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Article

High-Linoleate and High--Linolenate Diets Affect Learning Ability and Natural Behavior in SAMR1 Mice

^a Department of Nutrition, Koshien University, 10-1 Momijigaoka, Takarazuka, Hyogo 665-0006, Japan, ^b Senescence Biology, Chest Disease Research Institute, Kyoto University, Kyoto, Japan, ^c Department of Molecular Physiology Chemistry, Osaka University Medical School, Osaka, Japan, ^d Department of Neurology, Faculty of Medicine, Kyoto University, Kyoto, Japan and ^e Department of Psychology, Faculty of Letters, Kyoto University, Kyoto, Japan

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Semipurified diets incorporating either perilla oil [high in -linolenate, 18:3(n-3)] or safflower oil [high in linoleate, 18:2(n-6)] were fed to senescence-resistant SAMR1 mouse dams and their pups. Male offspring at 15 mo were examined using behavioral tests. In the open field test, locomotor activity during a 5-min period was significantly higher in the safflower oil group than in the perilla oil group. Observations of the circadian rhythm (48 h) of spontaneous motor activity indicated that the safflower oil group was more active than the perilla oil group during the first and second dark periods. The total number of responses to positive and negative stimuli was higher in the safflower oil group than in the perilla oil group in the light and dark discrimination learning test, but the correct response ratio was lower in the safflower oil group. The difference in the (n-6)/(n-3) ratios of the diets reflected the proportions of (n-6) polyunsaturated fatty acids, rather than those of (n-3) polyunsaturated fatty acids in the brain total fatty acids, and in the proportions of (n-6) and (n-3) polyunsaturated fatty acids in the total polyunsaturated fatty acids of the brain phospholipids. These results suggest that in SAMR1 mice, the dietary -linolenate/linoleate balance affects the (n-6)/(n-3) ratio of brain phospholipids, and this may modify emotional reactivity and learning ability.

KEY WORDS: • senescence-accelerated mouse • -linolenic acid • linoleic acid • open field activity • circadian rhythm • discrimination learning

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Docosahexanoate [22:6(n-3)] derived from -linolenate [18:3(n-3)] is abundant in the brain and retina (Harman et al. 1976 , Lamptey and Walker 1976 ), and we thus hypothesized a negative effect on brain function of (n-3) fatty acid deficiency in the presence of sufficient (n-6) fatty acids. Behavioral studies reported deficits in learning paradigms associated with dietary (n-3) fatty acid deficiency in rats and mice (Bourre et al. 1989 , Lamptey and Walker 1976 , Wainwright 1992 , Yamamoto et al. 1987 and 1988 ). The inferior learning of rats fed an -linolenate-deficient diet was reported in a simple Y-maze test (Lamptey and Walker 1976 ), but not in a more complex X-maze test (Bivins et al. 1983 ). The correct response ratios in a brightness-discrimination learning test were higher in rats fed an -linolenate-rich diet than in those fed an -linolenate-deficient diet (Yamamoto et al. 1987 and 1991 ). In the studies of learning tasks in which food or electrical shock was used as the motivating stimulus, it is difficult to determine whether these diet-induced effects on learning performance should be attributed to differences in learning and memory improvement, or whether they reflect differences in sensory thresholds or behavioral reactivity to the test situation.

The senescence-accelerated mouse (SAM),⁴a murine model of accelerated senescence, was successfully established by our group (Takeda et al. 1981 and 1991 ). We obtained nine inbred strains of senescence-prone SAM-P strains (SAMP1, P2, etc.) and three inbred strains of senescence-resistant SAM-R strains (SAMR1, R4, R5 etc.) (Chen et al. 1989 , Higuchi et al. 1983 , Hosokawa et al. 1988 , Matsushita et al. 1986 , Miyamoto et al. 1986 , Shimada et al. 1992 ). The SAMP8 mice showed a significant age-related impairment in learning tasks, such as passive avoidance, one-way active avoidance and water maze tasks, compared with SAMR1 mice, a control strain with normal aging characteristics and no age-related deterioration of memory or learning ability (Flood and Morly 1992 , Ingram 1988 , Miyamoto et al. 1986 , Yagi et al. 1988 ). SAMP8 mice also showed an age-associated increase in spontaneous motor activity (SMA) and in diurnal SMA (Miyamoto et al. 1986 ), as well as hyperactivity in open field tests (Yagi et al. 1988 ), and age-related reduced anxiety-like behavior (Miyamoto et al. 1992 ).

