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Daily access to sucrose impairs aspects of spatial memory tasks reliant on pattern separation and neural proliferation in rats


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High sugar diets reduce hippocampal neurogenesis, which is required for minimizing interference between memories, a process that involves "pattern separation." We provided rats with 2 h daily access to a sucrose solution for 28 d and assessed their performance on a spatial memory task. Sucrose consuming rats discriminated between objects in novel and familiar locations when there was a large spatial separation between the objects, but not when the separation was smaller. Neuroproliferation markers in the dentate gyrus of the sucrose-consuming rats were reduced relative to controls. Thus, sucrose consumption impaired aspects of spatial memory and reduced hippocampal neuroproliferation.
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Brief Communication
Daily access to sucrose impairs aspects of spatial
memory tasks reliant on pattern separation and
neural proliferation in rats
Amy C. Reichelt,
Margaret J. Morris,
and Reginald Frederick Westbrook
School of Psychology;
School of Medical Sciences, UNSW Australia, UNSW Sydney, New South Wales 2052, Australia
High sugar diets reduce hippocampal neurogenesis, which is required for minimizing interference between memories,
a process that involves “pattern separation.” We provided rats with 2 h daily access to a sucrose solution for 28 d and
assessed their performance on a spatial memory task. Sucrose consuming rats discriminated between objects in novel
and familiar locations when there was a large spatial separation between the objects, but not when the separation was
smaller. Neuroproliferation markers in the dentate gyrus of the sucrose-consuming rats were reduced relative to controls.
Thus, sucrose consumption impaired aspects of spatial memory and reduced hippocampal neuroproliferation.
[Supplemental material is available for this article.]
The hippocampus is critically involved in many learning and
memory processes. Hippocampal-dependent forms of learning
and memory are particularly vulnerable to the detrimental effects
of the overconsumption of high fat and high sugar diets (Molteni
et al. 2002; Beilharz et al. 2014; Hsu et al. 2015; Reichelt et al.
2015a,b; Abbott et al. 2016). Furthermore, these detrimental ef-
fects can be long lasting. For example, we (Reichelt et al. 2015a)
recently demonstrated that rats who consumed 10% sucrose for
2 h a day across their adolescence exhibited object-in-place mem-
ory deficits assessed 6 wk after cessation of sucrose access.
Memory involves not only remembering information over
time, but also keeping memories distinct and minimizing inter-
ference among them. The computational process of making non-
overlapping representations of events distinct has been termed
“pattern separation” (Marr 1971; Leutgeb et al. 2007; Bakker
et al. 2008; Kumaran and McClelland 2012; Kesner 2013).
However, more loosely, “behavioral pattern separation” refers to
processes that enhance discrimination among similar stimuli
(Kent et al. 2016). The dentate gyrus (DG) is a site of adult hippo-
campal neurogenesis (Kuhn et al. 1996; Cameron and McKay
2001) and is hypothesized to be a neural substrate for behavioral
pattern separation processes (Sahay et al. 2011; Tronel et al.
2015). Reductions in adult hippocampal neurogenesis by X-ray ir-
radiation impaired performance when an array of visual target
touchscreen stimuli were presented with little spatial separation,
but not when the stimuli were more widely separated in space, in-
dicating that neurogenesis is required to discriminate between
similar spatial locations (Clelland et al. 2009). Furthermore,
high sugar diets have been reported to reduce proliferation of neu-
rons measured by BrdU immunoreactivity in the DG (van der
Borght et al. 2011), suggesting that such diets may impair behav-
ioral pattern separation processes.
We examined whether 2 h daily access to 10% sucrose
(w/vol; CSR white sugar; energy density 1.7 kJ/mL) in young
male albino Sprague Dawley rats over a 28-d period affected
performance on a modified spontaneous location recognition
task (SLR) (Bekinschtein et al. 2013, 2014; Kent et al. 2015). The
rationale behind the SLR task (see Fig. 1B) is that when objects
are closer together in space it is more cognitively challenging to
form spatial representations that are distinct, and places greater
demands on behavioral pattern separation processes than when
the objects are further apart (Bekinschtein et al. 2013, 2014;
Kent et al. 2015). This task requires brain-derived neurotrophic
factor (BDNF) in the DG to allow the encoding of spatial memories
(Bekinschtein et al. 2013, 2014). Thus, such evidence suggests that
the SLR task is DG-dependent and sensitive to manipulations of
neuroplasticity and depletion of neurogenesis by disrupting
Wnt-signaling (Bekinschtein et al. 2013, 2014).
Figure 1A shows the timeline of behavioral experiments. Rats
in the sucrose consumption group had access to 10% sucrose sol-
ution for 2 h each day for 24 d, as well on each of the 4 d of behav-
ioral training and testing. Rats that consumed sucrose did not
differ in body weight from control rats (F,1) (Fig. 1C) and the
overall energy intake between groups did not differ (F,1), as
sucrose consuming rats reduced their chow intake (Fig. 1D).
Sucrose intake increased across the 28-d period (Fig. 1E, F
60.8, P,0.001).
The SLR task (Fig. 1B) consisted of a 10-min sample phase in
which rats were exposed to a familiar gray plastic circular open
field arena (100 cm diameter ×50 cm high). Three identical ob-
jects (A1, A2, and A3—opaque yellow plastic bottles measuring
22-cm high, 8-cm wide), were arranged in a triangle shape (see
Supplemental Materials). The arena was surrounded by three dis-
tinctive proximal spatial cues (black and white posters with
unique patterns 35 cm high ×50 cm wide, located equidistantly
around the arena, and distal cues provided by room furniture).
