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Suppression of seizure-like activity by optogenetic stimulation in reticular thalamus

Suppression of seizure-like activity by optogenetic stimulation in reticular thalamus. Student: Hsueh Tai-En 薛岱恩 Department of Psychology, NTU Advisors: Dr. Shyu Bai -Chuang 徐百川 老師 Chang Wei-Jen 張瑋仁 , Chang Wei-Pang 張維邦 IBMS, Academia Sinica. Importance of seizure.

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Suppression of seizure-like activity by optogenetic stimulation in reticular thalamus

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  1. Suppression of seizure-like activity by optogenetic stimulation in reticular thalamus Student:Hsueh Tai-En 薛岱恩 Department of Psychology, NTU Advisors: Dr. ShyuBai-Chuang 徐百川老師 Chang Wei-Jen 張瑋仁, ChangWei-Pang 張維邦 IBMS, Academia Sinica

  2. Importance of seizure • Seizure is abnormal excessive or synchronous neural activity in the brain, producing a physical convulsion, minor physical signs, thought disturbances, or a combination of symptoms (Fisher et al., 2005). • Seizure affects 1 % of population, and 30 % are suffered from drug-resistant epilepsy. Clinical application uses non-invasive approaches or deep brain stimulation for the treatment of drug-resistant seizures. • Thalamus plays an important role on modulating the brain cortical seizure activity (Chang et al., 2011;Polack 2009; Ates et al., 2005; Blumenfeld, 2002). Wei-Pang Chang(2011). Epilepsia, 52(12)

  3. Thalamocortical mechanism of seizure Reticular Thalamus Nucleus GABA Red: inhibitory GABA-containing neuron Green: excitatory glutamate-containing neuron Jon-Paul(2003). TRENDS in Pharmacological Sciences, Vol.24, No.10

  4. Relation between Seizure and reticular thalamus • A gain in GABAergic inhibitory strength in thalamus reduces the length and power of absence seizure (Schofield et al., 2009). • The net effect of increased GABAergic synaptic transmission within NRT reduces synchronized burst-firing of thalamic relay neurons. GABAA receptor-mediated inhibition of NRT outflow decrease the likelihood of absence seizures ( Hosford et al., 1997). Seizure GABAergic interneuron GABA

  5. The problem • Pharmacology • Electrical stimulation  Using light stimulation

  6. Optogenetic • Optogenetic technology combines genetic targeting of specific neurons or proteins with optical technology for imaging or control of the targets within intact, living neural circuits (Deisseroth et al., 2006). Channelrhodopsins Aravanis. J. Neural Eng,4. 2007 Pastrana. Nature Methods 8. 2011

  7. Hypothesis: Activation of nRT will modulate cortical seizure • Aim: 1. Use Pv-ChR2 mice as model, and verify the expression of channelrhodopsin. 2. Induce cortical seizure-like activity by injecting pentylenetetrazol(PTZ) (GABAA antagonist). 3. Use light to specifically activate nRT neuron output to investigate the effect of nRT activation during seizure.

  8. Material & Method • Pv-chr2 transgenic mice • Michigan probe - In the reticular thalamic nucleus, nearly all neurons are parvalbumin-immunoreactive (Csillik et al., 2005). 16 electrode laser

  9. pv-chr2 transgenic mice Injected 60mg/kg PTZ Experiment setup CC Tungsten electrode corpus callosum (CC) stimulate RT S1 Optic fiber-optic electrode Reticular thalamus stimulate Michigan probe Recording: Primary somatosensory cortex

  10. Procedure Light stimulate + Induce seizure Record 30 mins Induce seizure 6 times Turn on light CC stimulation Light stimulation

  11. The expression of channelrhodopsin cerebellum Hippocampus Cortex Olfactory bulb Reticular thalamus 2 mm 100 mm Anti EYFP Anti PV merge

  12. Light stimulationmodulates RT and thalamus firing rate Stimulation reticular thalamus(RT) Stimulation on thalamus(Th)

  13. Light stimulation in RT changes the firing pattern in cortex Th Cx Reticular thalamus (RT) Primary somatosensory cortex(S1) P 3.5mm L 2.0mm P 1.82 mm L 2.5mm

  14. Corpus callosum(CC) stimulation induces seizure Superficial layer Control Corpus callosum stimulate Deeper layer 0.5 mV 300 ms

  15. Antiepleptic drug Ethoxusimideblocks CC induced seizure Control CC stimulation 2 mV 1 sec

  16. Light stimulation suppressing CC induced seizure light stimulation 5Hz pulse duration 100ms duration 20s 2 mV No light stim CC stim 10HZ 500uA 4s 1 sec

  17. Different light stimulation condition in suppressing seizure * Most effective light stimulation pattern in suppressing seizure is 100Hz 30s light pulse

  18. Light stimulation in RT is necessary for suppressing seizure >60% 30%~60% <30% Cortex Hippocampus Corpus callosum Reticular thalamus Lateral 2.04mm

  19. Summary • Light stimulation can activate reticular thalamus and thalamus by activating channelrhodopsin-2 on them. • High frequency light is more effective in suppressing seizure. • Location of optic fiber is crucial, those in the reticular thalamus(RT) and thalamus are more effective in suppressing seizure.

  20. Acknowledgment • Dr. Shyu Bai-Chuang • N327 members: • Chang Wei-Jen • Chang Wei-Pang • NPAS

  21. Thanks for your attention!!

  22. Mechanism of seizure suppression • 130 Hz is in the range that can evoke Long-Term Potentiation (LTP) (Bliss and Collingridge, 1993;Malenka and Nicoll, 1999). It changes synapse plasticity and network activity. • High synaptic activity, as is induced by HFS , would then lead to downscaling of the neuronal excitability with an increase in seizure threshold as a result. • Depolarization block occlude the kindling stimulus, which may explain why HFS has more potential than LFS. Wyckhuys(2010). Epilepsy Research. 88, 239—246

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