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Written by | Jun
Spinal cord injury (SCI) interrupts the connection from the brain and brainstem to the lumbar spinal cord, leaving the patient unable to walk and permanently paralyzed
.
Previous studies have shown that epidural electrical stimulation (EES) can reactivate neurons in the lumbar medulla that have lost normal function, allowing patients to walk
.
The application of EES (EES REHAB) in the process of neurorehabilitation can further promote the recovery of walking ability, allowing independent walking
even without electrical stimulation.
HOWEVER, THE PHYSIOLOGICAL BASIS OF HOW EESREHAB RESHAPES THE LUMBAR CORD TO RESTORE WALKING ABILITY IS UNCLEAR
.
On November 9, 2022, the team of Jocelyne Bloch, Jordan W.
Squai and Grégoire Courtine of the Ecole Polytechnique de Lausanne published an article in the journal Nature The neurons that restore walking after paralysis , showing that EESREHAB promotes neurorehabilitation and restores walking ability in patients with chronic SCI, while identifying subsets
of neurons that mediate recovery of walking ability after paralysis.
The authors first treated nine patients with SCI for five months and found that the patients who were able to travel normally after receiving the treatment, and even four of them who retained some function before the treatment had significantly increased lower limb motor scores after treatment and could walk independently even without electrical stimulation
。 This restoration of walking ability suggests that EESREHAB treatment reshaped spinal cord structure, and the authors hypothesized that this change could be reflected by neuronal activity during walking, so further studies were made using fluorine-18-labeled deoxyglucose positron emission tomography (18FDG-PET).
Surprisingly, EESREHAB treatment reduced the activity of
spinal neurons in the lumbar segment.
To identify subsets of neurons affected by EESREHAB treatment, the authors next conducted preclinical studies
in mice.
Combining virus-mediated neural tracking technology and CLARITY tissue clearance technology, the authors found disruption of corticospinal tract fibers in the brains of mice with midthoracic contusion (SCI modeling), which also led to permanent paralysis in mice
.
Mice treated with EES REHAB also restored their motility, and a combination of tissue clearance and CFOS detection found a significant reduction
in the number of activated neurons in mice treated with EESREHAB.
Next, the authors combined single-cell nuclear RNA sequence (snRNA-seq) technology, spatial transcriptomics, and multiplex RNAscope technology to establish a spatial distribution map of lumbar pulp single cells, with neuronal subsets with specific transcriptional characteristics distributed in specific locations.
Using this atlas can help further identify neurons
of interest in EESREHAB treatment.
Augur Machine Learning can screen out the cell types that are most sensitive to biological disturbances in single-cell data, and the authors used this method to identify the subpopulation of neurons affected by EESREHAB treatment—two types of excitatory lumbar cord interneurons (SCVsx2::Hoxa10) expressing VSx2 or Hoxa10
。 Extending this computational approach to cell types to spatial transcriptome data, the authors developed Magellan and determined that the spinal cord midband responds to walking-related experimental conditions, where SCVsx2::Hoxa10 neurons are
distributed.
So do these neurons have consistent anatomical and functional characteristics with EESREHAB treatment? Anatomically, cross-synaptic tracing techniques show that SCVsx2::Hoxa10 neurons receive large-diameter afferent fibers from dorsal root ganglia-expressing small albumin-expressing neurons and projections from ventral giant cell reticular nuclei (vGi), which are associated
with walking.
In terms of functional characteristics, in vivo electrophysiological recordings determined the rapid response
of SCVsx2::Hoxa10 neurons to these two upstream stimuli.
In addition, EESREHAB treatment will enhance the synaptic connection strength
of these two circuits.
Downstream studies found that SC Vsx2::Hoxa10 neurons only project to the ventral spinal cord to form synaptic connections with neurons, including 52% glutamatergic neurons, 77% GABAergic neurons, 56% cholinergic neurons, and SCI significantly reduces the synaptic connections of SCVsx2::Hoxa10 neurons and GABAergic neurons, EES REHAB The connection returned to normal
after treatment.
If EES REHAB treatment is selectively activity-dependent for SCVsx2::Hoxa10 neurons, these neurons must remain activated during the walk after EESREHAB treatment.
It was found that the transcriptional activity of cFos within SCVsx2::Hoxa10 neurons increased twofold
, despite a decrease in the number of cFos-positive neurons.
Finally, the activation and inhibition of such neurons were respectively performed in mice to verify their adequacy and necessity for EESREHAB treatment to restore walking ability
.
The results showed that EES on paralyzed mice restored their ability to walk, but walking stopped
as soon as SCVsx2::Hoxa10 neurons were inhibited during this process.
Activating SCVsx2::Hoxa10 neurons in chronically paralyzed mice restored their ability to walk even without EES
.
Long-term inhibition of mouse SCVsx2::Hoxa10 neurons disrupts the therapeutic effect
of EESREHAB.
Is this role of SCVsx2::Hoxa10 neurons limited to EESREHAB therapy? The authors found that inactivation of such neurons in mice with mild SCI resulted in the inability to recover their ability to walk, indicating that SCVsx2::Hoxa10 neurons are necessary for recovery after SCI
.
In summary, the authors demonstrated the critical role of SCVsx2::Hoxa10 neurons in regaining the ability to walk after paralysis from PET studies in clinical humans to preclinical mouse studies, and established a method to combine Augur and Magellan to resolve cell types that respond preferentially to biological disturbances and their spatial distribution characteristics.
Helps identify key neurons
that mediate complex behavior.
Original link: https://doi.
org/10.
1038/s41586-022-05385-7
Platemaker: Eleven
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