Food restriction increases long-term memory persistence in adult or
aged mice
F. Talhati
a, C.L. Patti
a,⁎, K.A. Zanin
a,b, L.B. Lopes-Silva
a,b, L.M.B. Ceccon
a, A.W. Hollais
a, C.S. Bizerra
a, R. Santos
a,
S. Tu
fi
k
b, R. Frussa-Filho
a,1aDepartamento de Farmacologia, Universidade Federal de São Paulo, R. Botucatu, 862, Ed. Leal Prado, 1° andar, 04023062, São Paulo, SP, Brazil bDepartamento de Psicobiologia, Universidade Federal de São Paulo, R. Napoleão de Barros, 925, 04024002, São Paulo, SP, Brazil
a b s t r a c t
a r t i c l e
i n f o
Article history:
Received 6 October 2013
Received in revised form 11 December 2013 Accepted 11 December 2013
Available online 19 December 2013
Keywords:
Consolidation Food deprivation Learning Mice Retrieval
Food restriction (FR) seems to be the unique experimental manipulation that leads to a remarkable increase in lifespan in rodents. Evidences have suggested that FR can enhance memory in distinct animal models mainly during aging. However, only few studies systemically evaluated the effects FR on memory formation in both adult (3-month-old) and aged (18–24-month-old) mice. Thus, the aim of the present study was to investigate the effects of acute (12 h) or repeated (12 h/day for 2 days) FR protocols on learning and memory of adult and aged mice evaluated in the plus-maze discriminative avoidance task (PM-DAT), an animal model that con-currently (but independently) evaluates learning and memory, anxiety and locomotion. We also investigated the possible role of FR-induced stress by the corticosterone concentration in adult mice. Male mice were kept at home cage with foodad libitum(CTRL—control condition) or subjected to FR during the dark phase of the cycle for 12 h/day or 12 h/2 days. The FR protocols were applied before training, immediately after it or before testing. Our results demonstrated that only FR for 2 days enhanced memory persistence when applied before training in adults and before testing in aged mice. Conversely, FR for 2 days impaired consolidation and exerted no effects on retrieval irrespective of age. These effects do not seem to be related to corticosterone concentration. Collectively, these results indicate that FR for 2 days can promote promnestic effects not only in aged mice but also in adults.
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
Several hypotheses had been postulated to understand the myriad of effects of food restriction (FR), done without commitment of nutrients necessary for body maintenance or causing denutrition (Masoro, 2005; Yu, 1996). In this concern, reducing calorie intake has been pro-posed to increase both lifespan, and the resistance of neurons to degen-eration (Mattson, 2000a). It can also increase resistance to cancer, diabetes and other age-related diseases in rodents (Duan et al., 2001), monkeys (Lane et al., 1999) and humans (Roth et al., 1999).
The most commonly used protocols of calorie restriction are inter-mittent feeding and paired feeding, which employs food pellets contain-ing 30–40% less calories than pellets in the control diet (Goodrick et al., 1983; Sohal et al., 1994; Talan and Ingram, 1985). Previous studies have shown that both FR protocols are neuroprotective and improve func-tional outcome in animal models of stroke, Parkinson's, Huntington's and Alzheimer's diseases (Halagappa et al., 2007; Mattson, 2005). The FR may benefit the brain by reducing levels of oxidative stress and by enhancing cellular stress resistance mechanisms.
Aging refers to the biological changes that occur during a lifetime that result in the reduced resistance to stress, increased vulnerability to disease and an increased probability of death (Anson et al., 2003). Im-portantly, aging can also affect learning and memory in rodents (Barnes, 1998; Gallagher and Burwell, 1989; Mizumori and Kalyani, 1997) and humans (Evans et al., 1984; Maki et al., 1999; Sharps and Gollin, 1987). In animals, the aging-induced memory impairments have been demonstrated in memory tasks such as the Morris water maze (Gage et al., 1989; Gallagher and Burwell, 1989; Rapp et al., 1987; van der Staay, 1997) and the radial maze (Caprioli et al., 1991; Winocur and Gagnon, 1998). While studies have shown that long-term dietary re-striction ameliorates age-related impairments in learning and memory (Goodrick, 1984; Yanai et al., 2004), other studies failed to confirm
Abbreviations:FR, food restriction; PM-DAT, plus-maze discriminative avoidance task; NIH, National Institute of Health; EDTA, ethylenediaminetetraacetic acid; CTRL, control condition; FR 12 h, food restriction lasting 12 h during 1 night; FR 2 days, food restriction lasting 12 h during 2 nights; ANOVA, analysis of variance; BDNF, brain-derived neuro-trophic factor; %TAv, percent time spent in the aversive enclosed arm; %TO, percent time spent in the open arms; NE, total number of entries.