In the d-SLR condition, the distance between each object was
equal (49 cm), whereas in the s-SLR condition A2 and A3 were
closer to each other (20.5 cm) than they were to A1, which was
Present address: School of Health and Biomedical Sciences, RMIT
University, Melbourne, Victoria 3083, Australia
Corresponding author:
#2016 Reichelt et al. This article is distributed exclusively by Cold Spring
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at an equal distance from the other two. Twenty-four hours later,
rats were tested. This consisted of rats in both conditions being ex-
posed for 5 min to two identical copies of the sample objects: one
of which (A4) remained in the same location as had been occupied
by A1 and the other (A5) located halfway between where A2 and
A3 had been located (Bekinschtein et al. 2013). In the d-SLR con-
dition, behavioral pattern separation processes would ensure that
representations of the object locations remained distinct from
each other. Hence, rats in this condition should be likely to detect
the object in the new location and spend more time exploring this
novel location. In contrast, in the s-SLR condition, the task con-
fronting pattern separation processes is more difficult. Hence, if
the history or sucrose exposure impaired these processes, then
rats with this history would be less likely
to detect the object in the new location
than control rats.
In the d-SLR task control (N¼6)
and sucrose-exposed (N¼6) rats spent
equal amounts of time exploring each
of the three objects (A1, A2, A3) during
the d-SLR sample phase as shown in
Figure 2A [no significant main effects of
object, group, discrimination (Fs,1.0);
no interactions were significant (Fs,
1)]. The control and sucrose-exposed
rats performed comparably at test—
spending more time exploring the object
in the novel location (Fig. 2C). This was
confirmed statistically by ANOVA which
revealed a significant main effect of ob-
ject (F
¼33.1, P,0.001), but no sig-
nificant main effect of sucrose (F,1) or
object ×sucrose interaction (F,1).
In the s-SLR task control (N¼6) and
sucrose-exposed (N¼6) rats spent equal
amounts of time exploring each of the
three objects (A1, A2, A3) during the
s-SLR sample phase as shown in Figure
2B [no significant main effects of object,
group, discrimination (F,1); no inter-
actions were significant (Fs,1)]. How-
ever, in the s-SLR task, control rats
spent more time exploring the object in
the novel location, but sucrose-exposed
rats spent equal time exploring the ob-
ject moved to the new location as the
one that remained in the old location
(Fig. 2D). Repeated-measures ANOVA
demonstrated a significant main ef-
fect of object (F
¼30.6, P,0.001),
but no significant main effect of group
¼1.2, P¼0.31). A significant
object ×group interaction was observed
¼30.5, P,0.001). Simple main
effects analysis demonstrated a signifi-
cant effect of object in control (F
61.1, P,0.001) but not sucrose (F,1)
Data were transformed to discri-
mination ratios (Fig. 2E). Significant
main effects of group (F
¼12.6, P,
0.01), test type (F
¼4.6, P,0.05),
and a significant group ×test interaction
¼6.6, P,0.05) were observed.
Simple main effects analysis demon-
strated a significant effect of sucrose ex-
posure during the s-SLR (F
¼18.7, P,0.001) but not the
d-SLR test (F,1). Thus, rats exposed to sucrose were able to re-
call the original layout of the objects when tested 24 h later
as they spent more time exploring the object moved to the new
location than the one that remained in its original position.
We then assessed whether daily exposure to sucrose affected
cell proliferation in the DG. Twenty-four hours after testing, the
brains of sucrose and control rats were analyzed by immunohis-
tochemistry for proliferating cell nuclear antigen (PCNA) and
doublecortin (DCX). PCNA is a marker for neuroprogenitor cell
proliferation (Olariu et al. 2007; Snyder et al. 2009; Dimitrov
et al. 2014), which is expressed during all active phases of the
cell cycle and for a short period of time after cells become
Figure 1. (A) Timeline of experimental events. (B) Schematic of the spontaneous location recognition
task showing the relation of the extra-maze cues (1, 2, 3) and the arrangement of the objects (sample
phase: A1, A2, A3 and test phase: A4, A5) in the d-SLR and s-SLR configurations in a 100-cm diameter
open field arena. See Supplemental Information for full details of the behavioral methods. (C) Body
weights of rats across the sucrose access period. (D) Total energy consumed (kJ) per cage of four rats
in each of the diet conditions across a 24-h period. (E) Daily consumption of 10% sucrose averaged
across the three cages (each containing 4 rats) (F) Mean white adipose tissue (WAT) as percentage of
body weight in control and sucrose rats. Data are presented as means +SEM. N¼12 per group. ()
Sucrose consumption impairs pattern separation 387 Learning & Memory
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post-mitotic (Christie and Cameron 2006; von Bohlen und
Halbach 2011). DCX is a microtubule-associated protein that is
expressed in migrating neuronal precursor cells (Gleeson et al.
1998; Couillard-Despres et al. 2001) and is used as a marker for
new adult born neurons in the DG (Couillard-Despres et al.
2005). Rats that received daily exposure to sucrose for 28 d had
significantly fewer DCX immunopositive cells per DG (DCX+;
¼3.8, P¼0.001, Fig. 3A,B) and PCNA immunopositive cells
per DG (PCNA+;t
¼2.6, P¼0.016), Fig. 3C,D) in the granule
cell layer of the DG of the hippocampus than control rats.
Analysis of the retroperitoneal and gonadal fat pad weights
(Fig. 1F) revealed that rats which consumed sucrose had signifi-
cantly greater body fat than control rats (t
¼2.3, P,0.05).
