Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction

Area of Science:

• Neuroscience
• Gerontology
• Anesthesiology

Background:

• Postoperative cognitive dysfunction (POCD) is a significant concern linked to increased patient morbidity and mortality.
• The underlying mechanisms of POCD, particularly the role of the central cholinergic system, remain incompletely understood.
• Age is a known risk factor for developing POCD, suggesting age-related vulnerabilities.

Purpose of the Study:

• To investigate the hypothesis that degeneration of central cholinergic neurons contributes to POCD.
• To examine the effects of anesthesia and surgery on learning, memory, and cholinergic biomarkers in adult and aged mice.
• To evaluate the therapeutic potential of enhancing cholinergic function in preventing POCD.

Main Methods:

• Anesthesia and appendectomy were performed on adult and aged mice.
• Cognitive function was assessed using the Morris Water Maze test.
• Protein levels of central cholinergic system biomarkers (ChAT, AChE, VAChT, CHT) were measured via Western blot.
• Aged mice were pretreated with donepezil (an AChE inhibitor), and adult mice with mu-p75-saporin (a cholinergic immunotoxin).

Main Results:

• Anesthesia/surgery led to memory decline and reduced ChAT and VAChT levels in aged mice, but not in adult mice.
• Donepezil pretreatment in aged mice mitigated cholinergic impairment and prevented cognitive deficits post-surgery.
• Pre-injury of cholinergic neurons in adult mice with mu-p75-saporin induced cognitive dysfunction after anesthesia/surgery.

Conclusions:

• Central cholinergic neuronal degeneration is a key facilitator in the development of POCD.
• Targeting and preserving the central cholinergic system may be a viable strategy for preventing POCD, particularly in aged individuals.
• This study provides mechanistic insights into POCD, highlighting the vulnerability of the cholinergic system to anesthesia and surgery.