⁎ Corresponding author at: Departamento de Farmacologia, UNIFESP, Rua Botucatu, 862, Ed. Leal Prado, 1° andar, 04023062, São Paulo, SP, Brasil. Tel.: +55 11 5549 4122; fax: +55 11 5549 4122 r. 222.
E-mail addresses:camila.patti@unifesp.br,clpatti@gmail.com(C.L. Patti). 1In memoriam.
0278-5846/$–see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2013.12.007
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this preventive effect (Beatty et al., 1987; Bond et al., 1989; Yanai et al., 2004). Even though the majority of studies show facilitatory effects of FR on cognition, these results are still inconsistent.
Although the effects of FR had been extensively studied during aging, its beneficial effects on memory formation in adulthood are little elucidated. Currently, there is no direct evidence from human studies showing the protective effect of either short-term or long-term FR on cognition in adults (Kretsch et al., 1997; Martin et al., 2007). Thus, while the vast majority of studies only evaluate the effects of a long-term FR protocol, we aimed to investigate the effects of FR for 12 h or 12 h/day for 2 days on learning and memory in adult and aged mice. These protocols occur more commonly in modern society, thus representing a better translational model. In addition, shortening the FR duration would constitute an advantage in clinical practice. Specifically, we investigated the influence of FR on an aversive mem-ory formation (acquisition, consolidation and retrieval) evaluated in the plus-maze discriminative avoidance task (PM-DAT). The PM-DAT was used to concomitantly evaluate learning, memory, anxiety-like behavior, and motor activity, as previously described (Kameda et al., 2007; Patti et al., 2006, 2010; Sanday et al., 2012, 2013a,b,c; Silva and Frussa-Filho, 2000).
2. Methods
2.1. Subjects
A hundred and forty 3-month-old andfifty-eight 18–24-month-old Swiss male mice (outbred, raised, and maintained in the Centre for Development of Experimental Models in Medicine and Biology of Universidade Federal de São Paulo) were used. Animals weighing 35–40 g were housed by a number of 4–5 in ventilated cages (Alesco®, 32 × 20 × 21 cm) under conditions of controlled temperature (22– 23 °C) and lighting (12 h light, 12 h dark; lights on at 6:45 a.m.). Food and water were availablead libitumthroughout the experiments, with the exception of those groups submitted to a period of FR.
The animals used in this study were maintained in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023), revised 2011 and with the Brazilian Law for Procedures for Animal Scientific Use (#11794/2008). The experimental procedures were approved by the Institutional Animal Care and Use Committee under the protocol #0325/12.
2.2. Food restriction (FR) protocol
During the food restriction (FR) procedure, the mice were main-tained in cages with foodad libitumall day long (CTRL—control con-dition) or were subjected to FR. The FR procedure consisted in removing all food pellets (but not water) from the cages in the be-ginning of the dark phase of the cycle (6:45 p.m.) and replacing them at 6:45 a.m. Groups of mice underwent to acute FR (lasting only 12 h during 1 night) or to repeated FR (which lasted 12 h for 2 consecutive nights).
2.3. Plus-maze discriminative avoidance task (PM-DAT)
The apparatus employed was the plus-maze discriminative avoidance task (PM-DAT), a modified elevated plus-maze, made of wood, containing two enclosed arms with sidewalls, and no top (28.5 × 7 × 18.5 cm), opposite to two open arms (28.5 × 7 cm). A non-illuminated, 100-W lamp and a hair dryer were placed over the exact center of one of the enclosed arms (aversive enclosed arm). In the training session, each mouse was placed at the center of the appara-tus and, during a 10-min period, an aversive stimulus was administered every time the animal entered the enclosed arm containing the lamp and was continued until the animal left the arm. The aversive stimuli
were the 100-W light and an air blow produced by the hair dryer over the aversive enclosed arm. In the testing, the mice were again placed in the center of the apparatus and were observed for 3 min; however, the mice did not receive an aversive stimulus when they entered the aversive enclosed arm (although the non-illuminated lamp and the hair dryer were still placed on the middle of this arm to help distinguish between the aversive and non-aversive arm). In all the experiments, the animals were observed in a blind manner, and the apparatus was cleaned with a 5% alcohol solution after each behavioral session. Total number of entries in any of the arms, percent time spent in the aversive enclosed arm (time spent in aversive enclosed arm/time spent in both enclosed arms × 100), and percent time spent in open arms (time spent in open arms/time spent in both open and enclosed arms × 100) were calculated. Learning was evaluated by the percent time spent in the aversive enclosed arm throughout the training. Memory was evalu-ated by the percent time spent in the aversive enclosed arm in the testing as whole. Anxiety-like behavior and motor activity were evaluated by the percent time spent in the open arms and the total number of entries in all the arms of the apparatus, respectively.