Thus, despite consuming similar amounts of energy, rats that con-
sumed sucrose developed greater adiposity than control rats.
The behavioral results indicated that a history of sucrose con-
sumption spares spatial recognition memory in the d-SLR task.
In contrast to this, sucrose consumption impaired test perfor-
mance on the s-SLR version of the task
when the objects had been located
closer to each other during the sample
phase, indicating that sucrose had im-
paired recognition memory. Immuno-
histochemical analysis of the neuronal
proliferation marker PCNA and im-
mature neurons (DCX) showed that
consumption of 10% sucrose reduced
proliferating neuronal precursor popula-
tions, potentially underpinning the cog-
nitive deficits observed. This is in line
with the hypothesis that adult neuro-
genesis provides an added functionality
to the hippocampus when the cognitive
load is taxed (Garthe et al. 2016), thus
impairments were observed in the s-SLR
task, but not in the d-SLR task.
Despite the memory impairment on
the s-SLR task in sucrose-consuming rats,
proliferating cells were still present in
the DG, albeit at a significantly reduced
level (80% of control levels). This
complements the observation that per-
formance on cognitive tasks relying on
pattern separation, such as a touchscreen
location discrimination task, were im-
paired by both a reduction and a com-
plete ablation of neural differentiation
by irradiation. Clelland et al. (2009) in-
fused an anti-Wnt lentivirus into the
DG to diminish neuroproliferation in
mice. This manipulation produced a
10% decrease in total cell numbers in
the DG and a spatial separation-depen-
dent impairment on the touchscreen
task. Moreover, Wnt-knockdown pro-
duced performance impairments simi-
lar to hippocampal lesions (McTighe
et al. 2009) or irradiation-induced ab-
lation of DG neurons (Clelland et al.
2009). Taken together, these results sug-
gest that there is a critical threshold of
differentiating neuron populations, be-
low which deficits in pattern separation
processes arise (Clelland et al. 2009).
Previous studies have demonstrat-
ed that diminishing adult neurogenesis
by the lentiviral-induced knockdown of Wnt-signaling impairs
performance when the cognitive load for pattern separa-
tion was high in the s-SLR task (Bekinschtein et al. 2013).
Performance in the xs-SLR task, where the distance between
the two objects, A2 and A3, was closer than in the s-SLR, was
enhanced by infusion of BDNF into the DG. Furthermore, per-
formance on both the s-SLR and the xs-SLR was enhanced by
14 d of systemic administration of the orexigenic hormone
acyl-ghrelin (Kent et al. 2015). Acyl-ghrelin treatment enhanced
both neuroproliferation measured by DCX immunoreactivity
and performance on s-SLR when measured 8– 10 d after the ces-
sation of treatment (Kent et al. 2015), further indicating that
metabolic changes that influence neuroplasticity can modulate
performance of this task.
Populations of newborn neurons in the DG are regulated by
a variety of factors (Ming and Song 2005). Manipulations that
increase the number of newborn granule cells, such as physical
activity, are associated with improved cognitive performance in
Control Sucrose Control Sucrose
Control Sucrose Control Sucrose
Time (sec)Time (sec)
Discrimination ratio
** **
d-SLR Sample s-SLR Sample
d-SLR Test s-SLR Test
Figure 2. (A) Time spent exploring the three identical objects (A1, A2, A3) during the d-SLR sample
phase by sucrose-exposed (sucrose) and control rats. (B) Time spent exploring the three identical
objects (A1, A2, A3) during the s-SLR sample phase by sucrose-exposed and control rats. (C) Time
spent exploring the two identical objects (A4, A5) during the d-SLR test phase by sucrose-exposed
and control rats. (D) Time spent exploring the two identical objects (A4, A5) during the s-SLR test
phase by sucrose-exposed and control rats. (E) Test performance during the d-SLR and s-SLR [D2 dis-
crimination ratio ¼Time
] by sucrose consuming and
control rats. Data s how mean +SEM. (∗∗)P,0.01, (∗∗∗)P,0.001 compared with control rats.
Sucrose consumption impairs pattern separation 388 Learning & Memory
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touchscreen discriminations (Creer et al. 2010) and in context fear
conditioning where discrimination between shocked and non-
shocked contexts (Sahay et al. 2011). Further studies are required
to establish the mechanisms by which daily access to sucrose im-
pairs hippocampal function. Continuous consumption of sucrose
for 4 wk decreased neurogenesis measured by reduced BrdU im-
munoreactive cells in the DG (van der Borght et al. 2011), however
this more direct assay of neurogenesis was not measured in the
current study. Neuroinflammation is another likely candidate as
it inhibits neurogenesis (Monje et al. 2003), and high sugar diets
increase levels of pro-inflammatory cytokines in the hippocam-
pus (van der Borght et al. 2011; Beilharz et al. 2014; Hsu et al.
2015). Despite consuming similar amounts of energy overall as
control rats, the rats that consumed sucrose had increased adipos-
ity. Thus, adipose derived cytokines may have contributed to an
enhanced inflammatory state (Park et al. 2005). Additionally,
the s-SLR task has been shown to depend on BDNF expression in
the DG (Bekinschtein et al. 2013, 2014). As consumption of a
high fat/high sugar diet for 8 wk reduced hippocampal BDNF
mRNA expression (Molteni et al. 2002), it is possible that the daily
access to sucrose in the present experimentlikewise reduced BDNF
expression in the DG.
