Optogenetic neuronal stimulation promotes functional recovery after stroke

Abstract

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery. stroke recovery | channelrhodopsin

Selective Manipulation of Neural Circuits

“…For Parkinson's disease [191,192], the goal has been to modulate the basal ganglia circuits in a way that is achieved with deep brain stimulation but with better spatial and temporal control. For stroke [193], excitatory optogenetics has been used to strengthen the function of intact circuits so that they can restore lost motor function. After spinal cord injury [194,195], optical control of spinal neurons distal to the lesion could establish control of circuits that have been disconnected from brain control.…”

Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery

“…In stroke patients with good recovery, there is often a transient bilateral activation that occurs in both cortical hemispheres while moving the affected limb, suggesting the involvement of contralesional cortical activation in stroke recovery [23][24][25]. Data from our laboratory and that of others have shown that increasing the excitability of the ipsilesional motor cortex (iM1) after stroke is beneficial for recovery [5,23,26,27]. However, it is less clear whether activation of other areas such as the contralesional cortex is beneficial or maladaptive, or not involved [28].…”

“…This cell type specificity allows manipulation of specific circuits and thus more targeted manipulations, which should help pinpoint the circuits and molecular mechanisms that underlie diseases. Optogenetic approaches have been used in rodents to probe neural circuits for several neurological/neurodegenerative diseases, including Parkinson's disease [78,79], epilepsy [80,81], and stroke [26,82]. In the next sections we will first introduce optogenetics and its developments, and then review the current understanding of remapping and recovery after stroke from recent studies using peripheral and optogenetic stimulation, as well as the use of optogenetic stimulation to enhance post-stroke recovery.…”

“…Thus, direct stimulations in the lesion area or peri-infarct area may have a negative effect on recovery. In our optogenetic studies, we target healthy areas that project to the lesion area, which demonstrated a beneficial effect on recovery [26]. Given the approximate laser power for stimulation, the frequency, duration, and intervals of stimulations should be determined empirically depending on the brain region and cell type of interest.…”

“…While these studies yielded important insights on activation patterns and circuit remapping after stroke, it is unclear whether some of these activated regions/circuits are beneficial or maladaptive for recovery. To interrogate circuits involved in stroke recovery, our group used optogenetics to manipulate directly specific cell types and neural circuits after stroke and investigate the effects on stroke recovery [26]. One of the first brain regions we focused on was the ipsilesional primary mortex cortex (iM1).…”