In the PM-DAT, avoidance of the aversive enclosed arm during testing has been validated as a measurement of memory retention be-cause amnestic manipulations decreased this effect (Carvalho et al., 2006; Claro et al., 1999; Gulick and Gould, 2009a,b, 2011; Kameda et al., 2007; Patti et al., 2006, 2010; Silva and Frussa-Filho, 2000; Silva et al., 1999, 2002a,b, 2004) and memory improving treatments increased it (Claro et al., 1999; Silva et al., 1997, 1999). This behavior-al model has behavior-also been shown to be effective in concomitantly evbehavior-alu- evalu-ating anxiety-related behaviors (Kameda et al., 2007; Patti et al., 2010; Sanday et al., 2012, 2013a,b,c; Silva and Frussa-Filho, 2000, 2002; Silva et al., 2002b) and exploratory activity (Carvalho et al., 2006; Niigaki et al., 2010; Patti et al., 2010; Silva et al., 2002a,b; Zanin et al., 2013).
2.4. Determination of plasmatic corticosterone concentration
The animals were euthanized by decapitation and the trunk blood was collected in plastic tubes containing anticoagulant (EDTA) and cen-trifuged at 3500 rpm for 15 min at 4 °C. After that, the supernatant was pipetted to another tube and stored at−80 °C until the assays.
Cortico-sterone concentration was determined in duplicate by a double anti-body radioimmunoassay method that is specific for rats and mice, using a commercially available kit (MP Biomedicals®, EUA). The sensi-tivity of the assay was 0.25 ng/ml. In addition, mice were all euthanized at the same time of day (between 07:00 and 08:00 a.m.) to minimize circadian variations.
2.5. Experimental design
2.5.1. Experiment I: effects of pre-training FR on learning and consolidation of the PM-DAT in adult mice
Thirty 3-month-old mice were allocated to 3 groups: control condi-tion (CTRL, n = 10) with foodad libitum, acute FR for 12 h (FR 12 h, n = 10) or FR for 2 days (FR 2 days, n = 10). Immediately after the FR period, the mice were trained in the PM-DAT. Ten days after training the animals were tested. A retest session was performed 30 days after the training. In this experiment, the FR groups were subjected to the training under food deprivation (but not water). Immediately after the training, food was providedad libitumand continued until the retest performance.
2.5.2. Experiment II: effects of post-training FR on consolidation of the PM-DAT in adult mice
Thirty 3-month-old mice were trained in the PM-DAT without being submitted to any experimental manipulation. Immediately after training, animals were allocated to 3 groups: control condition (CTRL, n = 10) with foodad libitum, acute FR for 12 h (FR 12 h,
n = 10) or FR for 2 days (FR 2 days, n = 10). Ten days after train-ing the animals were tested. In this experiment, the FR groups were only subjected to food deprivation (but not water) immediately after the training. Before testing, food and water were provided ad libitum.
2.5.3. Experiment III: effects of pre-test FR on retrieval of the PM-DAT in adult mice
Thirty 3-month-old mice were trained in the PM-DAT without being submitted to any experimental manipulation. Ten days after training, the animals were assigned in 3 groups: control condition (CTRL, n = 10) with foodad libitum, acute FR for 12 h (FR 12 h, n = 10) or FR for 2 days (FR 2 days, n = 10). Immediately after the FR period, the animals were tested. A retest session was per-formed 30 days after training. In this experiment, the FR groups were subjected to the testing under food deprivation (but not water). Immediately after it, food was providedad libitumand con-tinued until the retest performance.
2.5.4. Experiment IV: effects of FR on plasmatic corticosterone concentration in adult mice
Thirty 3-month-old mice were maintained in control condition (CTRL, n = 10) or were restricted of food for 12 h (FR 12 h, n = 10)
or for 2 days (FR 2 days, n = 10). Immediately after the FR period, the mice were euthanized by decapitation and their blood collected for the analysis of plasmatic corticosterone concentration.
2.5.5. Experiment V: effects of pre-training or pre-test FR on learning and consolidation or on retrieval of the PM-DAT in aged mice
Ten adult mice (3-month-old) and 12 aged mice (18–24 month-old) were subjected to control conditions (Adult-CTRL and Aged-CTRL groups, respectively). Aged mice were submitted to 2-day FR immedi-ately before training (Aged-Pretraining-FR, n = 12) or before testing (Aged-Pretest-FR, n = 12). All the groups were trained in the PM-DAT and 10 days later animals were tested. A retest session was performed 30 days after training. The Aged-Pretraining-FR group was subjected to the training session under food deprivation (but not water). On the other hand, the Aged-Pretest-FR group was submitted to food depriva-tion only before testing.
