Written by - Yang Li

Editor-in-charge - Wang Sizhen

Editor — Binwei Yang

Stress-induced inflammation in the brain is thought to be a core cause of some psychiatric disorders

On September 1, 2022, Yang Li's research group at the Gene Editing Engineering Center of the School of Life Sciences of Guangzhou University and the Long Cheng research group of the School of Life Sciences of South China Normal University cooperated to publish a paper entitled "Minocycline offers neuroprotection by ameliorating chronic unpredictable mild" at Molecular Neurobiology stress-induced neuroinflammation and mPFC-HIPP oscillatory activity in mice" research paper

After 21 days of CUMS, the results of the New Environmental Feeding Inhibition Experiment (NSF) and contextual anxiety test showed that the feeding delay time (Figure 1C), quiescent (F), and stiff response (G) of CUMS mice increased, indicating that CUMS caused anxious behavior

Figure 1.

(Source S Tabassum, et al.

Psychiatric disorders occur with activation of microglia, which produce inflammatory cytokines [3,4].

Figure 2.

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Figure 3.
CUMS increases the activation of HIPP microglia and inflammatory cytokine levels, reduces nAChRα7 levels, and minocycline improves the CUMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Mitochondrial and energy (ATP) synthesis, ROS signaling pathways, neuroinflammation, and anxiety are closely related [7,8], and the authors tested CUMS-induced changes in
ATP-5A, Nitrotyrosine, mitochondrial cleavage, and fusion proteins.

The western blotting results showed that CUMS elevated levels of the ROS-mediated oxidative stress (nitrotyrosine) and mitochondrial lysis protein Drp-1 by mPFC (Figure 4) and HIPP (Figure 5), reducing ATP synthesis
.

These experimental results show that CUMS causes abnormal mPFC and HIPP mitochondria and their related functions.
Inhibition of activation of microglia with minocycline improves the above abnormalities
.

Figure 4.
Effects of CUMS on mPFC mitochondria and energy synthesis, etc.
, and minocycline improved the CUMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Figure 5.
Effects of CUMS on HIPP mitochondria and energy synthesis, etc.
, and minocycline improved cuMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Neuronal oscillations and their functional connections are functional indicators of mood and cognitive function [9,10], and the authors went on to simultaneously record the local field potentials of mPFC and HIPP brain regions using in vivo dual-channel electrophysiology techniques, and found that CUMS elevated hipp beta and gamma oscillations (Figure 6
).

Phase locking value is a method of measuring the degree of synchronization of the signals of the two channels based on the functional connection of phases, and the results show that CUMS enhances the degree of synchronization between the two brain regions of mPFC and HIPP (Figure 7
).

The dual-channel field potential results suggest that CUMS changes the degree
of synchronization of the mPFC-HIPP loop.

Thus, abnormalities in mPFC-HIPP circuit function caused by the above molecular-cellular level alterations may be the neural mechanisms of CUMS leading to anxious behavior; Inhibition of microglia activation with minocycline improves mPFC-HIPP circuit abnormalities
.

Figure 6.
CUMS raises hipp's beta and high and low gamma oscillating potentials
.

Minocycline improves the CUMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Figure 7.
CUMS increased the phase-locked values of high and low gamma oscillations between mPFC and HIPP, and minocycline improved the CUMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

GABA signaling pathways, particularly GABA_AR-mediated inhibition of gamma oscillation production [10,11], the authors thus tested the expression
of GABA pathway-related proteins by western blotting.

The results showed that CUMS reduced the levels of GABA_Aα1 receptors for mPFC and HIPP, as well as glutamine GS and aminobutyric acid transporter Vgat, which are important for GABA synthesis (Figure 8
).

RT-PCR results showed a decrease in GABA_Aα1 receptor mRNA levels (Figures 8F, L
).

These results suggest that abnormal GABA signaling pathway protein expression may be the direct cause of abnormal mPFC-HIPP circuit function, while pro-inflammatory factors, nAChRα7 receptors, and abnormal expression of mitochondrial proteins may be upstream factors
in gaBA signaling pathway protein changes.

Figure 8.
CUMS reduces protein expression
in the GABA signaling pathway in the mPFC and HIPP brain regions.

Minocycline improves the CUMS effect

(Source S Tabassum, et al.
,Mol.
Neurobiology, 2022)

Figure 9.
Work summary Figure CUMS causes anxiety in mice molecular mechanisms and minocycline targets

(Source S Tabassum, et al.
, Mol.
Neurobiology, 2022)

In summary, the study uses molecular biology, somatic electrophysiology, behavior and pharmacology to reveal the potential causal relationship between microglia activation and anxiety caused by CUMS, suggesting that neuroinflammation and associated mitochondrial changes after microglia activation and mPFC-HIPP circuit abnormalities may be one of the pathological mechanisms of anxiety (Figure 9
).

Studies provide an important reference
for the anti-inflammatory treatment of anxiety targeting microglia.

There are two main deficiencies: 1) minocycline is not a specific inhibitor of microglia activation, so the experiment does not completely rule out the possibility that minocycline acts on other targets to improve anxious behavior; 2) There is no direct evidence of an upper and lower line or causal relationship between mitochondrial proteins, ATP synthesis, and nAChRα7 receptor abnormalities and the inflammatory response after microglia activation, and only the correlation
between them is discussed.

