Wicker Evan, Hyder Safwan K, Forcelli Patrick A
Department of Pharmacology & Physiology, Georgetown University, Washington DC, USA.
Department of Pharmacology & Physiology, Georgetown University, Washington DC, USA; Interdisciplinary Program in Neuroscience, Georgetown University, Washington DC, USA; Department of Neuroscience, Georgetown University, Washington DC, USA.
Prog Neurobiol. 2022 Jul;214:102286. doi: 10.1016/j.pneurobio.2022.102286. Epub 2022 May 12.
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.
对于颞叶癫痫（TLE）的改进治疗存在巨大的未满足需求；在这方面，破坏癫痫发作起始和传播的特定回路操作很有前景。包括背内侧核（MD）在内的中线丘脑是癫痫活动的关键传播者，但其介导癫痫活动的传入和传出通路尚不清楚。在此，我们在大鼠TLE点燃模型中使用化学遗传学使MD到额叶皮质离散区域的输入和输出投射沉默。从杏仁核到MD的投射的化学遗传学抑制消除了癫痫发作，使用光遗传学抑制也重复了这一效果。从MD到前边缘皮质的投射的化学遗传学抑制同样消除了癫痫发作。相比之下，抑制从MD到其他额叶区域的投射会使行为或脑电图癫痫活动部分减弱（眶额皮质、边缘下皮质）或无减弱（扣带回、岛叶皮质）。这些结果突出了MD到前边缘皮质的投射在杏仁核点燃癫痫发作传播中的特殊重要性。