2.5.6. Experiment VI: effects of post-training FR on consolidation of the PM-DAT in aged mice
Ten adult mice (3-month-old) and 10 aged mice (18–24 month-old) were subjected to control conditions (Adult-CTRL and Aged-CTRL groups, respectively). Twelve aged mice were submitted to FR for 2 days immediately after training (Aged-FR group). The
mice were tested in the PM-DAT 10 days after training. In this ex-periment, the FR group was only subjected food deprivation (but not water) immediately after the training. Before testing, food and water were providedad libitum.
2.6. Statistical analysis
The decrease in percent time spent in the aversive enclosed arm throughout the training session was compared by ANOVA with
Fig. 2.Effects of pre-training food restriction (FR) on testing performance of adult mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Mice underwent anad libitumdiet (control condition—CTRL, n = 10) or food restriction for 12 h (FR 12 h group, n = 10) or for 2 days (FR 2 days group, n = 10) before training. Ten days after training, mice were tested. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed, (B) percent time spent in the open arms and (C) num-ber of entries in all arms of the PM-DAT apparatus. ANOVA.
Fig. 3.Effects of pre-training food restriction (FR) on the retest performance of adult mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Mice underwent an
ad libitumdiet (control condition—CTRL, n = 10) or food restriction for 12 h (FR 12 h group, n = 10) or for 2 days (FR 2 days group, n = 10) before training. Ten days after training, mice were tested and were retested after 20 days. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus.
pb0.05 compared to the other groups (ANOVA and Duncan's test).
repeated measures. All of the remaining parameters were evaluated by one-way ANOVA followed by Duncan's test when necessary. A probabil-ity of pb0.05 was considered significant.
3. Results
3.1. Experiment I: effects of pre-training FR on learning and consolidation of the PM-DAT in adult mice
In the training session, two-way ANOVA with repeated measures for the percent time spent in the aversive enclosed arm throughout the ses-sion revealed significant effects only for the time factor (minutes of ob-servation) [F(9,234) = 4.77; pb0.001] (Fig. 1A). In fact, during training there was a progressive decrease on this parameter with similar magni-tude for all of the groups. There were no significant differences among groups when the percent time spent in the aversive enclosed arm was analyzed in the session as a whole [F(2,27) = 1.60; p = 0.22] (Fig. 1B).
Regarding anxiety-like behavior, as depicted inFig. 1C, ANOVA did not show significant differences among groups in the percent time spent in the open arms of the apparatus during training [F(2,27) = 0.51, p = 0.60]. Still in this session, there were no significant differ-ences on motor activity [F(2,27) = 0.82; p = 0.45] (Fig. 1D).
In the test session, performed 10 days after training, ANOVA did not reveal significant differences for the percent time spent in the aversive enclosed arm [F(2,27) = 0.17; p = 0.84] (Fig. 2A). Still in this session, ANOVA did not show differences among groups neither for the percent time spent in the open arms [F(2,27) = 0.58; p = 0.57] nor for the total number of entries [F(2,27) = 0.20; p = 0.82] (Fig. 2B and C, respectively).
In the retest session, performed 30 days after training, ANOVA followed by Duncan's test revealed that the animals subjected to FR for 2 days presented a decreased percent time in the aversive enclosed arm compared to the other groups (the CTRL and the FR 12 h groups) [F(2,27) = 3.84; p = 0.03] (Fig. 3A). Concerning the percent time spent in the open arms, there were no significant differences among the groups [F (2,27) = 0.06; p = 0.93] (Fig. 3B). As shown inFig. 3C, no significant differences regarding the total number of entries were found [F(2,27) = 0.54; p = 0.58].
3.2. Experiment II: effects of post-training FR on consolidation of the PM-DAT in adult mice
In the training session, as expected, there were no significant differ-ences among the groups when the percent time spent in the aversive enclosed arm was evaluated [F(2,27) = 0.66; p = 0.53]. Still, ANOVA did not show differences among groups for the percent time spent in the open arms [F(2,27) = 0.33; p = 0,72]. Regarding motor activity, there were no differences among groups when the total number of en-tries was analyzed [F(2,27) = 1.11; p = 0.34] (Table 1).
In the testing, ANOVA revealed a significant effect of dietary condition [F(2,27) = 3.03; pb0.05] concerning the percent time spent in the aversive enclosed arm. In fact, Duncan's test showed that the FR,
Table 1
Basal performance in training session in PM-DAT of adult mice that underwent post-training FR.
