Mease, A. Sumser, B. Sakmann and A. Groh. Cerebral Cortex. (2016).

    Cortical control of adaptation and sensory relay mode in the thalamus. R.A. Mease, P. Krieger and A. Groh. Proceedings of the National Academy of Sciences USA. (2014).

Desired Profile of the Applicant:

Applicant should have above-average quantitative background and interest in neuroscience and behavior. Previous experience in data analysis or programming using MATLAB/Python/R etc. is required. Experience handling high-speed video data is strongly desired. Experience in behavioral assays is desirable but not necessary.

!! Please contact us directly before applying for the Junior Career Stipend. Please include a brief description of your interest in the project, your CV, and your academic transcripts.

______________________________________

 

In vivo optogenetic modulation of astrocytic PKA signaling 

Dr. Anna M. Hagenston Hertle and Prof. Dr. Hilmar Bading

Institute for Neurobiology and Intradisciplinary Center for Neuroscience (IZN)

Im Neuenheimer Feld 366, 1. OG

69120 Heidelberg

______________________________________

cAMP-PKA signaling plays a key role in processes involved in astrocytic plastic responses to synaptic activity, including the regulation of gene expression and glycogen metabolism. In this project, we aim first to establish tools to optogenetically inhibit PKA signaling specifically in spinal cord astrocytes during the acquisition phase of chronic pain. We will then employ this method to examine the importance of astrocytic PKA signaling for acutely-triggered pain-evoked astrocytic gene expression changes, astrocytic glycogen metabolism changes, and the development of nociceptive hypersensitivity. 

Publications:

  • Bas-Orth C, Tan YW, Lau D, Bading H. Synaptic activity drives a genomic program that promotes a neuronal Warburg effect. J Biol Chem 2017; 292(13):5183-5194.

    Hagenston AM, Bading H, Bas-Orth C. Functional consequences of calcium-dependent synapse-to-nucleus communication: Focus on transcription-dependent metabolic plasticity. Cold Spring Harb Perspect Biol 2019; doi: CSHPERSPECT/2019/035287; in press.

    Simonetti M, Hagenston AM, Vardeh D, Freitag HE, Mauceri D, Lu J, Satagopam, VP, Schneider R, Costigan M, Bading H, Kuner R. Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron 2013; 77(1):43-57.

Key Methods:

Spinal cord rAAV injection and fiber implantation surgeries, behavioral analysis of nociceptive hypersensitivity, ribosome affinity purification, gene expression analyses, glycogen assay.

______________________________________

Establish a behavioral paradigm to test sustained attention in mice 

Hannah Monyer

Email:

______________________________________

Based on viral tracing, we discovered a novel type of GABAergic neurons that connect the prefrontal cortex with several brain areas known to be involved in pain perception. These include the anterior cingulate cortex, insula and amygdala. Optogenetic manipulation of long-range projecting GABA neuron axons is associated with altered nociceptive responses. While interesting, it is not clear whether altered attention contributes to the change in pain response, as most of the brain areas belonging to the pain matrix are also involved in attentional processing. While well established in rats, behavioural tests to quantify sustained attention in mice remain to be established. This will be the topic of the research proposed here. The methods to be used include virus injection and brain surgery, optogenetic manipulation and behavioural testing.

Publications:

Melzer S, Michael M, Caputi A, Eliava M, Fuchs EC, Whittington M, Monyer H: Long-range projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science 335 (6075): 1506-1510 (2012).

Caputi A, Melzer S, Michael M, Monyer H: The long and short of GABAergic neurons. Curr. Opin. Neurobiol. 23: 179-186 (2013).

Melzer S, Gil M, Koser DE, Michael M, Huang KW, Monyer H: Distinct corticostriatal GABAergic neurons modulate striatal output neurons and motor activity. Cell Rep. 19:1045-1055 (2017).

______________________________________

Epigenetic control of structural and functional plasticity in spinal circuits

Prof. Dr. Daniela Mauceri

______________________________________

The Department of Neurobiology, at the Interdisciplinary Center for Neurosciences (IZN) –Heidelberg University is looking for a motivated MD or Master Biosciences (Major Neuroscience) student to join the group of Prof. Dr. Daniela Mauceri. Our group investigates the molecular, transcriptional and cellular mechanisms governing neuronal morphology.

You will investigate epigenetic-regulated transcription and neuronal architecture remodeling in models of inflammatory pain, with a focus on histone deacetylation. Your work will include the functional validation of pain-related genes under the control of epigenetic regulation, which we recently identified in a RNAseq experiment. You will also have the chance to perform in vivo experiments in which neurons of the spinal cord dorsal horn of adult mice are being manipulated using genetic tools. Additional experiments will be done with dissociated cultured mouse spinal cord neurons. Overall, the project relies on an integrative approach that combines molecular, genetic, and biochemical methods with in vitro and in vivo imaging techniques and behavioral assays in mice.

