Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury

Abstract

Cerebrocortical injuries, such as stroke, are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, yet mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. Here we report in rats the first evidence that the thalamus – a structure remote from but connected to the injured cortex – is required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex undergo changes in HCN channel expression and become hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy demonstrates that reducing their activity in real-time is sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, since it spares cortical function between seizures, in contrast to existing treatments such as surgical lesioning or drugs.

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

“…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.…”

Deep Brain Stimulation for the Treatment of Epilepsy: Circuits, Targets, and Trials

“…Several early studies of optogenetics in vitro and in animal models of epilepsy have shown promising results. The earliest application of optogenetics to epilepsy was by Tønnesen et al [33], who demonstrated that halorhodopsin-an inhibitory chloride pump-was capable of suppressing epileptiform activity in hippocampal organotypic slice cultures. More recently, 3 groups have demonstrated that inhibition of particular targets can interrupt seizures in vivo in rat models of epilepsy.…”

“…Thalamic relays are also thought to mediate the benefits from lesions and electrical stimulation of the cerebellum for epilepsy, but this circuit and its influence is less clearly defined [30][31][32]. More precise work identifying and manipulating neural signaling within the thalamocortical network is currently being performed [33].…”

Potentiel thérapeutique de la neuromodulation optogénétique

“…Une large fraction des neurones thalamocorticaux (excitateurs) interconnectés avec la région corticale lésée étaient ensuite photosensibilisés par expression de la NpHR à l'aide d'un vecteur viral. Le protocole d'illumination de ces neurones en boucle fermée s'est révélé capable de stopper les crises d'épilepsie moins d'une seconde après leur apparition, et ce jusqu'à un an après implantation du système chez les animaux [51]. Dans une deuxième étude, un modèle d'épilepsie du lobe temporal était obtenu chez la souris par lésion pharmacologique focale de l'hippocampe à l'acide kaïnique.…”