Suppression of seizure like activity by optogenetic stimulation in reticular thalamus
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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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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. ShyuBai-Chuang 徐百川老師

Chang Wei-Jen 張瑋仁, ChangWei-Pang 張維邦

IBMS, Academia Sinica


Importance of seizure

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)


Thalamocortical mechanism of seizure

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


Relation between seizure and reticular thalamus

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


The problem

The problem

  • Pharmacology

  • Electrical stimulation

     Using light stimulation


Optogenetic

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


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

  • 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.


Material method

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


Pv chr2 transgenic mice injected 60mg kg ptz

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


Procedure

Procedure

Light stimulate

+

Induce seizure

Record 30 mins

Induce seizure

6 times

Turn on light

CC stimulation

Light stimulation


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

The expression of channelrhodopsin

cerebellum

Hippocampus

Cortex

Olfactory bulb

Reticular thalamus

2 mm

100 mm

Anti EYFP

Anti PV

merge


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

Light stimulationmodulates RT and thalamus firing rate

Stimulation reticular thalamus(RT)

Stimulation on thalamus(Th)


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

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


Corpus callosum cc stimulation induces seizure

Corpus callosum(CC) stimulation induces seizure

Superficial layer

Control

Corpus callosum stimulate

Deeper layer

0.5 mV

300 ms


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

Antiepleptic drug Ethoxusimideblocks CC induced seizure

Control

CC stimulation

2 mV

1 sec


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

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


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

Different light stimulation condition in suppressing seizure

*

Most effective light stimulation pattern in

suppressing seizure is 100Hz 30s light pulse


Suppression of seizure like activity by optogenetic stimulation in reticular thalamus

Light stimulation in RT is necessary for suppressing seizure

>60%

30%~60%

<30%

Cortex

Hippocampus

Corpus callosum

Reticular thalamus

Lateral 2.04mm


Summary

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.


Acknowledgment

Acknowledgment

  • Dr. Shyu Bai-Chuang

  • N327 members:

    • Chang Wei-Jen

    • Chang Wei-Pang

  • NPAS


Thanks for your attention

Thanks for your attention!!


Mechanism of seizure suppression

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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