Causal contributions of structural neuronal plasticity in the cingulate cortex to chronic pain

 

The cingulate cortex has been suggested to function as a major hub of circuits underlying chronic pain. Recent volume-based morphometry magnetic resonance imaging (VBM-MRI) studies in humans identified a reversible decrease of the anterior cingulate cortex (ACC) gray matter volume triggered by chronic pain states. Equivalent observations were also made in mice. Furthermore, multiple layers of evidence obtained from studies of cellular mechanisms support a key role of the cingulate cortex in the expression of chronic pain states.

Dorsal root ganglia section showing putative C-LTMRs in green and myelinated neurons in red

For example, changes in long-term potentiation (LTP), plasticity-associated mediators or loss of functional connections between inhibitory and excitatory cortical neurons revealed potential cellular mechanisms of chronic neuropathic pain states. Alternative to functional plasticity such as LTP, activity-dependent adaptive changes of neuronal communication and network function can arise from structural plasticity. This more recent concept of activity-dependent plasticity puts forward that the dynamic formation and destruction of spines, possibly also of presynaptic terminals and entire dendritic segments, produces long-lasting changes in brain function. We hypothesise that structural plasticity is a strong candidate cellular mechanism for the expression of chronic pain in the cingulate cortex and that thalamocortical projections involving the cingulate cortex undergo critical structural remodeling in chronic pain states. In this project we suggest to examine structural plasticity of thalamocortical axonal and dendritic compartments in the cingulate cortex associated with chronic pain states; furthermore, we aim to transcend correlational analysis and address causal functional contributions.  

 

Dorsal root ganglia section showing putative C-LTMRs in green and myelinated neurons in red
Maximum-intensity projection of a neuron situated in layer 2/3 of mid-cingulate cortex. Two-photon imaging was done in an anaesthetised mouse through a cortical window. The same neuron was imaged over a time period of 6 months. Note the detailed appearance of spines. Structures shown in red originate from a neighbouring neuron.

We designed a longitudinal approach combining a neuropathic pain model (SNI) with repeated assessments of mechanical withdrawal responses and two-photon in vivo imaging of structural plasticity through a chronically implanted brain window. Viral expression of membrane-bound green fluorescent protein (mGFP) at high density (>75%) or low density (1-5 per imaging volume) allows us to follow the structure of identified ACC neurons on a global as well as local scale. On the global scale, we will attempt parallel VBM-MRI to correlate grey matter volume decrease with changes on the cellular level.

Dorsal root ganglia section showing putative C-LTMRs in green and myelinated neurons in red
Changes in spine density in response to spared nerve injury. Maximum intensity projections of the same stretch of dendrite imaged at different time points.

Using KeimaRed expressed in a thalamic projection nucleus, thalamocortical axons and boutons can be visualized in parallel to dendritic structure. This longitudinal approach will allow us to correlate structural plasticity with chronic neuropathic pain states. In a separate set of experiments, causality can be derived by interfering with molecular mechanisms of structural plasticity just prior to SNI. This manipulation should prevent structural plasticity and the development of a chronic pain state, if both are causally related.

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