Original link: https://doi.
org/10.
1007/s12035-022-03018-8

First author Sidra Tabassum (front row, second from left), first author Afzal Misrani (front row left), first author Huo Qingwei (not in the picture), corresponding author Long Cheng (front row fourth from left), corresponding author Yang Li (front row fourth from right)

(Photo courtesy of Longcheng Lab)

About the Author:

1.
Long Cheng, Professor, School of Life Sciences, South China Normal University, whose research interests include brain mechanisms and interventions in neural signal transduction, stress, depression and anxiety, and his research projects include the National Natural Science Foundation of China (31871170), the Natural Science Foundation of Guangdong Province (2021A1515010804) and the sub-projects
of "Brain Science and Brain-like Research" (2018B030332001) in Guangdong Province.

2.
Yang Li, Professor, Gene Editing Engineering Center, School of Life Sciences, Guangzhou University, is mainly engaged in the research
of the neurobiological mechanism of Alzheimer's disease and emotions.

The research projects include the National Natural Science Foundation of China (32170950, 31970915) and the sub-project of "Major Special Projects in Brain Science and Brain-like Research" (2018B030336001) of the Guangdong Provincial Key Area R&D Program
.

3.
 

The representative papers jointly published by Yang Li and Long Cheng's research group in the past five years are as follows:

1.
     Jiang J#, Tang B#, Wang L#, Huo Q#, Tan S#, Misrani A, Han Y, Li H, Hu H, Wang J, Cheng T, Tabassum S, Chen M, Xie W, Long C*, Yang L*.
Systemic LPS-induced microglial activation results in increased GABAergic tone: A mechanism of protection against neuroinflammation in the medial prefrontal cortex in mice.
Brain, Behavior, and Immunity.
2022; 99: 53-69.
IF=19.
227

2.
     Chen M#, Chen Y#, Huo Q#, Wang L, Tan S, Misrani A, Jiang A, Chen J, Chen S, Zhang J, Tabassum S, Wang J, Chen X, Long C, Yang L*.
 Enhancing GABAergic signaling ameliorates aberrant gamma oscillation of olfactory bulb in AD mouse models.
 Molecular Neurodegeneration.
 2021; 16: 14.
IF=18.
907

3.
     Feng XY#, Hu HD#, Chen J, Long C, Yang L*, Wang L*.
Acute neuroinflammation increases excitability of prefrontal parvalbumin interneurons and their functional recruitment during novel object recognition.
Brain, Behavior, and Immunity.
2021; 98: 48-58.
IF=19.
227

4.
     Li HD, Li DN, Yang L, Long C*.
Deficiency of the CYLD impairs fear memory of mice and disrupts neuronal activity and synaptic transmission in the basolateral amygdala.
Front in Cellular Neuroscience.
2021; 15: 740165.
IF=6.
147

5.
      Peng YG, Cai PJ, Hu JH, Jiang JX*; Zhang JJ, Yang L*, Long C*.
Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice.
Experimental Neurology.
2021; 344: 113805.
IF=5.
620

6.
      Han YY, Jin K, Pan QS, Li B, Wu ZQ, Gan L, Yang L*, Long C*.
Microglial activation in the dorsal striatum participates in anxiety-like behavior in Cyld knockout mice.
Brain, Behavior, and Immunity.
2020; 89: 326-338.
IF=19.
227

Chen M, Wang J, Jiang J, Zheng X, Justice NJ, Wang K, Ran X, Li Y, Huo Q, Zhang J, Li H, Lu N, Wang Y, Zheng H, Long C, Yang L*.
APP modulates KCC2 expression and function in hippocampal GABAergic inhibition.
eLife.
2017; 6: e20142.
IF=8.
713

Selected articles from previous issues

【1】Nat Commun | Chen Zhong's team revealed the circuits and molecular mechanisms of lower support involved in temporal lobe epilepsy

[2] Cereb Cortex—The Team of Shanbao Tong/Xiangfei Hong reveals important influencing factors of EEG alpha rhythm in the visuospatial attention task

[3] Mol Psychiatry-Yingfei Wang's research group revealed the role of KDM6B protein in neuronal synaptic plasticity and learning and memory

[4] Cereb Cortex—The Team of Shanbao Tong and Xiangfei Hong reveals important influencing factors of EEG alpha rhythm in the visuospatial attention task

[5] Cereb Cortex: Excavation and Analysis of Imaging Subtypes for the Heterogeneity of Schizophrenia

[6] Front Cell Neurosci Review:Gamma Neural Oscillation and Central Nervous System Diseases: Mechanisms and Therapeutic Advances

[7] The NAR-He Cheng/Su Zhida team found that topoisomerase IIA can regulate adult neurogenesis in the subependymal region

[8] The Sci Adv-Liao Wenbo team has made important progress in the adaptive evolution of amphibian brain volume

[9] J Neuroinflammation—From Changchun/Jian Zhang's team found that targeted proteoglycan receptors after hemorrhagic stroke protected white matter integrity and promoted neurological recovery

[10] Front Aging Neurosci—Zeng Yanbing's team established a predictive model and revealed the effects of behavioral changes on cognitive impairment in the elderly

Recommended for high-quality scientific research training courses

【1】Special Training on Biomedical Statistics for Clinical Prediction of R Language (October 15-16, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing)

Meeting/Forum Preview

[1] Trailer | Conference on Neuromodulation and Brain-Computer Interface (U.
S.
Pacific Time: October 12-13)

Welcome to "Logical Neuroscience" [1] Talent Recruitment—"Logical Neuroscience" Recruitment Article Interpretation/Writing Positions ( Online Part-time, Online Office)

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End of this article