Project Overview

A01 (Lechner/Schmelz): Silent nociceptors in mice and human (human-rodent tandem project)

This project will focus on mechano-insensitive nociceptors, which become sensitized during inflammation. We will utilize optogenetics, cell ablation and DREADD technology in order to study the role of these afferents in pain signalling with electrophysiological recording techniques and behavioural assays. In corresponding human experiments characteristics of silent nociceptors and their sensitization by inflammatory mediators will be studied using microneurography and psychophysics to allow for bidirectional translation.

A03 (Jende/Bendszus:): Longitudinal analysis of structural and functional changes in peripheral circuits determining the clinical symptoms of painful diabetic neuropathy

Diabetic polyneuropathy comprises a wide spectrum of painful, but also non-painful symptoms related to structural and functional changes of neural circuits within the peripheral and central neuronal system. Therefore a combined human-mouse approach will be used to describe and understand subtypes of diabetic neuropathy, with the long term goal to pave the way for specific novel therapies.

A04 (Carr/Oehler): Interactions between nociceptive and non-nociceptive circuits: role of GABAergic control.

Our perception of pain can be modulated by simultaneous activation of other sensory modalities such as smell, touch and temperature. To examine how diverse sensory modalities can impact on pain signalling and behaviour we will explore nociceptive pathways in the trigeminal system. Transgenic and viral tracing techniques will be used to determine anatomical sites of cross-talk with non-nociceptive (e.g. olfactory) signalling pathways. Using optogenetic stimuli, the modulatory effect of olfactory signals on nociceptive processing will be quantified with neuronal recordings and behavioural tests. If we understand the cross-modal pathways in trigeminal nociception, we are in a position to look for treatment.

A06 (Weidner/Puttagunta): Functional and structural plasticity following spinal cord injury: contributions to chronic central neuropathic pain (human-rodent tandem project)

In the proposed studies, we plan to examine structural changes underlying chronic neuropathic pain in spinal cord injury patients and in mouse models of spinal cord injury. Rodent models will take advantage of transgenic animals to label, silence or ablate specific neuronal subpopulations. The influence of sensorimotor deprivation versus activation in promoting or reversing the development of pain and its influence on spinal and supraspinal structural plasticity will be examined in parallel in rodents and humans using histology, and electrophysiology and MRI, respectively.

A07 (Siemens): Activity-regulated gene programs leading to short-term and long-term metabolic plasticity in the spinal cord: role in acute and pathological forms of pain.

Building on our previous findings elucidating central and peripheral mechanisms of phantom limb pain (PLP) as well as modulating factors, we are taking a next step forward. Employing a combination of virtual reality-based phantom movements and brain stimulation techniques, we aim to explore the degree to which we can influence PLP. By introducing varying degrees of peripheral changes and manipulating associated brain circuits, our study seeks to shed light on the potential therapeutic approaches for individuals suffering from PLP.

A08 (Mauceri/Ruiz de Almodóvar/Tappe-Theodor): Pain-associated epigenetic alterations and spinal sensitization: role of the neurovascular unit

Chronic pain is a pathological manifestation of neuronal plasticity in nociceptive pathways. Behavioural changes in chronic pain require gene transcription and are accompanied by structural alterations of synapses. We demonstrated that nuclear calcium governs a transcription program controlling the numbers of dendritic spines in spinal cord neurons. Nuclear calcium tunes transcription also via the modulation of several epigenetic mechanisms. We will study the functional link between pathological pain, epigenetic phenomena, gene expression, and structural remodelling of spinal cord neurons.

A09(Agarwal/Kirchhoff/Simonetti):Glial adrenergic receptor as targets for the treatment of neuropathic pain

We will study the cellular and molecular mechanisms by which activation of adrenergic signalling in glial cells can lead to analgesia in neuropathic pain, as well as the differential responses of astrocytes, microglia and satellite glia in the brain, spinal cord and DRG in a mouse model of neuropathic pain.

A10 (Pham/Sommer/Üçeyler): Mechanisms of globotriaosylceramide induced dorsal root ganglion pathology and pain in Fabry disease (human-rodent tandem project)

Fabry disease (FD) is an X-linked lysosomal storage disorder with triggerable, episodic, and acral burning pain as one of its major early symptoms. Typically, patients lose thermal sensitivity and skin innervation. The pathophysiology of the cellular and neural circuits underlying pain in FD is unknown, and pain-related non-invasive surrogate markers for objective evaluation, patient stratification, and follow-up are not available. We apply a translational approach to understand pain mechanisms linking the peripheral and central nervous system in FD linking human and murine in vivo and in vitro models.

B01 (Kuner R.): Exploiting prefrontal, somatosensory and motor cortex circuitry for pain relief

Imaging studies in humans implicate the medial prefrontal cortex (mPFC), including the prelimbic and infralimbic cortices (PrL/IL) in pain. However, functional studies are missing. This project aims to address the functional roles of circuits involving the PrL/IL and their bilateral connections with the insular cortex in mice using optogenetics, DREADDs, behavioural assays and in vivo electrophysiological recordings in mouse models of acute and chronic pain. These experiments promise insights on structure-function properties of cortico-cortical circuits and will help reveal how specificity for pain is generated.

