Because sites of seizure origin may be unknown or multifocal, identifying targets from which activation can suppress seizures originating in diverse networks is essential. We evaluated the ability of optogenetic activation of the deep/intermediate layers of the superior colliculus (DLSC) to fill this role. Optogenetic activation of DLSC suppressed behavioral and electrographic seizures in the pentylenetetrazole (forebrain+brainstem seizures) and Area Tempestas (forebrain/complex partial seizures) models; this effect was specific to activation of DLSC, and not neighboring structures. DLSC activation likewise attenuated seizures evoked by gamma butyrolactone (thalamocortical/absence seizures), or acoustic stimulation of genetically epilepsy prone rates (brainstem seizures). Anticonvulsant effects were seen with stimulation frequencies as low as 5 Hz. Unlike previous applications of optogenetics for the control of seizures, activation of DLSC exerted broad-spectrum anticonvulsant actions, attenuating seizures originating in diverse and distal brain networks. These data indicate that DLSC is a promising target for optogenetic control of epilepsy.

Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.

Temporal lobe epilepsy is the most common form of medically-intractable epilepsy. While seizures in TLE originate in structures such as hippocampus, amygdala, and temporal cortex, they propagate through a crucial relay: the midline/intralaminar thalamus. Prior studies have shown that pharmacological inhibition of midline thalamus attenuates limbic seizures. Here, we examined a recently developed technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), as a means of chemogenetic silencing to attenuate limbic seizures. Adult, male rats were electrically kindled from the amygdala, and injected with virus coding for inhibitory (hM4Di) DREADDs into the midline/intralaminar thalamus. When treated with the otherwise inert ligand Clozapine-N-Oxide (CNO) at doses of 2.5, 5, and 10 mg/kg, electrographic and behavioral seizure manifestations were suppressed in comparison to vehicle. At higher doses, we found complete blockade of seizure activity in a subset of subjects. CNO displayed a sharp time-response profile, with significant seizure attenuation seen 20-30 mins post injection, in comparison to 10 and 40 mins post injection. Seizures in animals injected with a control vector (i.e., no DREADD) were unaffected by CNO administration. These data underscore the crucial role of the midline/intralaminar thalamus in the propagation of seizures, specifically in the amygdala kindling model, and provide validation of chemogenetic silencing of limbic seizures.

Three decades of studies have shown that inhibition of thesubstantia 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.

Reward contingencies are dynamic: outcomes that were valued at one point may subsequently lose value. Action selection in the face of dynamic reward associations requires several cognitive processes: registering a change in value of the primary reinforcer, adjusting the value of secondary reinforcers to reflect the new value of the primary reinforcer, and guiding action selection to optimal choices. Flexible responding has been evaluated extensively using reinforcer devaluation tasks. Performance on this task relies upon amygdala, Areas 11 and 13 of orbitofrontal cortex (OFC), and mediodorsal thalamus (MD). Differential contributions of amygdala and Areas 11 and 13 of OFC to specific sub-processes have been established, but the role of MD in these sub-processes is unknown. Pharmacological inactivation of the macaque MD during specific phases of this task revealed that MD is required for reward valuation and action selection. This profile is unique, differing from both amygdala and subregions of the OFC.