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One or more keywords matched the following properties of hloride dysregulation and neuropathic pain: Linking molecular mechanisms with altered pain processing via identification of cellular and circuit level changes

abstract Neuropathic pain results from abnormal sensory processing caused by damage to the nervous system. It is notoriously hard to treat. This difficulty reflects poor understanding of how molecular changes impact cell and circuit function. Nonlinear cell and circuit properties control how sensory input is processed. These nonlinearities must be taken into account to explain how quantitative molecular changes confer qualitative changes in perception, and to design better molecular interventions to alleviate neuropathic pain. The goal of this project is to elucidate the cellular and circuit basis for spinal pain processing and to explain how pathological disruptions at these intermediate levels contribute to neuropathic pain. We will focus on a well-characterized molecular mechanism, namely chloride dysregulation (CD) caused by downregulation of the K-Cl cotransporter KCC2. In animal studies, injury-induced reduction of KCC2 and the consequent impairment of synaptic inhibition are necessary and sufficient to explain neuropathic pain. We will decipher how CD affects nonlinear processes at the cell and circuit level, and, in turn, how altered nonlinearities impact signal processing algorithms regulating perception. Aim 1 – To determine how CD impacts spinal neuron function. Working in vitro from the bottom-up, we will determine which spinal cell types experience CD and how their spontaneous and evoked spiking is altered. Aim 2 – To determine how CD impacts spinal circuit function. Working in vivo from the top-down, we will determine how CD-induced changes in circuit function affect sensory processing algorithms. We will also determine how specific cell types contribute to those algorithms and how those contributions are pathologically altered by CD. Aim 3 – To link molecular, cellular and circuit level changes to explain how chloride dysregulation impacts spinal pain processing. Based on experimental data from Aims 1 and 2, we will build a robust computer model that reproduces normal spinal pain processing and its pathological disruption. By deciphering how CD disrupts pain processing via effects on cellular and circuit nonlinearities, we will begin to address the broader issue of how other molecular changes, alone or together, also affect pain processing. Critically, although experimental manipulations can target single molecules, nerve injury affects many molecules simultaneously. We hypothesize that the necessity and sufficiency of any given molecular change to cause neuropathic pain depends on other co-occurring changes (whose pattern may differ from one patient to the next). The sheer number of combinations preclude experimental testing of interactions; instead, we will use a computational approach, predicting which molecular changes interact based on the cell and circuit nonlinearities they mutually influence. Mutually affected nonlinearities are the origin of meta-effects, i.e. the influence of one factor over the effects of another factor. If a given molecular change is necessary to produce neuropathic pain only in certain conditions because of meta-effects, therapeutically reversing that change will alleviate pain only in certain patients. Being able to predict meta-effects through computer simulations that utilize diagnostic patient data would transform clinical practice. Our project will develop the computational tools and systems-based approach to enable this – to capitalize on rather than be thwarted by nonlinear meta-effects.

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  • Synaptic
  • Inhibition