We recently established that SAMP8 mice fed an -linolenate-rich (perilla oil) diet had greater learning ability and exhibited less hyperactive behavior than those fed an -linolenate-deficient (safflower oil) diet (Umezawa et al. 1995 ). The improvement in learning and behavior in SAMP8 mice receiving perilla oil led us to consider whether the -linolenate-rich diet improved a learning and memory mechanism and/or affected behavioral reactivity. This study was undertaken to clarify the differences in learning ability and natural behavior between SAMR1 and SAMP8 mice fed an -linolenate-rich diet and those fed an -linolenate-deficient diet. The tests used were open field activity, circadian rhythm of spontaneous motor activity and light and dark discrimination learning.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Animals and diets.

SAMR1 mice, born and reared in our laboratory under conventional conditions, were used. Purified diets containing 9% perilla oil or safflower oil were fed to SAMR1 mice from 6 wks of age. These mice were mated at 12 wk of age, and the offspring were fed the same diet as their parents. The composition of the diet was published (Umezawa et al. 1993 ). Briefly, the diets contained the following: 25% soybean protein isolate, 0.3% DL-methionine, 32.7% corn starch, 25% sucrose, 2% cellulose powder, 5% mineral mixture (Umezawa et al. 1990 ), 1% vitamin mixture (Umezawa et al. 1990 ) and 9% oil. The major fatty acids compositions of the diets are shown in Table 1. The offspring (males from several dams) were subjected to learning and behavioral tests at 15 mo of age. All the mice were housed in groups of 2–4 in cages, with free access to food and tap water, at a temperature of 24 ± 2°C under a 12-h light/dark cycle with lights on at 0700 h. All the tests were performed between 1400 and 1900 h; background noise was constant. All animals were maintained according to the policies and recommendations of the Kyoto University Animal Care and Use Committee.

To investigate age-related changes in exploratory behavior, the activities of each mouse were observed in a novel open field environment according to the method described previously (Shimada et al. 1992 ). The open field box was a 72-cm square with walls 50 cm high and made of gray plastic. The floor was divided by thin black lines into 64 squares measuring 9 x 9 cm. The field was illuminated with ceiling fluorescent lights. Each mouse was placed in one of the 4 squares in the center of the field and observed directly and continuously for 5 min, including the time spent on grooming and freezing. The following behavioral components were registered: locomotion—the number of squares into which the center of the body of the mouse entered during the 5-min test period; rearing—the number of times the mouse stood on its hind legs with the forepaws free; learning—the number of times the mouse stood on its hind legs with one or two forepaws against the wall; grooming—the number of groomings; face cleaning—the number of face-cleaning episodes using two forepaws; defecation—the number of defecations; urination—the number of urinations.

Measurement of spontaneous motor activity (SMA).

SMA was determined by the measurement of locomotor activity using the Animex Auto (Muromachi Kikai Instruments, Kyoto, Japan). For assessing the circadian rhythm, the SMA counts of each mouse were recorded from time zero to 48 h after being placed in the activity box at 0700 h, under a 12-h light/dark cycle with lights on at 0700 h and free access to food and water.

Light and dark discrimination learning test.

This learning test was performed as previously described (Umezawa et al. 1995 ). A Skinner box for mice in a sound-attenuated cubicle had a food container on its front wall and a lever near the right-hand corner of the same wall. A light for presenting a positive or a negative stimulus (S+ or S-) was located on the ceiling. Experimental events were controlled and recorded automatically by a microcomputer.

Each dietary group was divided into two equal subgroups, one being subjected to light and the other to dark as positive stimuli to avoid the influence of visual sensitivity in the learning tests (Benolken et al. 1973 , Neuringer et al. 1986 ). The food consumption of the mice was controlled to maintain body weight at 85–90% of normal throughout the experiments. The mice were trained in the Skinner boxes by continuous reinforcement of light or dark stimulation for 15 min/day. From d 1 to d 6, each mouse was given one pellet when it touched or pressed a lever, up to a maximum of 20 reinforcements. After the completion of reinforcement, the mouse was trained for variable intervals of 5 s, on average, of pellet reinforcement until the number of reinforcements reached 20. Then the light-and-dark-discrimination learning test was performed. When light was a positive stimulus, it shone on the floor for 20 s (S+), and the lever-pressing response was reinforced, and when it was dark (S-), no pellet was given when the mouse pressed the lever. When dark was positive and light the negative stimulus, the conditions were reversed. The variable interval was 15 s; the stimulus was presented for 20 s and randomized by the Gellerman sequence (Gellerman 1933 ). One session consisted of 20 S+ and 20 S- stimuli (20 S+ and 20 S-), and was carried out once a day with 18 sessions being run for each subject. The correct response ratio, R+/(R+ + R-) x 100, was calculated from the number of correct responses (R+) during S+ stimulation and that of incorrect responses (R-) during S- stimulation in a session.