%TAv %TO NE
CTRL 3.86 ± 0.48 20.06 ± 3.17 25.40 ± 1.97
FR 12 h 5.08 ± 1.37 24.06 ± 6.36 25.30 ± 3.14
FR 2 days 5.26 ± 0.71 19.30 ± 2.85 30.10 ± 2.54
Results are presented as mean ± SEM of percent time spent in the aversive enclosed arm (%TAv), percent time spent in the open arms (%TO), and total number of entries (NE) during the basal performance of mice in the training session of the PM-DAT. Mice (n = 10/group) were trained and their basal performance was obtained. Control condi-tion (CTRL), acute food restriccondi-tion for 12 h (FR 12 h) or repeated food restriccondi-tion for 2 days (FR 2 days). One-way ANOVA did not reveal significant differences among groups.
irrespective of its duration (FR 12 h and FR 2 days groups), induced an increase on this parameter compared to control (CTRL group) (Fig. 4A). There were no differences among groups concerning the time spent in the open arms [F(2,27) = 0.05; p = 0.95] or the total number of entries [F(2,27) = 1.69; p = 0.20] (Fig. 4B and C, respectively).
3.3. Experiment III: effects of pre-test FR on retrieval of the PM-DAT in adult mice
As expected, during training there were no significant differences among the groups when the percent time spent in the aversive enclosed arm was analyzed [F(2,27) = 0.81; p = 0.45]. Still, ANOVA did not show differences neither for the time spent in the open arms [F(2,27) = 0.13; p = 0.87], nor for the total number of entries [F(2,27) = 0.63; p = 0.54] (Table 2).
When the test session was analyzed, ANOVA did not reveal signifi -cant differences for all of the parameters analyzed: the percent time spent in the aversive enclosed arm [F(2,27) = 0.81; p = 0.45] (Fig. 5A), the percent time spent in the open arms [F(2,27) = 0.79; p = 0.46] (Fig. 5B) and the total number of entries [F(2,27) = 1.09; p = 0.35] (Fig. 5C).
In the retest session, no significant differences were detected concerning the percent time spent in the aversive enclosed arm [F(2,27) = 0.07; p = 0.93] (Fig. 6A) or in the opens arms [F(2,27) = 1.08; p = 0.35] (Fig. 6B). There were no differences among groups for the total number of entries [F(2,27) = 0.82; p = 0.45] (Fig. 6C).
3.4. Experiment IV: effects of FR on plasmatic corticosterone concentration in adult mice
As depicted inFig. 7, one-way ANOVA followed by Duncan's test re-vealed that both FR protocols (the FR 12 h and the FR 2 days groups) in-duced an increase in the plasmatic corticosterone concentration compared to the control condition (CTRL) [F(2,27) = 4,69; p = 0,01].
3.5. Experiment V: effects of pre-training or pre-test FR on learning and con-solidation or on retrieval of the PM-DAT in aged mice
In the training session, ANOVA with repeated measures for the per-cent time spent in the aversive enclosed arm throughout the session showed significant effects only for the time (minutes of observation) factor [F(9,369) = 7.34; pb0.001]. All of the groups presented a similar progressive decrement on the exploration of the aversive enclosed arm during training (Fig. 8A). Corroborating this result, there were no signif-icant differences in the percent time in the aversive enclosed arm in the session as a whole [F(3,41) = 1.19; p = 0.32] (Fig. 8B).
Regarding the percent time spent in the open arms, ANOVA did not show significant differences among the groups during training [F(3,41) = 0.59; p = 0.62] (Fig. 8C). There were no differences among the groups when the total number of entries was analyzed as well [F(3,41) = 1.13; p = 0.35] (Fig. 8D).
Regarding the test session, ANOVA did not show significant differ-ences among the groups when the percent time in the aversive enclosed
arm was analyzed [F(3,39) = 1.24; p = 0.30] (Fig. 9A). Still, ANOVA did not show differences neither for the time spent in the open arms [F(3,39) = 1.12; p = 0.35], nor for the total number of entries [F(3,39) = 1.13; p = 0.35] (Fig. 9B and C, respectively).
Table 2
Basal performance in training session in PM-DAT of adult mice that underwent pre-test FR.
%TAv %TO NE
CTRL 3.87 ± 0.55 23.52 ± 5.80 23.40 ± 2.15
FR 12 h 4.95 ± 0.67 21.52 ± 2.48 25.80 ± 2.09
FR 2 days 5.20 ± 1.06 19.96 ± 5.60 27.10 ± 2.79
Results are presented as mean ± SEM of percent time spent in the aversive enclosed arm (%TAv), percent time spent in the open arms (%TO), and total number of entries (NE) during the basal performance of mice in the training session of the PM-DAT. Mice (n = 10/group) were trained and their basal performance was obtained. Control condi-tion (CTRL), acute food restriccondi-tion for 12 h (FR 12 h) or repeated food restriccondi-tion for 2 days (FR 2 days). One-way ANOVA did not reveal significant differences among groups.