The maturation process of newborn neurons takes 1–2 mo
in rodents (Kempermann et al. 2004), but there are several phases
whereby the excitability of these young neurons decrease concom-
itant with their integration into existing neural circuits (van Praag
et al. 2002; Ming and Song 2005). Neuronal excitability is thought
to decrease from the time that spinogenesis begins; a time which
overlaps with the development of gamma-aminobutyric acid
(GABA) receptors (Esposito et al. 2005). Fast-spiking parvalbumin-
positive GABAergic interneurons regulate early phases of adult
hippocampal neurogenesis (Song et al. 2013). Previously, we ob-
served a reduction in parvalbumin neuron immunoreactivity
within the dorsal hippocampus of rats that consumed sucrose on
a daily basis (Reichelt et al. 2015a), which may have contributed
to the reduced neuroproliferation markers observed here.
The behavioral results indicate that daily intake of sucrose in-
duces deficits in spatial memory when objects are closer together
in space, yet spares performance when memory representations
are made more spatially distinct. A “cognitive map” describes
the spatial representations of an environment (O’Keefe and
Dostrovsky 1971; Eichenbaum 2000). The representations be-
tween the distal spatial cues and objects, as shown in Figure 1B,
may have differed between the d-SLR and s-SLR. During the test
phase, the rats may use spatial cue 1 to identify A4 as familiar,
whereas the new object A5 does not have a stored association
with the extra-maze cues, and hence elicits exploration. Thus,
the reduction in the distance between the A2 and A3 objects,
during the sample phase in the s-SLR task, also reduced the dis-
tances between the extra-maze cues. The question therefore re-
mains whether the critical factor in the s-SLR was the distance
between the objects and the extra-maze cues or the distance be-
tween the objects themselves. Further studies should examine
whether increasing the proximity of the spatial cues to the
to-be-remembered locations influences performance in this task.
The present results suggest that daily intake of sugar-
sweetened drinks has adverse effects on hippocampal-dependent
forms of learning that become apparent when “cognitive load” is
challenged. Further studies might examine whether treatments
and interventions known to promote neurogenesis (such as aero-
bic exercise) reverse diet-induced cognitive deficits in the s-SLR
task. Other measures of behaviors reliant on precursor neuropro-
liferation and indicative of cognitive flexibility, such water maze
reversal learning (Garthe et al. 2009) and spatial separation-
dependent touchscreen tasks (Clelland et al. 2009) should be
A.C.R. is the recipient of an Australian Research Council Discovery
Early Career Research Award (DE140101071). We thank Kirsten
Abbott for her assistance with collection of the behavioral data.
Figure 3. (A) Doublecortin-positive (DCX+) cells in the DG of control rats (N¼12) and rats sucrose-exposed rats (N¼12) (mean +SEM). (B)
Photomicrographs showing representative doublecortin immunoreactivity in the DG of control and sucrose-exposed rats (10 ×, Scale bar ¼100 mm)
and inset 40×Scale bar ¼25 mm. (C) PCNA-positive (PCNA +) cells in the DG of control rats and rats that consumed sucrose (mean +SEM). (D)
Photomicrographs showing representative PCNA immunoreactivity in the DG of control and sucrose consuming rats (10×, Scale bar ¼100 mm.
Arrows show PCNA-positive cells and inset 40×scale bar ¼25 mm). ()P,0.05, (∗∗∗)P,0.001 compared with control rats. See Supplemental
Information for details of the immunohistochemical methods utilized.
Sucrose consumption impairs pattern separation 389 Learning & Memory
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Sucrose consumption impairs pattern separation 390 Learning & Memory
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Amy C. Reichelt, Margaret J. Morris and Reginald Frederick Westbrook
reliant on pattern separation and neural proliferation in rats
Daily access to sucrose impairs aspects of spatial memory tasks
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... The SLR test can be implemented in a standard rodent facility, requires minimal specialist equipment, and is usable by personnel with basic animal behavioral training. SLR was first successfully implemented by researchers using a variety of rat strains including pigmented 9,19-21 and albino rats [22][23][24][25] . Most recently, we have successfully adapted this task for use in mice 26,27 , opening up a wealth of transgenic manipulations available only in murine models, and allowing the testing of neuropathologies associated with mouse models of neuropsychiatric and neurodegenerative disease. ...
... Most recently, we have successfully adapted this task for use in mice 26,27 , opening up a wealth of transgenic manipulations available only in murine models, and allowing the testing of neuropathologies associated with mouse models of neuropsychiatric and neurodegenerative disease. The SLR task has been used to examine spatial memory performance in states of reduced plasticity 9,22,24,25 or in enhanced plasticity 19,20 . ...
... Studies that have examined visual acuity in other tasks reliant on pattern discrimination and spatial cues have found that rodents with impaired visual acuity such as albino strains require either more time to learn a task or perform at chance levels when in bright light conditions [38][39][40] . However, studies have successfully used the albino Sprague Dawley rat strain in this SLR task [22][23][24][25] , under slightly dimmed ambient lighting conditions (20-30 lux). We anticipate that other pigmented (e.g., dark agouti) and albino rat strains (e.g., Wistar) will successfully perform this task. ...