B02 (Herpertz/Grinevich): Effects of intranasal oxytocin on the extinction of fear memories in patients and rodent models with chronic pain

The neuropeptide oxytocin (OT) is known to act as an endogenous anaesthetic. This tandem project intends to obtain a comprehensive picture of the role of the central OT system in the modulation of acute and chronic pain in rodents and humans by identifying the neuronal networks involved in OT-ergic pain modulation. OT has been shown to modulate pain experience, pain anticipation, and pain memory, and emerging evidence supports a mechanistic understanding of OT to regulate the salience of not only social but also non-social cues particularly in the context of fear, stress, and pain with overlapping brain circuits involved in pain and in fear. Fear extinction may be of particular relevance for specific forms of pain-related fear, such as fear of movement in chronic low back pain (cLBP). Thus, modulating pain-related fear may be a fundamental target for OT in the treatment of chronic pain, such as cLBP. Altogether, the ultimate goal is to provide the anatomical and functional basis for potential use of OT in the treatment of patients afflicted with chronic pain.

B04 (Spanagel/Tesarz/Tost/Wieland):Towards a mechanism-specific intervention of thalamo-limbic pain processing (human-rodent tandem project)

It is suggested that the reward circuitry, especially the nucleus accumbens and its glutamatergic input is critical involved in the formation of an aversive affective pain memory. Therefore the key questions we wish to answer in our proposal are: (i) Are different glutamate receptors within the nucleus accumbens critical for the formation and persistence of the negative affective component of pain in mice? (ii) Which structural changes and alterations in functional connectivity occur in the mouse reward system during pain chronification? Only, if we understand the molecular, structural and functional changes induced by chronic pain within the reward circuitry we will be able to deliver adequate treatments to our chronic pain patients.

B06 (Ploner/Kuner R): Modulation of pain by mouse forebrain local and long-distance GABAergic connections: cellular mechanisms and oscillatory rhythms

GABAergic interneurons play a key role in controlling network activity in many forebrain regions. In this study, we will investigate the contribution of local and long-range GABAergic neurons in defined brain circuits that underlie nociception and chronic pain. We will employ mouse genetics to uncouple intra-areal and optogenetics to disrupt inter-areal GABAergic connectivity and will study the effect at the network and behavioural level.

B07 (Flor/Andoh): Neural circuits involved in phantom limb pain

Building on our previous findings elucidating central and peripheral mechanisms of phantom limb pain (PLP) as well as modulating factors, we are taking a next step forward. Employing a combination of virtual reality-based phantom movements and brain stimulation techniques, we aim to explore the degree to which we can influence PLP. By introducing varying degrees of peripheral changes and manipulating associated brain circuits, our study seeks to shed light on the potential therapeutic approaches for individuals suffering from PLP.

B08 (Kuner T./Gangadharan): Multiscale analysis of structural plasticity in cortical circuits

This project aims at investigating if experience-dependent changes in the dendritic morphology of neurons in the cingulate cortex and axonal projections from the thalamus may underlie the development of chronic pain states. To achieve this, we use chronic two-photon in vivo imaging of fluorescently labelled neurons in mice to follow morphological changes caused by neuropathic pain. Parallel behavioural testing will allow us to relate the pain phenotype to dendritic and axonal structural plasticity.

B09 (Meyer-Lindenberg/Treede): Modulation of brain circuits underlying bidirectional interactions between chronic pain and depression

Project B09 investigates the interaction of depression and pain. It aims at understanding the mechanisms by which depression promotes the development of chronic pain syndromes. The techniques encompass a comprehensive assessment of somatosensory perception in patients with major depression and healthy control subjects, including pain, experimentally-induced pain plasticity and central pain control. The sensory assessments will be combined with magnetic resonance imaging (MRI) techniques to elucidate the functional and structural neural basis that favours chronic pain development in depressed patients.

B11N(Ditzen/Bilek): Social modulation of chronic pelvic pain: Neural inter-individual covariation and partner interaction

The perception of pain and the individual burden of chronic pain are modulated by social influences. In healthy individuals, social support or affectionate interaction can reduce acute pain perception and negative affect. Similarly, empathy for pain and neural covariation have been observed in both partners of healthy dyads during painful stimulation in one of the partners. Such measures of between-brain coupling during social contact relate to the state of mental disorders and recovery.

S02 (Schrenk-Siemens/Acuna Goycolea): Human pluripotent cell-derived neurons as a tool to study central and peripheral nociceptive mechanisms.

This service project represents a key human-cell based interface for members of the CRC to test mechanistic hypothesis and corroborate key molecular findings derived from work in rodents, as well as to test potential therapeutic approaches to treat pain. Along these lines, we expect to develop and standardise differentiation protocols to generate neuronal and non-neuronal pain-relevant cells with high efficiency, and to share them with teams studying cellular pain mechanisms in peripheral neurons.

S03N(Reininghaus/Ahmadi/Andoh):Multimodal intervention platform

Interventions for chronic pain have shown promises in relieving chronic pain symptoms but suffer from large interindividual variability in effectiveness. We aim to provide a multimodal intervention platform in order to facilitate, harmonize, optimize, and validate novel interventions for SFB1158 projects, including digital interventions based on ecological momentary assessment (EMA) as well as invasive and non-invasive neurostimulation methods.

Z02N-INF(Schwarz/Rupp/Weidner/Solinski):Central data, project and analytics infrastructure

To address the requirements for integrative, cross-project data analysis of converging, pain-related mechanisms during the 3rd funding period (FP), and to ensure the sustainable (re-)use of CRC1158 data after project completion, a new infrastructure project Z02N-INF will be created. Z02N-INF builds on the data infrastructure established in the first two FPs, and will particularly focus on enabling the harmonised, crossproject analysis of sensitive patient data in conjunction with neuroimaging and omics data. For