Fig. 5.Effects of pre-test food restriction (FR) on testing performance of adult mice submit-ted to the plus-maze discriminative avoidance task (PM-DAT). Mice underwent anad libitumdiet (control condition—CTRL, n = 10) or food restriction for 12 h (FR 12 h group, n = 10) or for 2 days (FR 2 days group, n = 10). Ten days after training, immedi-ately after the FR procedure, mice were tested. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus. ANOVA.
In the retest session, ANOVA and Duncan's test revealed that Aged-CTRL or Pretraining-FR groups presented an increased percent time in the aversive enclosed arm compared to the adult mice and aged mice restricted of food before testing (the Adult-CTRL and the Pretest-FR
groups, respectively) [F(3,36) = 3.66; p = 0.02] (Fig. 10A). Converse-ly, ANOVA did not show differences among groups neither for the percent time spent in the open arms [F(3,39) = 0.51; p = 0.67] (Fig. 10B) nor for the total number of entries [F(3,39) = 3.36; p = 0.02] (Fig. 10C).
3.6. Experiment VI: effects of post-training FR on consolidation of the PM-DAT in aged mice
As expected, in the training, there were no significant differences among groups when the percent time spent in the aversive enclosed arm was analyzed [F(2,31) = 0.96; p = 0.39]. There were also no dif-ferences concerning the percent time spent in the open arms [F(2,31) = 0.85; p = 0.44] or the total number of entries [F(2.31) = 0.49; p = 0.62] (Table 3).
In the testing, ANOVA and Duncan's test showed that aged mice subjected to post-training FR (the FR 2 days group) spent a significantly increased percent time in the aversive enclosed arm compared to aged mice kept under control condition (the Aged-CTRL group) [F(2,31) = 3.45; p = 0.04] (Fig. 11A). No significant differences were found in the percent time spent in the open arms [F(2,31) = 0.75; p = 0.48] (Fig. 11B) or in the total number of entries [F(2,31) 0.54; p = 0.58] (Fig. 11C).
4. Discussion
The key points of the present study are that FR for 2 days (but not the acute FR for 12 h) enhanced long-term memory persistence (evalu-ated in the retest session) both in adult and aged mice. Notably, this fa-cilitatory effect was associated with the moment that FR occurred. When FR for 2 days happened immediately before training or testing, this procedure was able to preserve the memory trace. Conversely, post-training FR for 2 days hindered consolidation regardless of age. These cognitive effects were not due to FR-induced plasmatic cortico-sterone enhancement.
Learning and memory abilities can be influenced by diet, not only during development, but also during adulthood (Gómez-Pinilla, 2008). Indeed, calorie restriction has been suggested to improve behavioral outcomes in some experimental animal models of neurodegenerative disorders and to enhance spatial memory (Mattson, 2000b). Further ro-dent studies have postulated that, as a type of metabolic stress, FR can Fig. 6.Effects of pre-test food restriction (FR) on the retest performance of adult mice
sub-mitted to the plus-maze discriminative avoidance task (PM-DAT). Mice underwent anad libitumdiet (control condition—CTRL, n = 10) or food restriction for 12 h (FR 12 h group, n = 10) or for 2 days (FR 2 days group, n = 10). Ten days after training, mice were tested and were retested after 20 days. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus. ANOVA.
facilitate memory plasticity, enhance cognition and stimulate adult hip-pocampal neurogenesis (Park and Lee, 2011).
The dopaminergic system has long been identified with the process-ing of rewardprocess-ing stimuli (Wise et al., 1978). Indeed, natural rewards (such as feeding, thirst, sex and relatives) as well as addictive drugs exert their effects by increasing dopaminergic transmission (Wise, 2008). Notably, feeding or feeding-induced prediction can induce dopa-mine release in the mesolimbic circuit (Kalivas and O'Brien, 2008; Schultz, 2004). Hence, it could be hypothesized that feeding reestablish-ment after pre-training FR for 2 days lead to dopamine stimulation. In this regard, it has been suggested that hippocampal dopamine modulates long-term memory encoding and consolidation during or early after training (Jay, 2003; O'Carroll et al., 2006). In fact, these dopamine-dependent mechanisms in the hippocampus may have fa-vored memory encoding when FR for 2 days occurred before training. On the other hand, when FR (irrespective of its duration) occurred im-mediately after training, the dopaminergic transmission might have been attenuated, thereby leading to long-term memory deficits in the discriminative avoidance task.