Keeping similar memories distinct from one another is a critical cognitive process without which we would have difficulty functioning in everyday life. Memories are thought to be kept distinct through the computational mechanism of pattern separation, which reduces overlap between similar input patterns to amplify differences among stored representations. At the behavioral level, impaired pattern separation has been shown to contribute to memory deficits seen in neuropsychiatric and neurodegenerative diseases, including Alzheimer’s disease, and in normal aging. This protocol describes the use of the spontaneous location recognition (SLR) task in mice and rats to behaviorally assess spatial pattern separation ability. This two-phase spontaneous memory task assesses the extent to which animals can discriminate and remember object locations presented during the encoding phase. Using three configurations of the task, the similarity of the to-be-remembered locations can be parametrically manipulated by altering the spatial positions of objects—dissimilar, similar or extra similar—to vary the load on pattern separation. Unlike other pattern separation tasks, SLR varies the load on pattern separation during encoding, when pattern separation is thought to occur. Furthermore, SLR can be used in standard rodent behavioral facilities with basic expertise in rodent handling. The entire protocol takes ~20 d from habituation to testing of the animals on all three task configurations. By incorporating breaks between testing, and varying the objects used as landmarks, animals can be tested repeatedly, increasing experimental power by allowing for within-subjects manipulations.
... Anxiety, depression, and cognitive deficits are strongly associated with impaired hippocampal neurogenesis in animal models, although evidence for a causative relationship is often lacking. Indeed, anxiety and spatial memory deficits elicited by long-term consumption of sucrose are accompanied by alterations in hippocampal neurogenesis and physiology (Molteni et al., 2002;Stranahan et al., 2008;van der Borght et al., 2011;Lemos et al., 2016;Reichelt et al., 2016). While drugs of abuse such as ethanol are known to negatively affect neurogenesis, the effect of high levels of sugar consumption requires further characterization since link between neurogenesis to anxiety and depression has not been fully explored (Xu and Reichelt, 2018). ...
... Therefore, further investigation is required to identify the mechanism underlying the effect of sugar on locomotor and impulsive behavior in mice. This could be explored further using delay discounting test (temporal discounting) or 5-choice serial reaction time task (visual attentional processes and impulse control) (Reichelt et al., 2015(Reichelt et al., , 2016Lemos et al., 2016). ...
... Excessive sucrose consumption in adolescent rats has been associated with deficits in spatial memory or object recognition memory (Reichelt et al., 2015(Reichelt et al., , 2016Lemos et al., 2016), and this could be principally mediated by the fructose component of sucrose (Hsu et al., 2015). However, the link between memory deficits and changes in hippocampal neurogenesis following long-term sucrose consumption has been relatively unexplored. ...
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Sugar has become embedded in modern food and beverages. This has led to overconsumption of sugar in children, adolescents, and adults, with more than 60 countries consuming more than four times (>100 g/person/day) the WHO recommendations (25 g/person/day). Recent evidence suggests that obesity and impulsivity from poor dietary habits leads to further overconsumption of processed food and beverages. The long-term effects on cognitive processes and hyperactivity from sugar overconsumption, beginning at adolescence are not known. Using a well-validated mouse model of sugar consumption, we found that long-term sugar consumption, at a level that significantly augments weight gain, elicits an abnormal hyperlocomotor response to novelty and alters both episodic and spatial memory. Our results are similar to those reported in attention deficit and hyperactivity disorders. The deficits in hippocampal-dependent learning and memory were accompanied by altered hippocampal neurogenesis, with an overall decrease in the proliferation and differentiation of newborn neurons within the dentate gyrus. This suggests that long-term overconsumption of sugar, as that which occurs in the Western Diet might contribute to an increased risk of developing persistent hyperactivity and neurocognitive deficits in adulthood.
... Several recent reports have documented the effects of high-fat and high-sugar diets on cognitive function in rodents (reviewed in [19]). A commonly reported phenotype is that behaviours requiring intact spatial memory, notably the novel object placement task, are markedly impaired in rats when chronically exposed to high sucrose diets (eg: [20][21][22]). However, tasks which are based on visual recognition memory, such as the novel object recognition task, appear relatively unaffected [20,23]. ...
... A related consideration which could explain the differences in our results compared to literature is whether the quantity of sucrose in the diet was sufficient -7 g/day, resulting in a 25% increase in caloric intake each day for ~3 months. However, these quantities are consistent with, or greater than, reports in the literature [21,22,35]. One additional consideration is that, because our animals were pair-housed, we could not calculate how much of the available 140 ml each cagemate consumed. ...
Introduction Western diets, including those consisting of saturated fats, simple sugars and processed foods, is rising at an unprecedented rate. These lead to obesity and metabolic diseases, and possibly cognitive deficits. Exploring this, recent studies demonstrate marked impairment in spatial learning in rodents exposed to high-sugar diets. We utilised advanced touchscreen technology to assess several spatial and non-spatial components of cognition in rats chronically exposed to a high sucrose diet. Methods Male Wistar rats received 70 ml of 10% sucrose solution each day, or control tap water, persisting for the experiment duration (total n=32). After 5 weeks of diet, rats performed Pairwise Discrimination, Location Discrimination, or Progressive Ratio tasks on automated touchscreens, and performance compared between groups. Results Sucrose rats consumed all the sugar solution provided to them, and had significantly increased caloric intake, compared to controls (p<0.0001). However, in all tests, we found no significant difference in cognitive performance between Sucrose and Control treated rats. This included the number of trials for acquisition, and reversal, in Pairwise Discrimination, and number of trials required to complete Location Discrimination (p>0.05 for all outcomes). No differences were observed in perseverative behaviour, motivation levels, or processing speed. Conclusion Our study found no evidence to suggest that chronic consumption of sucrose impairs cognition, including both spatial and non-spatial learning tasks. These findings suggest that not all aspects of spatial cognition are negatively impacted by high sugar diet in rodents, and that particular use of touchscreen technology may probe different aspects of cognition than traditional tasks.
