Ischemic stroke is the most common clinical type of stroke, a cerebrovascular disease caused by stenosis or obstruction of cerebral arteries supplying blood to the brain. Typically, ischemic stroke events are accompanied by cerebral necrosis associated ischemia and hypoxia, and result in sudden onset and focal neurological deficits, as well as significant motor dysfunction (Dundar et al., 2019). Accordingly, it is essential to increase current understanding of ischemic stroke to improve its prevention and post-stroke dysfunction treatments.

A theoretical model of mutual inhibition between the cerebral hemispheres, known as interhemispheric inhibition (IHI), is typical in healthy individuals, in which the activation of one hemisphere generally reduces the activity of the other,(Petrus et al., 2019) ensuring that only one hemisphere plays a dominant role in performing a function. It is thought that IHI underlies the rapid inhibition of the contralateral cortex during movement initiation, in order to suppress a mirrored movement that may be deleterious to the performance of task (Boddington and Reynolds, 2017). Neuroimaging findings demonstrated that, during unilateral hand movements, the activity of the contralateral primary motor cortex (cM1) increased while the activity of the ipsilateral M1 (iM1) decreased (Meyer et al., 1995; Meyer et al., 1998). This asymmetrical activity pattern might be associated with the inhibitory control of transcallosal cM1-to-iM1 (Genç et al., 2015). And in vivo experiment found that focal electrical stimulation of the cM1 decreased potentials of iM1 pyramidal neurons, inducing the IHI in the motor cortical circuitry (Barry et al., 2014).

In stroke patients with mixed cortical-subcortical lesions, the inhibition of brain activity on the infarcted side is exacerbated by iM1 neuron losses and cM1 overexcitation that leads to progressive motor impairment,(Guo et al., 2016) which was associated with the impaired initiation and poor performance of voluntary movement. Specifically, accumulating evidence supported that in the acute phase of stroke, the excitability in the iM1 was reduced(Neumann-Haefelin and Witte, 2000) and the cM1 becomes hyper-excitable (Buchkremer-Ratzmann and Witte, 1997). In addition, the normalization of contralateral hemisphere excitability appears to track with improvements in recovery, which means appropriate inhibition of contralateral excitation relieves excessive inhibition of the ipsilateral hemisphere (Mansoori et al., 2014; Jablonka et al., 2010). Therefore, up-regulating the excitability of the ipsilateral hemisphere or deactivating the hyper-inhibition from contralateral to ipsilateral may be an effective strategy for stroke rehabilitation.

Previous studies showed that optogenetic technology can be used to activate glutamate (Glu) neurons in the affected hemisphere to promote motor function recovery in ischemic mice (Cheng et al., 2014). Interestingly, from a rehabilitation perspective, the inhibition of the healthy hemisphere by repeated transcranial magnetic stimulation resulted in improved hand coordination and dexterity following stroke-induced impairment(Tretriluxana et al., 2013); while the continuous injection of γ-aminobutyric acid (GABA) agonists into the healthy hemisphere of stroke rats led to functional inactivation of the healthy hemisphere and improved contralateral motor function (Hu et al., 2019). These observations suggest that rehabilitation therapy based on the IHI theory can effectively promote the excitation/inhibition (E/I) balance of the sensorimotor cortex in both hemispheres and improve motor function following stroke episodes. However, another theory suggests that activity in the contralateral hemisphere is necessary to contribute to functional recovery and this pattern of reorganization is referred to as the vicariation model, in which activity in residual networks substitutes for those functions lost by damaged areas (Di Pino et al., 2014). A novel theoretical model, known as the bimodal balance-recovery model, predicts that corticospinal tract (CST) integrity in the affected hemisphere influences the patterns of brain recovery after stroke. At present, several lines of evidence support that IHI model may predominate in the presence of high CST reserve while limited CST integrity favors the vicariation model (Di Pino et al., 2014; Lin et al., 2020a).

Glu and GABA are major neurotransmitters regulating E/I balance of both cerebral hemispheres. Several studies showed that GABA-mediated changes in the neuroplasticity of the affected hemisphere were closely related to the recovery of motor function following stroke (Kim et al., 2014; Kokinovic and Medini, 2018). Moreover, nerve tracing technology revealed parvalbumin (PV) neurons present in the cM1 and connecting the iiM1 via the corpus callosum (iM1-CC-cM1) constitute an important part of the cortical circuit function (Rock et al., 2018). For example, layer 5 PV neurons of the iM1-CC-cM1 possess anatomical and molecular mechanisms that are able to decrease excitability and modulate interhemispheric inhibition. In turn, the inhibition of PV neurons in the primary sensorimotor cortex of mice by optogenetics can enhance motor function (Sachidhanandam et al., 2016).

Here, we aimed to explore whether optogenetic stimulation iM1-CC-cM1 PV neurons can regulate the E/I balance of both cerebral hemispheres in rats with ischemic stroke and improve motor function. In addition, we selected rats with milder stroke injury and expect our observations can help further explaining IHI theory and bimodal balance-recovery model, underlying the motor function rehabilitation following stroke events.