Supplemental Digital Content is Available in the Text.Deep learning-based analysis of large-scale bioimages of the dorsal root ganglion after nerve injury reveals satellite glial cell plasticity but no loss of sensory neurons.
At any moment in time, cells coordinate and balance their calcium ion (Ca2+) fluxes. The term ‘Ca2+ homeostasis’ suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca2+ imaging shows that resting Ca2+ levels are maintained by surprisingly dynamic Ca2+ fluxes between the ER Ca2+ store, the cytosol, and the extracellular space. The data show that the ER Ca2+ leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca2+ dynamics. Based on simplistic Ca2+ toolkit models, we discuss how the ER Ca2+ leak could contribute to evolutionarily conserved Ca2+ phenomena such as Ca2+ entry, ER Ca2+ release, and Ca2+ oscillations.
Background
Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response.
Results
Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (
p
< 0.001) and heat hypersensitivity (
p
< 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI.
Conclusions
Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.
Objective: Plexus injury results in lifelong suffering of flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts, such as cell replacement for restoring dorsal root ganglion (DRG) function, set high expectations. However, it is completely unclear which DRG cell types are affected by plexus injury. Methods: We investigated the cellular composition of human DRG in a clinically characterized cohort of patients with plexus injury. Avulsed DRG of 13 patients were collected during reconstructive nerve surgery. Then, we analyzed the cellular composition of the DRG with a human-adapted objective deep learning-based analysis of large-scale microscopy images. Results: Surprisingly, in about half of the patients, the injury-affected DRG no longer contained DRG cells. The complete entity of neurons, satellite glial cells, and microglia was lost and replaced by mesodermal/connective tissue. In the other half of patients, the cellular entity of the DRG was well preserved. We found no loss of neurons, no gliosis, and macrophages close to single sensory neuron/satellite glial cell entities. Patients with "neuronal preservation" had less pain than patients with "neuronal loss". Interpretation: The findings classify plexus injury patients in two categories: type I (neuronal preservation) and type II (neuronal loss). We call for early, post-accidental interventions to protect the entire DRG and improved MRI diagnostics to detect "neuronal loss". Regenerative medicine to restore DRG function will need at least two translational directions: reafferentation of existing DRG units for type I injuries; or replacement of the entire DRG structure for type II patients.
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