Applicants should have a background in molecular, cell biology and/or neuroscience. Candidates with prior experience in animal work (FELASA course), the spinal cord system, stereotactic surgery, behavioral analyses and/or cell culture will have priority. Fluency in English and the ability to work in an international environment is mandatory. Within the frameset of the SFB1158 focused on chronic pain, 6-months stipends are available.

We are looking forward to your application. Please send your CV, transcripts and a short motivation letter. Please contact us for any further questions.

References and links:

https://www.uni-heidelberg.de/izn/researchgroups/mauceri/

Litke, C., Bading, H., and Mauceri, D. (2018) Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D. The Journal of biological chemistry 293, 8196-8207

Oliveira, A. M., Litke, C., Paldy, E., Hagenston, A. M., Lu, J., Kuner, R., Bading, H., and Mauceri, D. (2019) Epigenetic control of hypersensitivity in chronic inflammatory pain by the de novo DNA methyltransferase Dnmt3a2. Molecular pain 15, 1744806919827469

Simonetti, M., Hagenston, A. M., Vardeh, D., Freitag, H. E., Mauceri, D., Lu, J., Satagopam, V. P., Schneider, R., Costigan, M., Bading, H., and Kuner, R. (2013) Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron 77, 43-57

 

MR-Imaging of neurovascular coupling of CNS and PNS

Prof. Dr. Mirko Pham

______________________________________

Chronic pain is a major burden for affected patients with still very limited treatment options. The Peripheral Nervous System (PNS) is an important site of pain generation and processing and is under the increasing focus of pain research and clinical treatment strategies such as electromodulation (Haberberger et all. Frontiers in Cellular Neuroscience 2019). As the major scientific and clinical diagnostic methodological limitation remains the inability to observe, measure and at the same time accurately localize neural activity in the PNS by imaging. Up to now, PNS imaging methods can visualize morphological changes only but not electrophysiological function (Pham et all. Ann Neurol. 2015). Therefore, novel research and clinical non-invasive methods to objectify pain processing in the human setting are highly desirable in clinical settings (Schmelz Pain 2018). To achieve this, functional MR imaging (fMRI), which is already well established in the CNS, needs to be applied in the PNS. The PNS poses unique demands on image data postprocessing and statistical image analysis.

Methods:

This project applies bioinformatic methods for the fully automated 3D segmentation of key target structures of the Central and Peripheral Nervous System and for tracking their position in 3D over time. The applicant’s contribution is an integral part of novel fMRI methods for the observation of neurovascular coupling in-vivo and non-invasively in the human setting. This innovative imaging method will have a significant impact on understanding sensory physiology, pain processing and contribute also to diagnostic improvements in the medical field of clinical neurophysiology. The MRI physics method (i.e. the MRI pulse sequence for data acquisition) and the experimental design on the stimulus side (sensory and pain stimulation paradigm) have been established and validated in human participants. As a result, a significant amount of data could be recorded already and is available at the beginning of the project. The experimental investigators will extend the available data for the applicant early throughout the course of the project, if necessary for the refinement of segmentation performance.

Collaboration Partners:

Martin Schmelz, Experimental Pain Research, Mannheim

Philip Kollmannsberger, Center for Computational and Theoretical Biology, Würzburg

Profile of candidate’s qualification: 

Applicants should have a biological/biomedical background and knowledge in Bioinformatics, image processing and ideally but not necessarily spatiotemporal imaging data analysis. Experience with Linux, the python programming language and its associated scientific computing libraries (numpy, scipy) is required. The research group and the lab meetings are located in Würzburg, local presence in Würzburg is necessary.

Publications:

  1. Haberberger et all. Human Dorsal Root Ganglia. Frontiers in Cellular Neuroscience June 2019:13 1-17
  2. Pham M et all. Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance. Ann Neurol. December 2015:78 939-48.
  3. Schmelz M Quantitative sensory test correlates with neuropathy, not with pain. Pain March 2018:159 409–410.

News

  • Bonn Researchers Identify Key Proteins for the Repair of Nerve Fibers

    Prof. Dr. Frank Bradke, and his colleagues at the German Center for Neurodegenerative Diseases (DZNE) have identified a group of proteins that help to regenerate damaged nerve cells.

    Read more ...  
  • Memory engrams discovered in the hypothalamus

    Read more ...  
  • Congratulations!

    The Heidelberg Pain Consortium goes into the second funding period.

    Read more ...  
  • Valery Grinevich appointed Professor for Neuropeptide research in psychiatry

    Read more ...  
  • The Challenge of Chronic Pain Conference

    Read more ...