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Elsevier

Brain, Behavior, and Immunity

Volume 116, February 2024, Pages 385-401
Brain, Behavior, and Immunity

Post-operative cognitive dysfunction is exacerbated by high-fat diet
via TLR4 and prevented by dietary DHA supplementation

Author links open overlay panelStephanie M. Muscat ^a ^b ^c, Michael
J. Butler ^a, Menaz N. Bettes ^a, James W. DeMarsh ^a, Emmanuel A. 
Scaria ^a, Nicholas P. Deems ^a, Ruth M. Barrientos ^a ^c ^d ^e
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https://doi.org/10.1016/j.bbi.2023.12.028Get rights and content

Highlights

  * *

    High-fat diet consumption before surgery extends duration of
    long-term memory deficits.

  * *

    High-fat diet consumption potentiates the neuroinflammatory
    response to surgery.

  * *

    TLR4 mediates the development of HFD + surgery-induced
    neuroinflammation & memory impairments.

  * *

    Dietary DHA supplementation prevents HFD + surgery-induced
    neuroinflammation & memory deficits.

Abstract

Post-operative cognitive dysfunction (POCD) is an abrupt decline in
neurocognitive function arising shortly after surgery and persisting
for weeks to months, increasing the risk of dementia diagnosis.
Advanced age, obesity, and comorbidities linked to high-fat diet
(HFD) consumption such as diabetes and hypertension have been
identified as risk factors for POCD, although underlying mechanisms
remain unclear. We have previously shown that surgery alone, or
3-days of HFD can each evoke sufficient neuroinflammation to cause
memory deficits in aged, but not young rats. The aim of the present
study was to determine if HFD consumption before surgery would
potentiate and prolong the subsequent neuroinflammatory response and
memory deficits, and if so, to determine the extent to which these
effects depend on activation of the innate immune receptor TLR4,
which both insults are known to stimulate. Young-adult (3mo) & aged
(24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days
immediately before sham surgery or laparotomy. In aged rats, the
combination of HFD and surgery caused persistent deficits in
contextual memory and cued-fear memory, though it was determined that
HFD alone was sufficient to cause the long-lasting cued-fear memory
deficits. In young adult rats, HFD + surgery caused only cued-fear
memory deficits. Elevated proinflammatory gene expression in the
hippocampus of both young and aged rats that received HFD + surgery
persisted for at least 3-weeks after surgery. In a separate
experiment, rats were administered the TLR4-specific antagonist,
LPS-RS, immediately before HFD onset, which ameliorated the
HFD + surgery-associated neuroinflammation and memory deficits.
Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset
blunted the neuroinflammatory response to surgery and prevented
development of persistent memory deficits. These results suggest that
HFD 1) increases risk of persistent POCD-associated memory
impairments following surgery in male rats in 2) a TLR4-dependent
manner, which 3) can be targeted by DHA supplementation to mitigate
development of persistent POCD.

Introduction

Gradual declines in cognition are associated with normal aging but
can turn precipitous following peripheral immune insults.
Perioperative neurocognitive disorders (PND) are a category of
surgical complications characterized by cognitive changes including
inattention and confusion, difficulty with executive tasks, and
memory deficits, which primarily affect older individuals in the
hours, weeks, or months following surgery (Evered et al., 2018,
Mahanna-Gabrielli et al., 2019). Given this often-variable
time-course of cognitive effects, recent recommendations suggest PNDs
should be sub-classified based on symptom duration, with
'post-operative delirium' (PD) used to describe cognitive symptoms
which occur in the immediate period after surgery in hospital and up
to 1-week post-surgery or until discharge (whichever occurs first).
In contrast, 'post-operative cognitive dysfunction' (POCD) refers to
a decline in cognitive function beyond 30 days after surgery, when
symptoms cannot be explained by any other medical condition (Evered
et al., 2018). While longitudinal studies of cognitive function
following PND are few, it is notable that persistent PNDs have been
associated with increased incidence of dementia diagnosis and/or
persistent cognitive declines relative to non-PND controls in older
individuals (aged 60 and over) 3-5 years following orthopedic surgery
(Bickel et al., 2008, Inouye et al., 2016, Lundstrom et al., 2003) or
cardiac surgery (Newman et al., 2001). Several meta-analyses also
support an association between PNDs and increased dementia risk
(Mahanna-Gabrielli et al., 2019, Witlox et al., 2010).

Many preclinical models of PNDs represent delirium, with cognitive
deficits lasting only ~ 1 week, but few have recapitulated the
persistent nature of POCD (Barrientos et al., 2012, Le et al., 2014,
Rosczyk et al., 2008, Wan et al., 2010, Wang et al., 2020). Normal
aging is associated with neuroimmune priming (Barrientos et al.,
2015a, Fonken et al., 2016, Frank et al., 2006) and thus, when
combined with subsequent inflammatory insults, a greater and
protracted neuroinflammatory response results (Barrientos et al.,
2006, Godbout et al., 2005, Muscat and Barrientos, 2021, Muscat et
al., 2021). Because of this, it is not surprising that advanced age
is the strongest risk factor for developing PNDs (Evered et al.,
2018, Mahanna-Gabrielli et al., 2019). For example, studies have
demonstrated that the combination of aging and surgery produces
exacerbated cognitive deficits compared to younger counterparts and
age-matched sham controls (Barrientos et al., 2012, Le et al., 2014,
Wang et al., 2018). Nonetheless, these deficits are relatively
short-lived. Recent research has established that multiple
neuroimmune insults resulting in long-lasting neuroinflammation is
critical to the development of persistent POCD (Hovens et al., 2015,
Muscat et al., 2023b, Muscat et al., 2021, Muscat and Barrientos,
2021). Specifically, we have previously reported that administration
of the pro-inflammatory opioid analgesic morphine causes memory
deficits lasting at least 8 weeks after surgery in aged male rats, a
significant prolongation from the 4-day long deficit observed without
morphine (Muscat et al., 2021, Muscat and Barrientos, 2021). We
demonstrated that these deficits were a result of long-lasting
neuroinflammation that was mediated by toll-like receptor 4 (TLR4)
(Muscat et al., 2023b). Clinically however, many patients develop
POCD even in the absence of analgesic opioid use, suggesting that
other perioperative factors may also come together to potentiate the
neuroimmune response and provoke POCD. Identifying these factors and
understanding their underlying mechanisms is critical to developing
effective interventions to prevent or slow progression towards
dementia.