... Diet-associated reductions of PV neuron immunoreactivity and PNNs were observed within the CA1 of the adult cohort, suggesting that this region may be more vulnerable to nutritional stress. This aligns with previous observations of pronounced obesity-induced cognitive deficits in spatial memory 14,15,63,64 , as PV-mediated inhibitory neurotransmission within the CA1 is required for the stabilisation of place cells 65 . The most prominent diet-evoked changes to PV neurons and PNNs were observed in the adult cohort, supported further by negative associations between adiposity and numbers of PNNs within the CA1 and CA2/3 in the adult cohort. ...
... Furthermore, the dentate gyrus is a key region of adult hippocampal neurogenesis, the disruption of which can lead to pronounced memory impairment 80 . It has previously been shown that high fat or high sugar diets decreased histological markers of neuroproliferation in the dentate gyrus 63,81,82 , indicating that even relatively small shifts in cellular populations in the dentate gyrus can have a profound impact on hippocampal function. Microglia activation is known to have a negative impact on hippocampal neurogenesis 77 which may provide another mechanism by which hippocampal function is disrupted by HFHS diet consumption 82 . ...
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Emergent evidence demonstrates that excessive consumption of high fat and high sugar (HFHS) diets has negative consequences on hippocampal and prefrontal cortex (PFC) function. Moreover, the delayed maturation of the PFC including the late development of parvalbumin-expressing (PV) interneurons and perineuronal nets (PNNs) may promote vulnerability to HFHS diet-induced nutritional stress. However, the young brain may have some resistance to diet-induced neuroinflammation. Thus, we examined the impact of a HFHS diet commencing either in adolescence or adulthood in male mice. PV interneurons, PNNs and microglia were assessed using immunohistochemistry. We observed greater numbers of PV neurons and PNNs in the hippocampus and the prelimbic and infralimbic PFC in adult mice in comparison to our younger cohort. Mice that consumed HFHS diet as adults had reduced numbers of hippocampal PV neurons and PNNs, which correlated with adiposity. However, we saw no effects of diet on PV and PNNs in the PFC. HFHS diet increased microgliosis in the adult cohort, and morphological changes to microglia were observed in the PFC and hippocampus of the adolescent cohort, with a shift to activated microglia phenotypes. Taken together, these findings demonstrate different regional and age-specific effects of obesogenic diets on PV neurons, PNNs and microglia.
... Altogether, these data indicate that juvenile animals are more susceptible to the adverse effects of sucrose consumption on cognition. It should be noted that these cognitive changes are observed in the absence of weight differences [7,64,66] suggesting that the metabolic disturbances in the diet, rather than obesity, underpin the cognitive deficits. ...
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We previously described that excessive consumption of sucrose during youth produces fear memory and anxiety-like behavior in adulthood. Here, we evaluated whether high cognitive function is also affected by studying early sucrose consumption in object recognition memory (NOR). Male Sprague Dawley rats were tested for short-term, long-term, and consolidated NOR after 25 days of unlimited sucrose access in juvenile (PD 25–50) or adult age (PD 75–100). All rats spent equal time exploring the two objects during the sample phase T1. When animals were exposed for 2, 24 h or 7 days later to a copy of the objects presented in T1 and a novel object, the sucrose-exposed juvenile group failed to distinguish between the familiar and the novel objects in contrast with the rest of the groups. Sucrose-exposed animals developed hypertriglyceridemia and glucose intolerance, but juvenile animals showed increased fasting glycemia and sustained the glucose intolerance longer. Moreover, sucrose decreased hippocampal proBDNF expression in juveniles while it was increased in adults, and sucrose also increased RAGE expression in adults. The NOR exploration ratio correlated negatively with basal glycemia and positively with proBDNF. Taken together, these data suggest that sucrose-induced alterations in glucose metabolism may contribute to a long-term decline in proBDNF and impaired recognition memory.
... These studies suggest that the mechanisms through which HSDs impair hippocampal neuroplasticity may include increases in pro-inflammatory cytokines, as well as decreases in neurotrophic factor expression, which may ultimately contribute to diet-induced cognitive deficits [18]. In rats, HSDs also led to a decrease in the level of markers of hippocampal neurogenesis in the dental gyrus [14] and neuroproliferation markers doublecortin and proliferating cell nuclear antigen (PCNA) immunoreactivity [19]. ...
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Due to the low cost of production and the strong evolutionary preference for sweet taste in humans, sugar is added to many food products. This leads to often involuntary overconsumption of high amounts of sugar. Yet, growing evidence indicates that high-sugar diets impact brain function and impair cognitive ability. It may be due to physiological changes in specific regions of the brain or/and maladaptive changes in dopamine signalling similar to those observed in the etiology of addiction. In our study, rats from the experimental group were kept on a feeding protocol involving intermittent access to sucrose solution for eight weeks. Then, the animals underwent a spontaneous exploration test in an experimental arena divided into three zones where stationary and movable objects were placed. Studying the rats’ exploratory behaviour allowed us to assess the impact of the sucrose diet on a broad spectrum of behaviours related to the general functioning of the organism in its environment. Analyses showed differences in reaction to novelty between different diet groups which had been placed in different experimental setups. Rats from the sugar-fed group responded to change with more pronounced exploratory behaviours directed at the source of the novel stimuli and the surrounding environment. These results may indicate a lower reward value of novelty resulting from diminished responsiveness of the reward system in the sugar-diet group. We have not found evidence for memory and/or learning impairments in rats on the sugar-rich diet.
