Toll-Like Receptor 9-Mediated Neuronal Innate Immune Reaction Is Associated with Initiating a Pro-Regenerative State in Neurons of the Dorsal Root Ganglia Non-Associated with Sciatic Nerve Lesion

One of the changes brought about by Wallerian degeneration distal to nerve injury is disintegration of axonal mitochondria and consequent leakage of mitochondrial DNA (mtDNA)—the natural ligand for the toll-like receptor 9 (TLR9). RT-PCR and immunohistochemical or Western blot analyses were used to detect TLR9 mRNA and protein respectively in the lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) ipsilateral and contralateral to a sterile unilateral sciatic nerve compression or transection. The unilateral sciatic nerve lesions led to bilateral increases in levels of both TLR9 mRNA and protein not only in the lumbar but also in the remote cervical DRG compared with naive or sham-operated controls. This upregulation of TLR9 was linked to activation of the Nuclear Factor kappa B (NFκB) and nuclear translocation of the Signal Transducer and Activator of Transcription 3 (STAT3), implying innate neuronal immune reaction and a pro-regenerative state in uninjured primary sensory neurons of the cervical DRG. The relationship of TLR9 to the induction of a pro-regenerative state in the cervical DRG neurons was confirmed by the shorter lengths of regenerated axons distal to ulnar nerve crush following a previous sciatic nerve lesion and intrathecal chloroquine injection compared with control rats. The results suggest that a systemic innate immune reaction not only triggers the regenerative state of axotomized DRG neurons but also induces a pro-regenerative state further along the neural axis after unilateral nerve injury.

Cortical representation of pain by stable dedicated neurons and dynamic ensembles

The perception of pain arises from distributed brain activity triggered by noxious stimuli. However, which patterns of activity make nociception distinct from other salient sensory experiences is still unknown. Using in vivo chronic two-photon calcium imaging in slightly anaesthetized mice, we identified a nociception-specific representation in the anterior cingulate cortex (ACC), that is attained by a core of neurons that code for a generalized concept of the pain experience. The overall ensemble activity allowed for an efficient discrimination of the sensory space, despite a drift in single-neuron sensory tuning over time. Following sciatic nerve lesion, the representation of nociceptive stimuli was impaired as a consequence of innocuous stimuli expanded into the nociception-specific ensemble, leading to a dysfunctional discrimination of sensory events in the ACC. Thus, the hallmark of chronic pain at the cortical neuronal network level is an impairment of pattern separation and classification identifying a circuit mechanism for altered pain processing in the brain.

Case 3

Sciatic nerve injury is a relatively uncommon lower extremity mononeuropathy. The various etiologies of sciatic neuropathies are highlighted in this case. The clinical manifestations and diagnosis include distinguishing foot drop due to sciatic neuropathy from peroneal (fibular) neuropathy across the fibular neck, L5 radiculopathy, and lumbosacral plexopathy. The electrodiagnostic features of sciatic nerve lesion are separated from those of foot drop due to other peripheral nerve causes. In contrast to sciatic nerve injury, the piriformis syndrome is mostly a painful syndrome with no or minimal sensory or motor deficits. The clinical manifestations of piriformis syndrome and controversies surrounding this syndrome completes the discussion in this case.

Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy

The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca2+ handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca2+ handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/CaV 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and CaV 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca2+ release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca2+ in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca2+-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca2+ release from the sarcoplasmic reticulum may contribute to pathology in CIM.