Interestingly, metabolic disturbances associated with consumption of
an unhealthy diet, such as diabetes and insulin resistance, have been
linked to heightened risk for POCD (Lachmann et al., 2018, Tang et
al., 2017, Zhang et al., 2019). Obesity may also contribute to PND
risk, although this relationship is less clear with some studies
supporting and others contradicting this claim (Feinkohl et al.,
2016, Lachmann et al., 2018, Zhang et al., 2019, Zhao et al., 2020).
Importantly, unhealthy diets such as those high in saturated fats and
refined carbohydrates are pro-inflammatory. Briefly, consumption of
high-fat diets (HFD) increase circulating free fatty acids, which can
induce inflammation in the periphery. Immune signaling from the
periphery to the nervous system can induce central inflammation and,
additionally, fatty acids and their metabolites can directly enter
the brain, either through passive diffusion or transport
protein-mediated mechanisms at the blood-brain barrier (Tracey et
al., 2018). Once in the parenchyma, these fatty acids are capable of
producing a pro-inflammatory response via activation of TLR4 or
through metabolism-dependent mechanisms (Duca and Yue, 2014, Fatima
et al., 2019, Sergi et al., 2020, Tse and Belsham, 2018, Wang et al.,
2012b). As a result, pro-inflammatory cytokines are released, which
can deteriorate cognitive functions (Gonzalez Olmo et al., 2023,
Muscat and Barrientos, 2021, Muscat et al., 2021). We have previously
demonstrated that short-term consumption of HFD elevates levels of
pro-inflammatory cytokines in the hippocampus and amygdala of aged,
but not young adult rats (Spencer et al., 2017). Furthermore, this
heightened neuroinflammation causes both hippocampal- and
amygdalar-dependent memory deficits in the acute period following HFD
consumption (Spencer et al., 2017). Given these HFD-induced
pro-inflammatory effects in aged rats, it is possible that
consumption of an unhealthy diet in the perioperative period might
exacerbate the inflammatory response to surgery, inducing deleterious
neuroinflammation sufficient to cause persistent cognitive
impairments.

The aim of the present study was to characterize the impact of HFD
consumption prior to surgery on memory function in adult and aged
rats. Based on our previous findings, we hypothesized that consuming
a HFD for three days immediately prior to surgery would induce a
heightened neuroinflammatory response and persistent memory deficits
consistent with POCD in aged male rats. Further, we speculated that
this effect would be mediated by activation of TLR4, and used the
TLR4-specfic antagonist LPS-RS to address this question. Finally, we
sought to identify a translationally relevant intervention that would
mitigate the effects of HFD on cognition after surgery, and thus
investigated the impact of pre-operative supplementation with
docosahexaenoic acid (DHA), which is known to be
anti-neuroinflammatory in part by reducing expression and activation
of TLR4 (De Smedt-Peyrusse et al., 2008, Tang et al., 2018, Wu et
al., 2023, Zhou et al., 2022).

Section snippets

Subjects

Subjects were young adult (3-5 months) and aged (22-24 months) male
F344xBN F1 rats obtained from the National Institute on Aging rodent
colony managed by Charles River. F344xBN F1 rats are particularly
useful for the study of aging and aging-associated conditions as aged
rats of this strain remain relatively healthy and show good cognitive
function at baseline. Unfortunately, female rats of this strain were
not available from this or any other vendor at the time these studies
were completed.

Impact of HFD on baseline and post-operative weight

At baseline, young adult rats (n = 6/group) weighed ~ 300 g and aged
rats (n = 8/group) weighed ~ 575 g. For each age group, average
starting weights did not differ between groups (p > 0.05; Fig. 1B,
D). A 3-way ANOVA with time, diet, and surgery showed that
consumption of HFD for 3 days (Fig. 1A) induced significant weight
gain in both young adult (F[(1,143)] = 21.46, p < 0.0001; Fig. 1C)
and aged rats (F[(1,196)] = 360.3, p < 0.0001; Fig. 1E). Whereas post
hoc comparisons revealed no

Discussion

Taken together, the present data indicate that consumption of a HFD
prior to laparotomy prolongs the neuroinflammatory response to
surgery and induces persistent memory deficits in young adult and
aged rats. We demonstrated that both age groups who ate HFD for
3 days prior to surgery displayed robust cued-fear memory deficits,
and aged rats additionally exhibited contextual memory deficits.
These memory impairments were associated with exaggerated and
prolonged (3 weeks post-surgery)

CRediT authorship contribution statement

Stephanie M. Muscat: Conceptualization, Data curation, Formal
analysis, Investigation, Methodology, Writing - original draft,
Writing - review & editing. Michael J. Butler: Investigation,
Methodology. Menaz N. Bettes: Methodology. James W. DeMarsh:
Methodology. Emmanuel A. Scaria: Methodology. Nicholas P. Deems:
Methodology. Ruth M. Barrientos: Conceptualization, Funding
acquisition, Investigation, Project administration, Resources,
Supervision, Writing - review & editing.

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