Paralysis is a major consequence of spinal cord injury (SCI). After cervical SCI, respiratory deficits can result through interruption of descending presynaptic inputs to respiratory motor neurons in the spinal cord. Expression of channelrhodopsin-2 (ChR2) and photostimulation in neurons affects neuronal excitability and produces action potentials without any kind of presynaptic inputs. We hypothesized that after transducing spinal neurons in and around the phrenic motor pool to express ChR2, photostimulation would restore respiratory motor function in cervical SCI adult animals. Here we show that light activation of ChR2-expressing animals was sufficient to bring about recovery of respiratory diaphragmatic motor activity. Furthermore, robust rhythmic activity persisted long after photostimulation had ceased. This recovery was accomplished through a form of respiratory plasticity and spinal adaptation which is NMDA receptor dependent. These data suggest a novel, minimally invasive therapeutic avenue to exercise denervated circuitry and/or restore motor function after SCI.
Figure: (click to enlarge) Phrenic motor neurons in the respiratory circuit show light-induced plasticity. A: anatomical diagram of the respiratory circuit. Dashed blue and red lines represent known ipsilateral and contralateral connections between the ventral respiratory group neurons, whereas the solid gray line represents potential cross talk between the phrenic motor neurons. Lesion region is highlighted in addition to the neurons targeted for Channelrhodopsin-2 (ChR2) expression (green circles). B: cellular model of how light-gated ion influx leads to classic potentiation. Photostimulation of ChR2 drives rapid cation influx, which in turn removes N-methyl-D-aspartate receptor (NMDAR) block and allows sparse glutamate signaling to activate NMDARs. NMDAR activation might then mediate classic potentiation mechanisms by promoting AMPA receptor insertion.
Monday, March 30, 2009
Restore damaged brain circuits with light...
I generally don't delve into cellular and molecular stuff in this blog (even though my previous lab research was at this level), but sometimes a trick comes along that is so neat that I want to mention it. Alilain et al. manage to restore breathing in rodents with acute spinal cord injury by infecting neurons that constitute the phrenic motor nucleus with a sindbis virus that expresses an algal light-gated ion channel that activates nerve cells by driving cation influx when illuminated with blue light, and also expresses green fluorescent protein (to visualize the nerve cells that have taken up the virus). The authors were able to both visualize and photostimulate the target cells that directly innervate the diaphragm muscles. Here is their abstract, following by a summary graphic from the review by Arenkiel and Peca.