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Effects of Chaihu Shugan San on Brain Functional Network Connectivity in the Hippocampus of a Perimenopausal Depression Rat Model

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Abstract

In this study, we used Chaihu Shugan San (CSS), a traditional Chinese herbal formula, as a probe to investigate the involvement of brain functional network connectivity and hippocampus energy metabolism in perimenopausal depression. A network pharmacology approach was performed to discover the underlying mechanisms of CSS in improving perimenopausal depression, which were verified in perimenopausal depression rat models. Network pharmacology analysis indicated that complex mechanisms of energy metabolism, neurotransmitter metabolism, inflammation, and hormone metabolic processes were closely associated with the anti-depressive effects of CSS. Thus, the serum concentrations of estradiol (E2), glutamate (Glu), and 5-hydroxytryptamine (5-HT) were detected by ELISA. The brain functional network connectivity between the hippocampus and adjacent brain regions was evaluated using resting-state functional magnetic resonance imaging (fMRI). A targeted metabolomic analysis of the hippocampal tricarboxylic acid cycle was also performed to measure the changes in hippocampal energy metabolism using liquid chromatography-tandem mass spectrometry (LC–MS/MS). CSS treatment significantly improved the behavioral performance, decreased the serum Glu levels, and increased the serum 5-HT levels of PMS + CUMS rats. The brain functional connectivity between the hippocampus and other brain regions was significantly changed by PMS + CUMS processes but improved by CSS treatment. Moreover, among the metabolites in the hippocampal tricarboxylic acid cycle, the concentrations of citrate and the upregulation of isocitrate and downregulation of guanosine triphosphate (GTP) in PMS + CUMS rats could be significantly improved by CSS treatment. A brain functional network connectivity mechanism may be involved in perimenopausal depression, wherein the hippocampal tricarboxylic acid cycle plays a vital role.

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Data Availability

The datasets for this study can be found in the jianguoyun (https://www.jianguoyun.com/p/DYUQoqUQstXtChi_oP8EIAA).

Abbreviations

CSS:

Chaihu Shugan San

PMS:

Perimenopausal syndrome

CUMS:

Chronic unpredictable mild stress

E2:

Estradiol

Glu:

Glutamate

5-HT:

5-Hydroxytryptamine

fMRI:

Functional magnetic resonance imaging

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

OVX:

Ovariectomized

BOLD:

Blood oxygen level-dependent

TCM:

Traditional Chinese Medicine

FST:

Forced swimming test

SPT:

Sucrose preference test

OFT:

Open field test

SPM:

Statistical Parametric Mapping

UPLC:

Ultra performance liquid chromatography

CUR:

Curtain Gas

ISVF:

Ion Sapary Voltage Floating

MRM:

Multiple reaction monitoring

MDD:

Major depressive disorder

HPA:

Hypothalamic–pituitary–adrenal axis (HPA)

CRS:

Chronic restraint stress

LAu:

Left auditory cortex

LCPu:

Left caudate putamen

LDTLN:

Left dorsal tegmental lateral nucleus

LHip:

Left hippocampus

LM:

Left motor cortex

LRS:

Left retrosplenial cortex

LV:

Left visual cortex

ROI:

Region of interest

RCPu:

Right caudate putamen

RDTLN:

Right dorsal tegmental lateral nucleus

RHip:

Right hippocampus

RMO:

Right medulla oblongata

RPFC:

Right prefrontal cortex

ROF:

Right olfactory cortex

RRS:

Right retrosplenial cortex

RS:

Right sensory cortex

FID-EPI:

Free induction decay echo planar imaging

FC:

Functional connectivity

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This study was funded by the National Natural Science Foundation of China (No. 82274409 and 82174248) and the Natural Science Foundation of Fujian Province (No. 2023J01868).

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Author notes

  1. Ruiting Huang, Min Gong, and Xue Tan contributed equally to this work and share first authorship.

Authors and Affiliations

  1. School of Traditional Chinese Medicine, Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, 350122, People’s Republic of China

    Ruiting Huang, Jianying Shen, You Wu, Xiaoshi Cai, Suying Wang, Li Min, Lin Gong & Wenna Liang

  2. Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, People’s Republic of China

    Ruiting Huang

  3. Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, People’s Republic of China

    Ruiting Huang

  4. College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China

    Min Gong

  5. Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China

    Xue Tan

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  1. Ruiting Huang
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Contributions

Conceptualization, R.T.H. and G.M.; data curation, R.T.H. and X.T.; formal analysis, S.X.L. and J.Y.S.; funding acquisition, W.N.L.; investigation, L.M.; methodology, L.M. and L.G.; writing original draft, R.T.H. and G.M.; writing—review and editing, W.N.L. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Wenna Liang.

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The animal study was reviewed and approved by the Animal Care and Use Committee of the Fujian University of TCM (Approval number: FJTCM IACUC 2020026).

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Huang, R., Gong, M., Tan, X. et al. Effects of Chaihu Shugan San on Brain Functional Network Connectivity in the Hippocampus of a Perimenopausal Depression Rat Model. Mol Neurobiol 61, 1655–1672 (2024). https://doi.org/10.1007/s12035-023-03615-1

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