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 (Nawroth/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/Lechner): 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/Bradke): 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/Bading): 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.
The proposed project is geared toward a deeper understanding about the neuronal populations involved in processing painful stimuli in the dorsal spinal cord. In particular, we are interested in identifying and characterizing molecular changes that develop in these spinal neurons as a consequence of pathological forms of pain. Subsequently, we aim to elucidate how the identified changes influence the manifestation (and resolution) of pain chronicity using mouse model systems.
A08 (Mauceri/Ruiz de Almodóvar): 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.
A09N (Agarwal/Kirchhoff/Simonetti): Calcium signalling in glial cells and their role in antidepressant-mediated analgesia in 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.
A10N (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 early hallmark symptoms starting in childhood. Over time, patients develop thermal hyposensitivity and skin denervation. 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.
B01 (Kuner R.): Cellular basis and mechanisms underlying the role of prefrontal cortex in nociception and chronic pain
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/Ditzen/Grinevich): Social influence on acute and chronic pain: Role of oxytocin dependent mechanisms with a focus on insular cortical circuitry (human-rodent tandem project)
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. We will dissect the contribution of OT in pain anticipation and perception as well as in psychological and homeostatic processes underlying chronic pain (low back pain and dysmenorrhea) in humans. Furthermore, we will decipher how does socially-triggered OT release alleviate pain, by assessing social influences on pain perception both in the laboratory and in everyday life using ecologically momentary assessment. 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.
B03 (Nees/Flor): The role of learning, stress and underlying brain circuits involving prefrontal-limbic interactions in the development of chronic back pain
Previous research has led to the assumption that chronic pain may be related to emotional learning, however, little is known about the associated changes in brain structure and function that might predict persistent pain. This project seeks to determine brain circuits related to learning mechanisms in pain such as aversive and appetitive, operant and respondent learning as well as the role of stress to predict the transition from acute to chronic back pain and to identify risk and resilience factors.
B04 (Spanagel/Tesarz/Tost/Wieland): Translational studies in pain chronicity: role of corticothalamostriatal pathway in stress-sensitisation and comorbidity development (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 (Monyer/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.
The primary sensorimotor cortices undergo reorganisation after limb amputation and the extent of this change is related to phantom pain. However, we still do not know which factors precede and which follow the pain. This project seeks to determine the development of phantom pain in a longitudinal fashion and will examine how central and peripheral changes as well as psychological factors develop over time. To address these questions we will employ psychological methods, magnetic resonance imaging, transcranial magnetic stimulation and neurofeedback.
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): Regulatory 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.
B10 (Groh/Mease): Cellular mechanisms of nociception and nociceptive modulation in lateral and medial thalamocortical circuits of mice
The relationship between thalamic sensory processing, cortical feedback and pain perception is not clear, in particular between pathophysiological changes in thalamic activity patterns and the chronicity of pain. We will address thalamic pain processing and its dependency to cortical feedback circuits using electrophysiology, cell-type specific modulation of neuronal activity, and behavioural assays in awake, behaving mice. Understanding pathophysiological changes in thalamic function and regulation that are associated with the development of chronic pain will help us to establish a causal relationship between thalamic operational states and pain perception and will be important for the identification of potential targets for pain treatment.
S01 (Treede/Tappe-Theodor): Standardisation and development of new pain-related models and methods in rodents and humans (human-rodent tandem project).
This project aims to ensure homogeneity of model systems and methods within this SFB. We plan to promote forward and back translation between rodent and human systems. In particular, we aim to develop novel rodent systems for phantom and low back pain, standardize rodent behavioural tests and pain models and develop novel tests for spontaneous pain in rodents and study the impact of anxiety, depression and stress in rodents as well as in humans. Additionally, we plan to validate behavioural and electrophysiological assessment of spinal sensitization and the contribution of the descending pathways in patients.
S02N (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.