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The gut-brain axis is believed to constitute a bidirectional communication mechanism that affects both mental and digestive processes. Recently, the role of the gut microbiota in cognitive performance has been the focus of much research. In this paper, we discuss the effects of gut microbiota and nutrition on spatial memory and learning. Studies have shown the influence of diet on cognitive capabilities such as spatial learning and memory. It has been reported that a high-fat diet can alter gut microbiota which subsequently leads to changes in spatial learning and memory. Some microorganisms in the gut that can significantly affect spatial learning and memory are Akkermansia muciniphila, Bifidobacterium, Lactobacillus, Firmicutes, Bacteroidetes, and Helicobacter pylori. For example, a reduction in the amount of A. muciniphila in the gut leads to increased intestinal permeability and induces immune response in the brain which then negatively affects cognitive performances. We suggest that more studies should be carried out regarding the indirect effects of nutrition on cognitive activities via alteration in gut microbiota.
The implications of poor maternal diet on offspring metabolic and neuroimmune development are well established. Increasing evidence now suggests that maternal obesity and poor diet can also increase the risk of postpartum mood disorders, but the mechanisms are unknown. Here we investigated the effects of a poor, high-fat-high-sugar diet (HFSD) on peripheral and central inflammation, neurogenesis and postpartum anxiety-like behaviours. We hypothesised that long-term consumption of a HFSD pre- and post-conception would increase the levels of circulating cytokines and induce microglial activation, particularly in the arcuate nucleus of the hypothalamus (ARC), as the primary brain region involved in the integration of satiety signalling; and this would lead to increased anxiety, stress responsivity and disrupted neurogenesis. We further hypothesised that these effects would be ameliorated by consumption of a healthier diet during pregnancy - specifically a diet high in omega-3 polyunsaturated fatty acids (PUFAs). As expected, the HFSD significantly increased pre-conception body weight, elevated circulating cytokines and activated microglia in the ARC, as well as in the basolateral amygdala. The HFSD also significantly increased the numbers of immature (doublecortin (DCX)-positive) neurons in the subgranular/granular region of the hippocampus, a neurogenic response that was, surprisingly, mimicked by consumption of a diet high in omega-3 PUFAs. Despite these effects of peri-pregnancy dietary imbalance, we detected no differences in anxiety-like behaviours or hypothalamic-pituitary-adrenal (HPA) axis reactivity between the groups. A shift to a healthier diet post-conception reversed the peripheral inflammation and alleviated the microglial activation. These novel data indicate the importance of a balanced peri-pregnancy diet and highlight the need for future research into key triggers that alter the neuroimmune balance in the maternal brain.
The neutral sphingomyelinase 2 (NSM 2) is involved in a multitude of diseases both inside and outside the brain. Since NSM 2 has been shown to affect dopamine signalling, which is crucial for the mesolimbic dopamine system, the effects of reduced central NSM 2 levels on reward learning were investigated in this study. To this effect, 12 male mice with a heterozygous deletion of the Smpd3 gene encoding NSM 2 (fro), resulting in a 50% reduction in its activity, and 12 male wildtype (WT) mice were observed in an unbiased conditioned place preference (CPP) paradigm with a palatable food reward (FCH) consisting of 50% powdered standard chow, 17.5% fat, and 32.5% carbohydrates. Both groups were tested in satiety due to ad libitum access to "regular chow" in their homecages. Unexpectedly, fro mice and the WT controls both established a CPP. There were no statistically significant behavioural differences between the fro mice and their WT controls. However, a trend for fro mice to eat over 40% more FCH food than WT mice during the first three days of treatment was observed and remained present after adjusting the average food consumption for the average weight of the animals. The FCH intake of fro mice remained relatively stable throughout conditioning, unlike WT mice, which increased their FCH intake steadily throughout conditioning, indicating a necessity for an initial accustomization period to a new food option in WT mice that is not present in fro mice. These findings suggest that reduced NSM 2 levels do not affect food reward learning in mice.
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Excessive consumption of sugar sweetened drinks is proposed to produce functional changes in the hippocampus, leading to perturbations in learning and memory. In this study we examined the impact of 2 h daily access to 10% sucrose (or no sucrose in controls) on recognition memory tasks in young male and female rats. In Experiment 1 we tested rats on memory tasks reliant on the hippocampus (place recognition), perirhinal cortex (object recognition), and a combination of hippocampus, prefrontal cortex and perirhinal cortex (object-in-place memory). Exposure to sucrose for 2 h a day for 14 days prior to behavioral testing did not affect object recognition, but impaired spatial memory to an extent in both male and female rats. Male rats exposed to sucrose were impaired at both place recognition and object-in-place recognition, however female rats showed no impairment in object-in-place performance. Plasticity within the hippocampus is known to increase during the proestrus phase of the estrous cycle and is related to higher levels of circulating estrogens. In Experiment 2 we tested place recognition and object-in-place memory in 10% sucrose exposed or non-exposed control female rats both during the metestrus (low estrogen) and proestrus (high estrogen) phases of their cycle on place recognition and object-in-place memory. Both sucrose exposed and control female rats were able to perform place object-in-place recognition correctly during metestrus and proestrus, however sucrose exposed rats were only able to perform place recognition correctly during proestrus. This indicates that when hippocampal function is compromised, endogenous estrogens may boost memory performance in females, and that males may be at more risk of high sugar diet induced cognitive deficits.
