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Post-Operative Neurocognitive Disorder: Potentiating Factors and the Role of Toll-Like Receptor 4

Muscat, Stephanie M
http://orcid.org/0000-0002-3669-8258
http://rave.ohiolink.edu/etdc/view?acc_num=osu1689173936682135

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
The work described herein aims to fill a gap in knowledge regarding specific mechanisms that underlie the development of persistent cognitive impairments following surgery, particularly in aging. These so-called perioperative neurocognitive disorders (PNDs) afflict as many as half of individuals over the age of 65 after a surgical procedure. Of those, many patients experience recovery in the initial days to weeks after surgery, termed post-operative delirium (PD). Yet a subset of patients continue to experience these cognitive deficits for months to years after surgery, referred to as post-operative neurocognitive disorder (POCD). Critically, it remains unclear what factors cause the development of short-term and self-resolving PD vs. persistent POCD. Accumulating evidence from both pre-clinical and clinical studies have established neuroinflammation as a critical mediator in the development of PNDs collectively, but it is still unknown how this contributes to PD vs. POCD pathogenesis. Additionally, specific inflammatory mechanisms have not been fully delineated. A variety of common immune exposures in the perioperative setting have been associated with heightened risk for PNDs, including experiencing an infection and receiving pro-inflammatory opioids as part of a pain management regimen. Additionally, metabolic disturbances associated with increased inflammation at baseline have also been linked to PND risk. In the present body of work, we investigated the impact of two such immune insults – post-operative morphine use and pre-operative consumption of a high-fat diet (HFD) – on post-surgical cognitive and inflammatory outcomes in male rats. We hypothesized that these pro-inflammatory immune challenges would potentiate the neuro-immune response to surgery, causing exaggerated neuroinflammation sufficient to cause long-lasting memory impairments. Indeed, both insults caused long-term memory deficits that lasted at least 8 weeks with morphine and 2 weeks with HFD (later time points were not investigated), much longer than the 4 day deficit observed with surgery alone. Further, the neuroinflammatory response to surgery was potentiated by both factors, evidenced by increased levels of the cytokines IL-1β, IL-6, and TNFα in the hippocampus of aged male rats approximately 2 weeks post-surgery. Additionally, we evaluated a role for the innate immune protein toll-like receptor 4 (TLR4) in the observed effects of both morphine and HFD on post-operative neuroinflammation and memory deficits. TLR4 is a pattern recognition receptor expressed by immune cells in both the periphery and nervous system associated with pro-inflammatory cytokine production. Critically, aging is associated with increased expression of this protein, and surgery, morphine, and HFD are all known to stimulate its activation. Therefore, we hypothesized that surgery and morphine, as well as surgery and HFD, would cause joint activation of this neuroimmune mechanism, to cause exaggerated neuroinflammation and subsequent memory deficits. This was tested in both models by centrally blocking TLR4 activation using the TLR4-specific antagonist lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS). For morphine-induced persistent POCD, we show that either a single pre-operative injection, or a 1 week regimen of LPS-RS after surgery+morphine, are capable of attenuating the synaptic- and memory-related deficits associated with surgery and morphine. Similarly, we demonstrate that LPS-RS administered prior to HFD onset can prevent HFD-induced persistent POCD. In the HFD model, we extend these findings to show that preventative supplementation with docosahexaenoic acid (DHA), a polyunsaturated fatty acid with anti-neuroinflammatory benefits (in part by reducing TLR4 expression and activation), reduces post-surgical neuroinflammation and prevents HFD-induced persistent POCD. Overall this body of work demonstrates that additional immune insults in the perioperative period increase neuroinflammation and subsequent risk of developing long-term memory deficits after surgery in aging. TLR4 plays a significant mediating role in these effects, and may present a promising therapeutic target for preventing and treating PNDs. Herein, these findings will be expanded on and placed in the context of the current state of aging, neuroimmune, and PND research.
Jonathon Godbout (Committee Member)
Michelle Humeidan (Committee Member)
Ruth Barrientos (Advisor)
Leah Pyter (Committee Member)
Benedetta Leuner (Committee Member)
Aging; Biomedical Research; Immunology; Neurosciences

Recommended Citations

Citations

  • Muscat, S. M. (2023). Post-Operative Neurocognitive Disorder: Potentiating Factors and the Role of Toll-Like Receptor 4 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1689173936682135

    APA Style (7th edition)

  • Muscat, Stephanie. Post-Operative Neurocognitive Disorder: Potentiating Factors and the Role of Toll-Like Receptor 4. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1689173936682135.

    MLA Style (8th edition)

  • Muscat, Stephanie. "Post-Operative Neurocognitive Disorder: Potentiating Factors and the Role of Toll-Like Receptor 4." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1689173936682135

    Chicago Manual of Style (17th edition)

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