iScience—Columbia University Peng Yueqing's team revealed that sensory input regulates abnormal EEG in mice with absence epilepsy through the thalamic cortex pathway

Absence epilepsy is a generalized seizure that is common in many neurodevelopmental disorders, and the hallmark EEG signal of absence seizure is spike discharge spike-wave discharge，SWD）
。 Many studies believe that the cortex-thalamic-cortical circuit is the most important source of SWD [1-3], along with the thalamic reticular nucleus GABAergic neurons, excitatory thalamic cortex cells, and neocortical vertebral neurons may form a circuit that maintains oscillatory patterns in the thalamic cortex in absence epilepsy [4-6].

Therefore, the two brain regions of the thalamus and cortex are essential
for the study of human absence epilepsy.
In recent years, many studies have described the pathway mechanism characteristics of SWD, but most of them are limited by in vitro experiments or computer simulations, and the study of the neural signals that trigger SWD is still very scarce [7, 8].

。 Therefore, it is a very meaningful neurobiological problem
to further understand the neural signals that trigger absence seizures through in vivo recording and neural regulation.

On November 3, 2022, Columbia University School of Medicine Teng Span and Zhen Fenghua (co-first author), Peng Yueqing ( Corresponding author) et al.
published a study entitled "Sensory regulation of absence seizures in a mouse model of Gnb1 encephalopathy" in iScience It was found that sensory input can regulate SWD by activating the thalamic cortical pathway.

In this study, we aim to explore the neural signals that trigger SWD in mice with absence epilepsy Gnb1 mutation, and to record and analyze the role
of thalamic activity in SWD.
The Gnb1 gene encodes subunit 1 β G protein
.
First, to determine the sleep/wake mode in which Gnb1 mice were at the time of SWD, the authors used EEG/EMG synchronization to record EEG/ EMG activity, and it was found that most SWD occurred frequently during wakefulness rather than REM and NREM sleep non-REM sleep), and the incidence of NREM sleep increased
after SWD.
At the same time, the quantitative analysis of EMG signal showed that absence seizures were accompanied by a decrease in autonomic activity.
Moreover, the longer the duration of SWD and the shorter the interval between SWD, the more obvious
the symptoms of termination of motor behavior during SWD.
In addition, Peng's team found that the same EEG/EMG recordings were made in Stxbp1 and Gria4 mutant mice with absence epileptic phenotypes, SWD It also occurs in the waking phase and promotes the occurrence of NREM sleep later
.
Results from all three epilepsy models indicate a strong regulation
of brain state for absence seizures in mice.

Since SWD mostly occurs in the awake phase, and based on past studies of sensory input from WAG/Rij rats, the authors speculate that sensory stimuli received by mice from peripheral to the brain during waking can be regulated Occurrence
of SWD.
To test this hypothesis, the team effectively stimulated Gnb1-mutant mice by light air puffs and quantified the effect
of this stimulation on the pre-, middle, and post-SWD stages.
The results showed that blowing stimulation had a large
effect on SWD.
Further analysis showed that the stimulus significantly increased the number and duration of SWD in the awake stage.
The incidence of SWD decreases at the beginning of stimulation and gradually increases
during subsequent stimulation periods.
This dynamic process between sensory stimulation and SWD suggests that sensory stimulation from the periphery can promote neural activity and thus possibly regulate more SWD occurrence
.

Figure 3: Sensory input regulates absence seizures in Gnb1 mice

(Source: Teng S, et al.
, iScience, 2022).

Existing studies have shown that the thalamic cortical circuit plays an important role in regulating absence epilepsy in humans and SWD in several model mice.

So in the Gnb1 mouse model, are thalamic cortex (TC) cells also involved in the neural mechanism by which sensory input promotes SWD? The research team injected AAV-CaMKII-GCaMP6s in VPM (posteromedial nucleus of the thalamus) of Gnb1+/- mice and passed the EEG/EMG two weeks later and fiber photometry, it was found that spontaneous neuronal activity during waking hours was indeed higher than expected during NREM phases
.
But shockingly, the team found that the total neural activity of TC cells was significantly inhibited during SWD, and TC cell activity was before SWD The 2-3 second time window is enhanced
.
This also suggests the important role of thalamic activity in inducing SWD.

The team also studied neural activity in the reticular nucleus (RT) of the thalamus.

To localize inhibitory neurons of RT, the researchers first crossed Gnb1 mice and PV-Cre mice, and then Gnb1; The RT of PV-Cre mice is injected into AAV-FELX-GCaMP6s
.
Fiber optic recordings found that RT cells were more active in the NREM phase than in the awake phase, while activity was inhibited
during REM.
The experiment also showed that RT cells are very active during SWD, while RT activity is relatively weakened before SWD begins, which coincides with TC Cells are the opposite
.
The authors further found that although RT and TC cells have opposite neural activity during SWD, calcium oscillations can be observed in both cells, and the oscillation frequency of both is in SWD Synchronous growth
during the period.
Therefore, the above experimental results show that the thalamic cortical pathway is indeed involved in the regulation of SWD in Gnb1-mutant mice
.

Finally, to further examine the causal relationship between thalamic activity and SWD regulation, the team activated thalamic excitatory neurons in Gnb1-mutant mice through chemogenetics while avoiding activation GABAergic RT neurons
.
Through EEG/EMG recordings and VPM implanted fiber recordings, it was found that activated TC cells made Gnb1-mutant mouse SWD The number increases significantly, and the increased effect can remain stable
within six hours of chemogenetic activation.
However, activation of TC cells had no significant effect
on the duration of SWD.
This is also enough to prove that the thalamus itself is also active enough to regulate SWD during absence seizures in this mouse.

Figure 4 Thalamic cell activity in Gnb1 mice during SWD genesis

(Source: Teng S, et al.
, iScience, 2022).

Figure 5 Thalangeal reticular nucleus activity during SWD occurrence

(Source: Teng S, et al.
, iScience, 2022).