I. López-Taboada et al.

Physiology & Behavior 257 (2022) 113969

Fig. 7. Total antioxidant capacity (TAC) levels in the prefrontal cortex (A) and the hippocampus (B) after maternal and postnatal exposure to a high-fat, high-sugar
diet (HFS) or standard diet (SD), and exposure to early life stress by maternal separation (MS) or briefly handling (HD) in adult male and female Wistar rats. *p <
0.001, **p < 0.01. Significant post-hoc comparison between experimental groups: *p ≤ 0.05; **p ≤ 0.001.

Fig. 8. Lipid peroxidation (MDA) levels in the prefrontal cortex (A) and the hippocampus (B) after maternal and postnatal exposure to a high-fat, high-sugar diet
(HFS) or standard diet (SD) and exposure to early life stress by maternal separation (MS) or briefly handling (HD) in adult male and female Wistar rats. *p < 0.001,
**p < 0.01. Significant post-hoc comparison between experimental groups: *p ≤ 0.05; **p ≤ 0.001A.

results agree with the idea that animals learn how to cope with stressful
events, showing a similar HPA axis response like the compensatory
mechanism after exposure to high-fat diets as commented before.
However, results were slightly different for the ventral hippocampus,
where HD males still having more CCO activity than females, although
no sex differences were found in MS animals. MS increased CCO activity
as compared to HD animals in females, especially in the dentate gyrus of
the ventral hippocampal (Fig. 6). This hippocampal region seems to be
more vulnerable to stress in females than males, maybe due to effect of
sex hormones, suggesting an organizational/activational effect of es­
trogens in hippocampal neurogenesis, having implications for adult
learning, stress responsivity and the vulnerability to insults or the risk to
develop several mental disorders [91, 92].
Regarding oxidative stress determinations, significant sex differences
were also found, and the prefrontal cortex was more vulnerable to
oxidative stress than the hippocampus, probably because the prefrontal
cortex is involved in stress regulation in rodents, particularly the pre­
limbic and infralimbic areas [83–85]. Total antioxidant activity (TAC)
and lipid peroxidation (LP) levels were higher in males fed with a HFS
diet than females, that revealed stress effects in the prefrontal cortex,
with higher oxidative stress levels in MS animals. It seems that males
could be more sensitive to oxidative stress than females, and females
would be protected by the anti-inflammatory action of sex hormones
like estrogens [93, 94]. Antioxidant enzymes increased in response to
ELS, inducing a protective effect probably mediated by estrogens as
reported by other studies where enzymatic antioxidant activity
increased as oxidative stress biomarkers decreased, and conferring
resilience to oxidative damage [95–97]. Therefore, females could be