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We here show that living in a stimulus-rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss-of-function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals' behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro-neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end-point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
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In this study we sought to determine the effect of daily sucrose consumption in young rats on their subsequent performance in tasks that involve the prefrontal cortex and hippocampus. High levels of sugar consumption have been associated with the development of obesity, however less is known about how sugar consumption influences behavioral control and high-order cognitive processes. Of particular concern is the fact that sugar intake is greatest in adolescence, an important neurodevelopmental period. We provided sucrose to rats when they were progressing through puberty and adolescence. Cognitive performance was assessed in adulthood on a task related to executive function, a rodent analog of the Stroop task. We found that sucrose-exposed rats failed to show context-appropriate responding during incongruent stimulus compounds presented at test, indicative of impairments in prefrontal cortex function. Sucrose exposed rats also showed deficits in an on object-in-place recognition memory task, indicating that both prefrontal and hippocampal function was impaired. Analysis of brains showed a reduction in expression of parvalbumin-immunoreactive GABAergic interneurons in the hippocampus and prefrontal cortex, indicating that sucrose consumption during adolescence induced long-term pathology, potentially underpinning the cognitive deficits observed. These results suggest that consumption of high levels of sugar-sweetened beverages by adolescents may also impair neurocognitive functions affecting decision-making and memory, potentially rendering them at risk for developing mental health disorders. © 2015 Reichelt et al.; Published by Cold Spring Harbor Laboratory Press.
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An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8–10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain.
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Pain and depression are frequently associated with and often persist after resolution of an initial injury. Identifying the extent to which depression remains causally associated with ongoing physical discomfort during chronic pain, or becomes independent of it, is an important problem for basic neuroscience and psychiatry. Difficulty in distinguishing between effects of ongoing aversive sensory input and its long-term consequences is a significant roadblock, especially in animal models. To address this relationship between localized physical discomfort and its more global consequences, we investigated cellular and behavioral changes during and after reversing a mouse model of neuropathic pain. Tactile allodynia produced by placing a plastic cuff around the sciatic nerve resolved within several days when the cuff was removed. In contrast, the changes in elevated O-maze, forced-swim, Y-maze spontaneous alternation and novel-object recognition test performance that developed after nerve cuff placement remained for at least 3 weeks after the nerve cuffs were removed, or 10-15 d following complete normalization of mechanical sensitivity. Hippocampal neurogenesis, measured by doublecortin and proliferating cell nuclear antigen expression, was also suppressed after nerve cuff placement and remained suppressed 3 weeks after cuff removal. FosB expression was elevated in the central nucleus of the amygdala and spinal cord dorsal horn only in mice with ongoing allodynia. In contrast, FosB remained elevated in the basolateral amygdala of mice with resolved nociception and persisting behavioral effects. These observations suggest that different processes control tactile hypersensitivity and the behavioral changes and impaired neurogenesis that are associated with neuropathic allodynia.
Excessive consumption of added sugars negatively impacts metabolic systems; however, effects on cognitive function are poorly understood. Also unknown is whether negative outcomes associated with consumption of different sugars are exacerbated during critical periods of development (e.g., adolescence). Here we examined the effects of sucrose and high fructose corn syrup-55 (HFCS-55) intake during adolescence or adulthood on cognitive and metabolic outcomes. Adolescent or adult male rats were given 30-day access to chow, water, and either [1] 11% sucrose solution, [2] 11% HFCS-55 solution, or [3] an extra bottle of water (control). In adolescent rats, HFCS-55 intake impaired hippocampal-dependent spatial learning and memory in a Barne's maze, with moderate learning impairment also observed for the sucrose group. The learning and memory impairment is unlikely based on nonspecific behavioral effects as adolescent HFCS-55 consumption did not impact anxiety in the zero maze or performance in a non-spatial response learning task using the same mildly aversive stimuli as the Barne's maze. Protein expression of pro-inflammatory cytokines (interleukin 6, interleukin 1β) was increased in the dorsal hippocampus for the adolescent HFCS-55 group relative to controls with no significant effect in the sucrose group, whereas liver interleukin 1β and plasma insulin levels were elevated for both adolescent-exposed sugar groups. In contrast, intake of HFCS-55 or sucrose in adults did not impact spatial learning, glucose tolerance, anxiety, or neuroinflammatory markers. These data show that consumption of added sugars, particularly HFCS-55, negatively impacts hippocampal function, metabolic outcomes, and neuroinflammation when consumed in excess during the adolescent period of development. © 2014 Wiley Periodicals, Inc.
Both obesity and over-consumption of palatable high fat / high sugar “cafeteria” diets in rats has been shown to induce cognitive deficits in executive function, attention and spatial memory. Adult male Sprague-Dawley rats were fed a diet that supplemented standard lab chow with a range of palatable foods eaten by people for 8 weeks, or regular lab chow. Memory was assessed using a trace fear conditioning procedure, whereby a conditioned stimulus (CS) is presented for 10 s and then 30 s after its termination a foot shock (US) is delivered. We assessed freezing to the CS (flashing light) in a neutral context, and freezing in the context associated with footshock. A dissociation was observed between levels of freezing in the context and to the CS associated with footshock. Cafeteria diet fed rats froze less than control chow fed rats in the context associated with footshock (P<0.01), indicating that encoding of a hippocampus-dependent context representation was impaired in these rats. Conversely, cafeteria diet fed rats froze more (P<0.05) to the CS than chow fed rats, suggesting that when hippocampal function was compromised the cue was the best predictor of footshock, as contextual information was not encoded. Dorsal hippocampal mRNA expression of inflammatory and neuroplasticity markers was analysed at the end of the experiment, 10 weeks of diet. Of these, mRNA expression of reelin, which is known to be important in long term potentiation and neuronal plasticity, was significantly reduced in cafeteria diet fed rats (P=0.003). This implicates reductions in hippocampal plasticity in the contextual fear memory deficits seen in the cafeteria diet fed rats.