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Direct septum-hippocampal cholinergic circuit attenuates seiz
AAV-Gcamp6s was used to monitor the activities of MS cholinergic neurons, hChR2 and Arch viruses were used for optogenetic manipulation, hM3Dq and hM4Di viruses were used for chemogenetic manipulation, AAV-flex-taCasp3 was used to specifically kill the MS cholinergic neurons in vivo.
The viruses used in this article are in the table below
Calcium sensors  AAV-EF1a-DIO-Gcamp6s
Optogenetic  AAV-EF1a-DIO-hChR2-eYFP
 AAV-EF1a-DIO-Arch-EGFP
Chemogenetics  AAV-EF1α-DIO-hM3Dq-mCherry
 AAV-EF1a-DIO-hM4Di-Cherry
Neuron Ablation  AAV-flex-taCasp3-TEVp
CRE Recombinase  AAV-Vgat-Cre
 AAV-PV-Cre
 AAV-SST-Cre a
Control  AAV-EF1a-DIO-mCherry
Pub Date: 2019-11-26, DOI: 10.1016/j.biopsych.2019.11.014 Email: [email protected]
Ying Wang, Yi Wang, Cenglin Xu, Shuang Wang, Na Tan, Cong Chen, Liying Chen, Xiaohua Wu, Fan Fei, Heming Cheng, Wenkai Lin, Yingbei Qi, Bin Chen, Jiao Liang, Junli Zhao, Zhenghao Xu, Yi Guo, Shihong Zhang, Xiaoming Li, Yudong Zhou, Shumin Duan, Zhong Chen
Background: Previous studies indicated the involvement of cholinergic neurons in seizure, however the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated.
Methods: In the present study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of MS-hippocampus circuit in 42 TLE patients, compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo/vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models.
Results: We found that TLE patients with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic neurons) significantly attenuated, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct, but not the indirect MS-hippocampal cholinergic projections, mediated the anti-seizure effect by preferentially targeting hippocampal GABAergic neurons. Further, chemogenetic inhibition of hippocampal somatostatin+ rather than parvalbumin+, subtype of GABAergic neurons reversed the anti-seizure effect of MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin+ neurons. 
Conclusions: These findings underscore the notable anti-seizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving downstream somatostatin effector. This may provide a better understanding of the changes of seizure circuit and the precise spatiotemporal control of epilepsy.

Fig.1 Hippocampal SST+, but not PV+, GABAergic neurons are involved in the anti-seizure MS cholinergic circuit.
To understand the brain regions involved and causal mechanisms underlying the neural circuits of TLE, using optogenetics and chemogenetics, combined with in vivo/vitro electrophysiology and retrograde rabies virus tracing, the researchers demonstrate that the MS-hippocampal cholinergic circuit reduces hippocampal seizures and dissect the complexities of the anti-seizure cholinergic MS-hippocampal circuit in TLE. This study provides a step ahead towards understanding the current network theory of epilepsy.
 
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