Thalamic homeostatic transcriptomic signatures are altered in a mouse model of cholestatic liver injury and are mitigated by systemic TNF neutralization.

Cholestatic liver diseases (CLD), including PBC and PSC, are frequently associated with debilitating sickness‑behavior symptoms such as fatigue, cognitive impairment, and anxiety/depression, which have poorly defined etiology and limited treatment options, substantially reducing quality of life. Across immune‑mediated diseases, thalamic changes have been well documented and found to correlate with a number of theses symptoms. Changes in thalamic structure and neural connectivity have been previously identified in PBC patients by us and other groups. These changes include findings indicating reduced tissue neuronal density and myelination, decreased thalamic size, and changes in functional neural connectivity between the thalamus and basal ganglia and cortical behavior-regulating areas that correlated with symptom severity. These observations implicate altered thalamic structure and function in the genesis of CLD-related sickness‑behavior symptoms. Therefore, we used a well characterized mouse model of CLD due to bile duct ligation (BDL) to mechanistically examine how CLD impacts thalamic structure and function. BDL mice showed reduced thalamic volume compared to sham-ligated controls, as determined by MRI, and an altered thalamic RNA-seq transcriptomic signature with predicted molecular activity consistent with inhibition of cellular growth, proliferation, neurite formation, neural function, and myelination, as well as enhanced apoptosis. Additionally, BDL was associated with changes in gene expression for key thalamic nervous system signaling pathways that regulate neurotransmission and behavior. We have previously demonstrated that systemic TNF is a key regulator of liver-to-brain communication and the development of adverse behavioral symptoms in BDL mice. Therefore, we administered anti-TNF antibody to neutralize systemic TNF in BDL mice and determined the impact on thalamic transcriptomic changes. TNF neutralization attenuated BDL-associated thalamic transcriptomic changes and enhanced gene expression in pathways regulating neurotransmission, cell proliferation, and those associated with neuron survival, although myelination pathways remained unaltered. We show that reduced thalamic volume in BDL mice is associated with transcriptomic alterations suggesting inhibition of structural machinery and dysfunction of neural signaling; findings that are significantly attenuated after systemic TNF neutralization. Our findings suggest that TNF inhibition may represent a potential novel approach to attenuate thalamic changes in CLD.