synaptic plasticity; cortex; pain; long-term potentiation; long-term depression; dendritic excitability; neuropathic pain; synapse; dendrite; channelopathy
Santello Mirko, Nevian Thomas (2015), Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation, in Neuron
, 86, 233-246.
Groen Martine R., Paulsen Ole, Pérez-Garci Enrique, Nevian Thomas, Wortel Joke, Dekker Marinus P., Mansvelder Huibert D., Van Ooyen Arjen, Meredith Rhiannon M. (2014), Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons, in Journal of Neurophysiology
, 112(2), 287-299.
Pérez-Garci Enrique, Larkum Matthew E., Nevian Thomas (2013), Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o-β-subunit interaction with Cav1 channels, in Journal of Physiology
, 591(7), 1599-1612.
Blom Sigrid Marie, Pfister Jean Pascal, Santello Mirko, Senn Walter M., Nevian Thomas (2013), Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex, in Journal of Neuroscience
, 34(17), 5754-5764.
Sieber Andrea Rahel, Min Rogier, Nevian Thomas (2013), Non-hebbian long-term potentiation of inhibitory synapses in the thalamus, in Journal of Neuroscience
, 33(40), 15675-15685.
Min Rogier, Nevian Thomas (2012), Astrocyte signaling controls spike-timing dependent depression at neocortical synapses, in Nature Neuroscience
, 15(5), 746-753.
Min Rogier, Santello Mirko, Nevian Thomas (2012), The computational power of astrocyte mediated synaptic plasticity., in Frontiers in Computational Neuroscience
, 6, 93.
Dendrites are an important feature of the nervous system. Most of a neuron’s membrane is part of the dendritic arborisation. Dendrites are the structure, which receive most of the synaptic contacts and they are the primary site for neuronal signal processing. Dendrites integrate signals to transform synaptic input to action potential output. In this respect dendritic excitability, i.e. the properties and distribution of ionic conductances along the dendrite are an important property. Dendrites and synaptic contacts are the primary site for learning and memory formation. Here, synaptic plasticity is a ubiquitous phenomenon, which is thought to be the cellular correlate for learning and memory in the brain. Its purpose in normal, physiological functioning of the nervous system is the establishment and refinement of neural networks in development, the formation of memory traces and information storage. In recent years, some types of pathological functioning of the brain attributable to synaptic transmission, like addiction or certain forms of epilepsy have been described as “a disease of synaptic plasticity”. In these cases the complex biochemical machinery that ensures the potential for the adaptation of the nervous system to a changing environment has been altered to a pathological condition that might be locked in a maladapted state that generates inappropriate synaptic signals. In this context the nociceptive system which is involved in signalling potentially harmful and damaging interventions to the organism is of particular interest. Noxious stimuli result in the activation of high threshold nociceptors that excite neurons in the spinal cord that transmit their information via the thalamus to cortical areas for perception. Strong activation of the nociceptive sensory system can result in sensitization of synaptic transmission on different levels along the nociceptive pathway. Much work has focused on peripheral receptor sensitization and central sensitization in the spinal cord, which is a form of long-term potentiation of synaptic transmission. So far, only a few studies have addressed the synaptic and cellular mechanisms of cortical pain processing and the role of synaptic plasticity in the expression of neuropathic chronic pain. Noxious stimuli result in the activation of a number of cortical areas, including the somatosensory cortices and in particular the anterior cingulated cortex and the insula cortex. Noxious stimuli result in increased activity in these areas, which might result in changes in synaptic strength, changes in cellular excitability or modifications in the neuronal connectivity pattern. These alterations might be the basis for persistent pain sensation long after cessation of the acute painful experience. Chronic pain is a common clinical syndrome. In a recent study it was estimated that about 19% of all Europeans above the age of 18 suffer from chronic pain syndromes. Therefore it is important to understand the basic mechanisms that control the changes in synaptic efficacy and neuronal excitability in brain areas related to pain processing and furthermore their potential changes and influence in the pathological case.This proposal aims to study the fundamental molecular mechanisms which govern the modification of synaptic efficacy at the level of single synaptic contacts, the properties of dendrites and the changes in dendritic excitability in the “normal”, physiological case and compare them to the pathological case in the chronic pain condition. These experiments will be performed in the anterior cingulate cortex, a region important for pain perception. The anterior cingulate cortex is so far relatively unexplored in this respect and in contrast to the five-layered somatosensory cortex, anterior cingulate cortex has three to four layers. Therefore, the properties of dendrites and of synaptic plasticity might be different. The synaptic biochemical machinery that converts an electrical activity pattern into a change in synaptic efficacy and the basis and properties of dendritic excitability will be elucidated under normal physiological and presumed pathological conditions in the anterior cingulate cortex in an animal model of neuropathic pain induced by constriction of the sciatic nerve. This model is a well established animal model for chronic pain. Then these changes in the chronic pain condition will be related to the plasticity mechanisms found in cingulate cortex of healthy animals. Thus a mechanistic link between the plasticity mechanisms present under normal conditions to the development of sustained neuropathic pain will be investigated. In order to identify cells involved in pain processing in the specific cortical areas, transgenic mice that express a marker for elevated neuronal activity, like enhanced green fluorescent protein (EGFP)-tagged Arc or cfos, which are immediate early genes that get activated by activity, will be used. Cells that are repetitively active will be labelled with GFP and can then easily be detected by fluorescence microscopy. We have preliminary results using EGFP-cfos expressing neurons as markers for cellular activity in the sciatic nerve constriction model showing the feasibility of this approach. In this way the “chronic-pain-matrix” will be mapped and direct comparisons of cellular and synaptic properties from cells that were involved in the development of chronic pain to “normal” control cells will be possible. The experiments that are aimed to understand the molecular mechanisms that induce and modify synaptic plasticity and dendritic excitability in cortical pain networks can then specifically be conducted on identified populations of cells. Particularly, the focus of this study will be on elucidating the biochemical signalling cascades that are triggered by spike-timing dependent plasticity and plasticity induced by local dendritic spikes, which might be activity patterns prevalent during physiological or pathological learning respectively. Furthermore, changes in synaptic efficacy might be accompanied by corresponding changes in dendritic and cellular excitability that can significantly change the input-output relationship of the so modified neurons. The mechanisms of changes in excitability will be investigated in relation to the changes in synaptic strength. In this respect, the question if neuropathic pain results in the modification of neuronal excitability will be studied on the cellular level. Finally, increased cortical activity evoked by neuropathic pain resulting in the long-term modification of pain perception and the development of persistent pain could be the result of structural alterations in the connectivity pattern of the cortical circuitry involved in pain processing. The basis of activity-dependent rewiring of cortical microcircuits in this respect will be investigated. This rewiring might occur in the chronic pain condition and therefore it will be tested if structural changes, for example an increased number of connections or increased synaptic strength, can be detected on the cellular level in this case.This study will make a fundamental contribution to our understanding of synaptic plasticity and dendritic excitability in learning and memory. Additionally, it will make important contributions to the understanding of neuropathic pain and its relation to synaptic plasticity and dendritic excitability on the cellular level thereby establishing a connection between basic physiological and pathophysiological mechanisms.