In line with this assumption, neurotrophic factors, including BDNF (brain-derived neurotrophic factor) may promote survivor and plastic-ity of neurons (Jankowsky and Patterson, 1999; McKay et al., 1999; Shen et al., 1997). Studies suggest that BDNF plays a crucial role in regulating dopaminergic tone. Indeed, BDNF administration was shown to pro-mote the survival and differentiation of cultured dopaminergic neurons (Hyman et al., 1991; Spina et al., 1992).
Experimental evidence has indicated that endogenous BDNF activity is also necessary for long-term memory persistence (Bekinschtein et al., 2007). It has been reported that BDNF is similarly increased in the hip-pocampus, cerebral cortex and striatum after FR in mice, suggesting that the effects of FR on BDNF levels is widespread (Duan et al., 2001). In our study, during the retest session, the adult mice subject to FR for 2 days displayed a greater avoidance of the aversive arm (Experiment I). In ad-dition, the same protocol abolished the aging-induced memory deficit (Experiment V), indicating that FR enhanced long-term memory persis-tence both in adult and aged mice without modifying encoding of the task. From a mechanistic point of view, BDNF seems to play an impor-tant role in regulating synaptic plasticity. Taking into account that FR can enhance BDNF levels, which seems to have a synaptic plasticity-enhancing effect, it could be proposed that BDNF could have exerted a beneficial effect on long-term memory persistence.
In Experiment V, the aged mice displayed memory deficits that were counteracted by the pre-test administration of FR. Several previous studies have shown that stress exposure has complex effects on cogni-tion. For the acquisition/consolidation of spatial information, the effects of stress and/or glucocorticoids follow an inverted U-shape dose– response relationship where high levels impair memory and moderate levels are necessary for the long-term storage of information (Akirav et al., 2004; de Quervain et al., 2009; Kogan and Richter-Levin, 2010; Salehi et al., 2010; Sandi, 2011; Sandi and Pinelo-Nava, 2007). Concerning retrieval, we have recently demonstrated that mild stress such as foot-shock, sleep deprivation and social isolation can reinstate Fig. 8.Effects of pre-training or pre-test food restriction (FR) on training performance of aged mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Adult (n = 10) or aged mice (n = 12) underwent anad libitumdiet (control condition—CTRL) or food restriction for 2 days before training (Pretraining-FR, n = 12) or before testing (Pretest-FR, n = 12). Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed arm throughout training session, (B) percent time spent in the aversive enclosed arm in the session as a whole, (C) percent time spent in the open arms and (D) number of entries in all arms of the PM-DAT apparatus. ANOVA.
Fig. 9.Effects of pre-training or pre-test food restriction (FR) on testing performance of aged mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Adult (n = 10) or aged (n = 12) mice underwent anad libitumdiet (control condition—CTRL) or food re-striction for 2 days before training (Pretraining-FR, n = 12) or before testing (Pretest-FR, n = 12). Mice were tested 10 days after the training session. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed arm, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus. ANOVA.
Fig. 10.Effects of pre-training or pre-test food restriction (FR) on the retest performance of aged mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Adult (n = 10) or aged (n = 12) mice underwent anad libitumdiet (control condition— CTRL) or food restriction for 2 days before training (Pretraining-FR, n = 12) or before testing (Pretest-FR, n = 12). Ten days after training, mice were tested and were retested after 20 days. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed arm, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus.★pb0.05 compared to the Adult-CTRL group and
a forgotten memory in the PM-DAT (Takatsu-Coleman et al., 2013a,b,c). In the same way, it could be hypothesized that pre-test FR had worked as a mild stress, facilitating the retrieval of the task in the retest session. It should be highlighted that Takatsu-Coleman and colleagues have re-ported the reinstatement of a forgotten memory in adult mice. In the present study, amnesia was physiologically induced by aging.
Any stressor can trigger corticosterone response (Qiu et al., 2010). In this way, it had been demonstrated that FR induced an increase of the peak concentration of plasmatic corticosterone in rodents (Sabatino et al., 1991). In the present study, the FR procedure, irrespective of its duration, enhanced plasmatic corticosterone concentration. Although the FR-induced corticosterone enhancement may have exerted some modulatory effect on cognitive performance, this modulation does not seem to be sufficient to explain the behavioralfindings, since both groups submitted to FR displayed augmented corticosterone concentra-tions but only the FR for the 2 days protocol increased memory persistence.