10
I. López-Taboada et al.
probably protected against the adverse effects of LP in specific brain
regions as shown here.
In this regard, it is important to emphasize that cellular antioxidant
defences are increased against the presence of free radicals, but anti­
oxidant capacity may be not able to counteract a high load of free rad­
icals [98]. Each environmental factor influenced oxidative stress
markers in a different way. Most studies which analyse TAC demonstrate
that the reduction of antioxidant enzymes increases ROS production
inducing mitochondrial dysfunction [99, 100]. Considering the in­
teractions altogether, HFS diet increased LP levels significantly as it was
reported in several studies, where a high-fat diet consumption induced
the accumulation of adipose tissue in rats and contributed to increased
levels of LP and ROS in brain mitochondria from obese rats [101, 102].
Oxidative stress derived from obesogenic diet has been related with
cognitive impairment [103], but in our case, the levels of oxidative
stress induced by HFS diet could have not been enough to impair spatial
learning and memory. In order to explain this effect, we could consider
an inverted U response phenomenon, similar to the relationship between
learning and stress [65]. In this regard, it is possible that low levels of
oxidative stress could be beneficial, although too low or too high levels
would be detrimental. As suggested by our results, the detrimental ef­
fects of a WD would be ameliorated by exposure to early stress because
animals subjected to MS had decreased LP levels, especially after con­
sumption of an HFS diet. A plausible explanation for this could be a
compensatory mechanism or development of resilience after early-life
stress (ELS) exposure that counteracts the effects of the HFS diet. ELS
provides metabolic protection against adverse effects induced by HFS
diet on lipid peroxidation. For example, as reported by Maniam et al.
(2015) ELS induced metabolic resilience in response to a high-fat and
high-sugar diet, though this study was performed only in male rats [29].
Oxidative damage of brain tissue has been widely acknowledged to
play a role in learning and memory impairment in animals, especially
the prefrontal cortex and hippocampus, which are very sensitive to
oxidative stress [104, 105]. Memory and learning are impaired by the
increased production of free radicals and oxidative stress in brain tissue
[106, 107]. High body adiposity may induce the production of ROS,
promoting chronic inflammation [108], and fatty acids are involved in
catabolism through peroxisomal β-oxidative and mitochondrial path­
ways [109]. Mitochondrial β-oxidation of free fatty acids is increased by
fat overconsumption, leading to a possible malfunction of the electron
transport chain that could increase the action of complex IV generating
an extra electron flow through CCO enzyme complex that impairs
oxidative phosphorylation, and increases ROS accumulation. Thus,
enhancement of mitochondrial function could be a compensatory
mechanism to counteract brain oxidative stress and inflammation [26,
110]. Accordingly, consumption of WD would trigger high oxidative
stress, leading to higher levels of antioxidant defence to avoid the in­
crease of lipid peroxidation, as well as increasing brain CCO activity.
However, males could develop prefrontal cortex dysfunction, being
related with impaired performance of groups exposed to the HFS diet in
the reversal learning task. Moreover, WD and/or ELS differently influ­
ence males and females, showing significant sex-differences. Therefore,
our results suggest that the effects of early life stress and WD are not
always detrimental and depend on the brain region studied [71]. The
interaction between a WD and ELS induced by MS may provide a neu­
roprotective effect on brain metabolic capacity counteracting oxidative
stress by increasing the antioxidant activity and increasing CCO activity
in the prefrontal cortex, and in specific subfields of the dorsal
hippocampus.
In conclusion, interaction between lifelong exposure to WD both
prenatally and postnatally and ELS by MS resulted in complex sex-
dependent effects on spatial memory and behavioural flexibility, and
induced brain region-specific changes in brain oxidative capacity and
levels of oxidative stress. However, interaction between WD and ELS did
partially compensate the adverse effects of each environmental factor
independently regarding spatial memory and behavioural flexibility, but
11
Physiology & Behavior 257 (2022) 113969
its effects on brain oxidative capacity and oxidative stress were sex- and
brain region-specific. Future studies should address the neurobiological
mechanisms involved in sex differences for vulnerability or resilience to
obesogenic diets and ELS.
Funding
This work was supported by the Spanish Ministry of Science and
Innovation grants PSI2017-83038-P to HGP and NMC, grant PGC2018-
101574-BI00 to GV, grants IDI/2021/000033 (Foundation for Biomed­
ical Research and Innovation in Asturias, FINBA, Principality of Astu­
rias, Spain) and PI17/02009 (Spanish Ministry of Science and
Innovation, Instituto de Salud Carlos III) to ACM.
CRediT authorship contribution statement
Isabel López-Taboada: Investigation, Visualization, Writing –
original draft. Saúl Sal-Sarria: Investigation, Visualization, Writing –
original draft. Guillermo Vallejo: Methodology, Data curation, Formal
analysis. Ana Coto-Montes: Resources, Writing – review & editing,
Funding acquisition. Nélida M. Conejo: Conceptualization, Supervi­
sion, Investigation, Writing – review & editing, Funding acquisition.
Héctor González-Pardo: Conceptualization, Supervision, Investiga­
tion, Writing – review & editing, Funding acquisition.
Declaration of Competing Interest
The authors report no conflicts of interest. The data that support the
findings of this study are available from the corresponding author, N.M.
C., upon reasonable request
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.physbeh.2022.113969.
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