Study identifies neurons in the lateral hypothalamus that can be therapeutically targeted to improve walking abilities following spinal cord injury (SCI).
Study
Recently, neuroscientists Gregoire Courtine, Jocelyne Blochm, and their colleagues optimized immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs (iDISCO+) to achieve whole-brain labeling of cFos, a marker of neuronal activity-induced transcription. High-resolution CLARITY-optimized light-sheet microscopy (COLM) facilitated the detection of the cFos signal.
Neuroscientists mapped the brain activity of mice with SCI during a recovery phase. This strategy harmonized whole-brain quantifications of transcriptionally active and spinal cord-projecting neurons during spontaneous recovery of walking after incomplete SCI.
An atlas comprising space-time brain-wide transcriptionally active and spinal cord-projecting neurons involved in recovery in walking after incomplete SCI was constructed. To map neuronal projections, a G protein-deficient rabies virus encoding fluorescent protein markers was infused into the lumbar region of the ipsilesional spinal cord below the injury. The atlas was validated using uninjured mouse brains with cFosON cells present in regions of the brain involved in the walking process.
The current study hypothesized that interrogating this atlas could help detect the brain regions and neurons that contribute to the spontaneous recovery of walking after incomplete SCI. Therefore, these regions could be therapeutically targeted to augment the recovery.
Results
Twelve uninjured and injured mouse brains were studied to capture the process of spontaneous recovery from SCI. Interrogation of the atlas led to the unexpected identification of a group of neurons in the lateral hypothalamus (LH) referred to as glutamatergic neurons (LHVglut2), which play an important role in spontaneous recovery in walking after SCI. Previous studies have highlighted LH function as being associated with emotions, arousal, and motivation.
Neuronal populations located in the LH express either the excitatory neurotransmitter Slc17a6 (Vglut2) or the inhibitory neurotransmitter Slc32a1 (Vgat). The current study tested whether LHVglut2 or LHVgat neurons contributed to the spontaneous recovery of walking in mice after a lateral hemisection SCI.
Photostimulation enabled the activation of LHVglut2 neurons, which improved residual gait deficits that persisted even after the spontaneous recovery of walking. Higher photostimulation frequencies proportionally increased the relative facilitation of walking, as demonstrated by powerful jumps in injured mice following exposure to high frequencies of photostimulation.
Comparatively, an optogenetic inactivation of LHVglut2 neurons disrupted the recovery in walking after SCI.
Improvements in walking following the activation of LHVglut2 neurons in mice with contusion SCI were attributed to indirect neuronal relays. More specifically, LHVglut2 neurons establish synaptic contacts with the neuron of the ventral gigantocellular nucleus (vGi) that retained residual projections below the contusion SCI. The vGiVglut2 neurons receive a significant amount of direct synaptic projections from the motor cortex and LH, which could actively relay information from LHVglut2.
Deep brain stimulation therapy of the LH (DBSLH) immediately and durably improved walking in mice and rats with SCI by reorganizing the residual lumbar-terminating projections from brainstem neurons.
Thereafter, a pilot clinical study was conducted to assess DBSLH in two human patients with chronic incomplete SCI who relied on assistive devices. In both patients, DBSLH improved lower body movement and walking performance during 10-meter and six-minute walking tests and did not lead to any serious adverse events.
Conclusion
Targeting the LH with deep brain stimulation has the potential to immediately improve the walking ability of individuals with SCI. In the future, large-scale trials must be conducted to further assess the safety and efficacy of DBSLH and determine how this treatment may lead to changes in psychological status, body weight, hormonal profiles, and autonomic functions.
Source:
https://www.news-medical.net/news/20241202/Hypothalamic-deep-brain-stimulation-restores-walking-after-spinal-cord-injury.aspx