As corticosterone alone cannot fully explain our cognitivefindings, another possibility that could be raised is the influence of glucose levels on memory. In this way, there is a large body of literature showing that administration of exogenous glucose can enhance memory performance, including performance on amygdala-mediated tasks (Canal et al., 2005; Gold, 1995; Korol and Gold, 1998; Krebs-Kraft and Parent, 2008; Lee et al., 1988; Manning et al., 1992; McNay and Gold, 1998, 2002; McNay et al., 2006; Pych et al., 2006), which is the case of the PM-DAT (Ribeiro et al., 2011). In this regard,Sandusky et al. (2013)suggested that the met-abolic demands of mnemonic processing could be similar throughout brain regions. The same authors also suggested that optimal memory per-formance might be limited by the available glucose supply.
In this vein, as suggested byWinocur (1995), the lack of glucose in the brain could be responsible for the age-induced memory impair-ment, as the amount of glucose which is taken up by the brain declines with age. Additionally, in aged rats, the FR alone could have worsened the brain glucose levels.
As we analyzed the effects of FR on different memory phases, the glucose levels may have distinctly influenced memory formation. Spe-cifically, when consolidation was evaluated, we observed that FR im-paired it in both adult and aged mice. It should be considered that the consolidation process requires syntheses of new proteins in the late phase of long-term potentiation (Bach et al., 1999), hence demanding glucose energetic support. Thus, the putative FR-induced hypoglycemic state possibly decreased brain energy, leading to a compromised mem-ory consolidation. When FR was applied immediately before training, the animals may have performed the task under a lower glucose condi-tion. However, the subsequent post-trainingad libitumfood may have restored glucose levels, thus preventing the consolidation impairment. The FR did not alter the retrieval of the discriminative task nor in adults or in aged mice. Interestingly, although pre-test FR had exerted a positive modulatory effect on long-term memory persistence in aged animals, the FR alone did not present a direct effect on the retrieval magnitude during the testing. From the best of our knowledge, this is thefirst study that systematically evaluated the effects of FR on memory formation of an aversive avoidance task in mice at different ages.
The PM-DAT has been shown to be effective in concomitantly evalu-ating anxiety-related behaviors (Kameda et al., 2007; Patti et al., 2010; Sanday et al., 2012, 2013a) and exploratory activity (Niigaki et al.,
Table 3
Basal performance in training session in PM-DAT of aged mice that underwent post-training FR.
%TAv %TO NE
Adult-CTRL 4.35 ± 0.95 20.16 ± 5.09 26.20 ± 2.55
Aged-CTRL 6.00 ± 0.73 24.41 ± 3.02 29.67 ± 2.66
Aged-FR 5.35 ± 0.83 17.88 ± 3.07 28.50 ± 2.14
Results are presented as mean ± SEM of percent time spent in the aversive enclosed arm (%TAv), percent time spent in the open arms (%TO), and total number of entries (NE) during the basal performance of mice in the training session of the PM-DAT. Adult (n = 10) or aged mice were trained and their basal performance was obtained. Control conditions (Adult-CTRL or Aged-CTRL, n = 10) or repeated food restriction for 2 days (Aged-FR, n = 12). One-way ANOVA did not reveal significant differences among groups.
Fig. 11.Effects of post-training food restriction (FR) on testing performance of aged mice submitted to the plus-maze discriminative avoidance task (PM-DAT). Adult or aged mice underwent anad libitumdiet (Adult-CTRL, n = 10 and Aged-CTRL, n = 10; respectively) or food restriction for 2 days immediately after training (Aged-FR, n = 12). Mice were tested 10 days after training session. Data are presented as mean ± SE for (A) percent time spent in the aversive enclosed arm, (B) percent time spent in the open arms and (C) number of entries in all arms of the PM-DAT apparatus.∙pb0.05 compared to the Aged-CTRL group (ANOVA and Duncan's test).
2010; Patti et al., 2010; Sanday et al., 2013b; Zanin et al., 2013). In our study, FR was not able to modify anxiety levels or motor activity.
5. Conclusion
In summary, our study showed that FR for 2 days enhanced long-term memory persistence in adult and aged mice. The same protocol also impaired consolidation but did not alter retrieval when applied im-mediately before testing. These cognitive effects do not seem to be relat-ed to corticosterone concentration. Collectively, these results indicate that FR can exert promnestic effects not only in aged mice but also in adults, inviting for further studies.
Acknowledgments
All authors declare no conflict of interests and have no disclosures. This research was supported by fellowships from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The au-thors would like to thank Ms. Teotila R. R. Amaral, Ms. Claudenice M. Santos, Mr. Cleomar S. Ferreira and Mr. Antonio Rodrigues dos Santos Ferreira for their capable technical assistance. S.T. is recipient of the CNPq fellowship.
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