SUMMARY The objective of this proposal is to investigate how temporal lobe (TL) seizures with different onset patterns propagate through the basal ganglia (BG) and to evaluate the implication of this circuit in the control of TL seizures. TL epilepsy is the most common form of focal epilepsy and a third of the patients do not respond to drug therapy. Resective surgery and deep brain stimulation can be effective, however, only some patients are eligible and very few become seizure free. There is then a clear need for better and more individualized epilepsy treatments based on a rigorous understanding of the networks and brain structures implicated in TL seizures. Studies on TL seizures have mainly focused on the interconnected structures of the limbic circuit, but there is also strong evidence suggesting that the BG could be a key contributor to the propagation and control of TL seizures. Several studies using neuropharmacological inhibition, electrophysiological recordings, metabolic alterations, and advanced imaging have suggested an inhibitory role of the BG in TL epilepsy. However, findings have been inconsistent, and the exact mechanisms and BG pathways implicated in TL seizures are still under debate. These heterogeneous results may be explained by seizure onset patterns. Recent studies focusing on the seizure pattern have proposed that the ictal activity originating from the same ictogenic area might propagate through different pathways depending on the seizure pattern, which could potentially explain the heterogeneity of previous findings. To better understand the implication of the BG and its dopaminergic system, we propose to use a non-human primate model, as it captures characteristics of the BG specific to primates, including humans. Our preliminary data support the hypothesis that seizures with a low amplitude, fast activity pattern will propagate primarily through the putamen-substantia nigra (Put-SNr) pathway, while seizures with a high amplitude, slow oscillation onset pattern are more likely to involve the nucleus accumbens-pallidum (NAcc-GPi) pathway. To further investigate the role of these pathways, we propose to investigate how TL seizures with different onset patterns propagate through the basal ganglia as well as the implication of these circuits in the control of TL seizures. In Aim 1, we will record the unit and local field potential activity of the NAcc-GPi and the Put-SNr pathway during TL seizures induced with intracerebral injection of penicillin. Based on the recordings performed in Aim 1, we will identify the area of the NAcc and Put that is most affected by TL seizures. In Aim 2, we will target these areas to evaluate the effect of dopaminergic modulation on TL seizures. Finally, in Aim 3, we will simultaneously record the activity of the SNr and GPi during TL seizures, identify the area with the strongest response, and evaluate the effect of pharmacological inhibition of the BG output structures on TL seizure frequ...