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1.
Epilepsia ; 64(2): 524-535, 2023 02.
Article in English | MEDLINE | ID: mdl-36448878

ABSTRACT

OBJECTIVE: Decades of studies have indicated that activation of the deep and intermediate layers of the superior colliculus can suppress seizures in a wide range of experimental models of epilepsy. However, prior studies have not examined efficacy against spontaneous limbic seizures. The present study aimed to address this gap through chronic optogenetic activation of the superior colliculus in the pilocarpine model of temporal lobe epilepsy. METHODS: Sprague Dawley rats underwent pilocarpine-induced status epilepticus and were maintained until the onset of spontaneous seizures. Virus coding for channelrhodopsin-2 was injected into the deep and intermediate layers of the superior colliculus, and animals were implanted with head-mounted light-emitting diodes at the same site. Rats were stimulated with either 5- or 100-Hz light delivery. Seizure number, seizure duration, 24-h seizure burden, and behavioral seizure severity were monitored. RESULTS: Both 5- and 100-Hz optogenetic stimulation of the deep and intermediate layers of the superior colliculus reduced daily seizure number and total seizure burden in all animals in the active vector group. Stimulation did not affect either seizure duration or behavioral seizure severity. Stimulation was without effect in opsin-negative control animals. SIGNIFICANCE: Activation of the deep and intermediate layers of the superior colliculus reduces both the number of seizures and total daily seizure burden in the pilocarpine model of temporal lobe epilepsy. These novel data demonstrating an effect against chronic experimental seizures complement a long history of studies documenting the antiseizure efficacy of superior colliculus activation in a range of acute seizure models.


Subject(s)
Epilepsy, Temporal Lobe , Rats , Animals , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/therapy , Pilocarpine/toxicity , Superior Colliculi , Optogenetics , Rats, Sprague-Dawley , Seizures/chemically induced , Seizures/therapy , Disease Models, Animal
2.
Prog Neurobiol ; 214: 102286, 2022 07.
Article in English | MEDLINE | ID: mdl-35537572

ABSTRACT

There is a large unmet need for improved treatment for temporal lobe epilepsy (TLE); circuit-specific manipulation that disrupts the initiation and propagation of seizures is promising in this regard. The midline thalamus, including the mediodorsal nucleus (MD) is a critical distributor of seizure activity, but its afferent and efferent pathways that mediate seizure activity are unknown. Here, we used chemogenetics to silence input and output projections of the MD to discrete regions of the frontal cortex in the kindling model of TLE in rats. Chemogenetic inhibition of the projection from the amygdala to the MD abolished seizures, an effect that was replicated using optogenetic inhibition. Chemogenetic inhibition of projections from the MD to the prelimbic cortex likewise abolished seizures. By contrast, inhibition of projections from the MD to other frontal regions produced partial (orbitofrontal cortex, infralimbic cortex) or no (cingulate, insular cortex) attenuation of behavioral or electrographic seizure activity. These results highlight the particular importance of projections from MD to prelimbic cortex in the propagation of amygdala-kindled seizures.


Subject(s)
Kindling, Neurologic , Thalamus , Amygdala/physiology , Animals , Frontal Lobe/physiology , Humans , Kindling, Neurologic/physiology , Rats , Seizures , Thalamus/physiology
3.
Epilepsy Curr ; 20(3): 157-159, 2020.
Article in English | MEDLINE | ID: mdl-32550837
4.
Proc Natl Acad Sci U S A ; 116(52): 27084-27094, 2019 Dec 26.
Article in English | MEDLINE | ID: mdl-31843937

ABSTRACT

Three decades of studies have shown that inhibition of the substantia nigra pars reticulata (SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN. Inhibition of cell bodies in SNpr suppressed generalized seizures evoked by pentylenetetrazole (PTZ), partial seizures evoked from the forebrain, absence seizures evoked by gamma-butyrolactone (GBL), and audiogenic seizures in genetically epilepsy-prone rats. Strikingly, these effects were fully recapitulated by silencing nigrotectal projections. By contrast, silencing nigrotegmental terminals reduced only absence seizures and exacerbated seizures evoked by PTZ. These data underscore the broad-spectrum anticonvulsant efficacy of this circuit, and demonstrate that specific efferent projection pathways differentially control different seizure types.

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