Cholestatic liver disease leads to significant adaptative changes in neural circuits regulating social behavior in mice to enhance sociability

Wagdi Almishri ¹, Mohammed O Altonsy ², Mark G Swain ³

⁰Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.

Biochimica Et Biophysica Acta. Molecular Basis of Disease +

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February 27, 2024

View abstract on PubMed

Summary

Cholestatic liver diseases (CLD) alter brain gene expression, leading to increased social interaction in mice. This suggests CLD

Area Of Science

Neuroscience
Hepatology
Genomics

Background

Cholestatic liver diseases (CLD) are linked to behavioral changes like social isolation, impacting patient quality of life.
The cause of CLD-associated social dysfunction is unclear, with possibilities including direct brain effects or psychological distress.
Animal models lack psychological components, necessitating investigation into CLD's direct impact on brain and behavior.

Purpose Of The Study

To investigate the impact of CLD on social behavior in a mouse model.
To analyze gene expression profiles in brain regions regulating social behavior in CLD mice.
To identify molecular networks and regulatory mechanisms disrupted by CLD in the brain.

Main Methods

Cholestatic liver disease was induced in mice via bile duct ligation (BDL).
Social behavior was assessed using the three-chamber sociability test.
RNA sequencing (RNA-seq) was employed to identify differentially expressed genes (DEGs) in three key brain regions.
Ingenuity Pathway Analysis (IPA®) was used to interpret DEG data and link it to social behavior pathways.

Main Results

Mice with CLD displayed enhanced social interactive behavior compared to controls.
Significant alterations in gene expression were observed in all three examined brain regions regulating social behavior.
DEGs in CLD mice were associated with key pathways, including Oxytocin, GABA, Dopamine, and Glutamate receptor signaling.

Conclusions

CLD induces complex changes in gene expression within brain areas crucial for social behavior, correlating with enhanced social interaction.
These findings suggest that psychological factors, rather than direct brain pathology, may primarily drive social interaction changes in CLD patients.
The study provides insights that could lead to novel therapeutic strategies for managing CLD-associated behavioral alterations.

Keywords:

Behavior Bile duct ligation Cholestasis Fatigue Liver Neural network PBC PSC QIAGEN ingenuity pathway analysis Sociability Social dysfunction Social isolation mRNA sequencing