In addition to the abovementioned experiments, we conducted another experiment during session 19 in the safflower oil and perilla oil groups. During this session, when the mouse pressed the lever, no pellet was given in response to either light or dark stimuli (S+ and S-), that is, a pellet was not given even in response to a positive stimulus. The aim was to confuse the mice and to observe the discrimination learning (the lever pressing response) of the mice when the learning situation unexpectedly changed.

Lipid extraction and analysis.

After the behavioral tests, the mice were anesthetized with pentobarbital and the brains were perfused with phosphate-buffered saline through the heart. The whole brains were removed, frozen and stored in liquid nitrogen. Lipid extraction and analysis were carried out as reported previously (Umezawa et al. 1995 ). Lipids were extracted from the frozen brains with hexane-2-propanol according to the method of Hara and Radin (Hara and Radin 1978 ). The lipid extracts were separated into major phospholipid classes by high performance liquid chromatography (Briand et al. 1981 , Kuhnz et al. 1985 ) with some modifications. The fatty acids of individual phospholipids were analyzed by gas–liquid chromatography using a capillary column (Omegawax 320, Spelo).

Statistical analysis.

For the circadian rhythm of SMA and the light and dark discrimination learning test, data were evaluated by two-way (diet and light, stimulus and training, and diet and training) ANOVA, and significant differences between dietary groups and between stimuli were determined by the Newman-Keuls test. For the open field activities, the differences between the two dietary groups were assessed by the Mann-Whitney U-test. Comparisons between fatty acid composition in brain phospholipids with the two dietary groups were made using Student's t test. Statistical significance of differences was established when P < 0.05.

	RESULTS

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Open field activities.

The amount of locomotor activity recorded during a period of 5 min was significantly greater in the safflower group than in the perilla group (P < 0.05) (Table 2 ).The extent of rearing behavior and leanings did not differ between the two groups. Neither group groomed during the 5-min observation period, and the groups did not differ in incidences of face-cleaning, defecation or urination.

A typical circadian rhythm with very high SMA in the dark period and very low SMA in the light period was observed in both groups (Fig. 1 A).In the safflower oil group, the SMA counts in both dark periods were significantly higher than in the perilla group (Fig. 1B , P < 0.05), and in addition, the SMA counts in the first dark period were higher than those in the second dark period (P < 0.05). On the other hand, the SMA counts in the first light period did not differ significantly between dietary groups, but in the second light period, the SMA counts in the safflower oil group were significantly higher than those in the perilla oil group (P < 0.05).

View larger version (31K): [in this window] [in a new window]   Figure 1. Circadian rhythm of spontaneous motor activity (SMA) of SAMR1 mice fed a safflower oil diet or a perilla oil diet at 15 mo of age for 400 d. Values are means ± SEM, n = 8 (safflower group) or 9 (perilla group). (A): number of SMA for 48 h starting at 0700 h. Each point represents the SMA counts per 2 h. (B): total number of SMA counts per dark and light periods. The effect of light was significant (P = 0.0001) as was the light x diet interaction (P = 0.03). Different letters indicate a significantly different means, P < 0.05.

In the training for the learning test, all mice obtained 20 reinforcement pellets within 5 min by d 6. The total number of lever presses in response to both the positive stimulus (R+; correct response) and the negative stimulus (R-; incorrect response) in the mice fed safflower oil increased gradually; the R+ response increased steadily (P < 0.05) from the 8th session, whereas the R- response tended to decrease (P < 0.10) as the sessions continued (Fig. 2 A).The total response (R+ + R-) in the perilla group decreased as the sessions continued; the R+ response slightly decreased (P < 0.05), while the R- response continued to decrease (P < 0.05) as the sessions continued (Fig. 2B) . In the two dietary groups, the level of R+ response was significantly higher than that of R- response after the 8th session. In consequence, as shown in Fig. 2C , the correct response ratio, R+/(R+ + R-) x 100, tended to be lower in the safflower oil group than in the perilla oil group (P = 0.09).

View larger version (22K): [in this window] [in a new window]   Figure 2. Light and dark discrimination learning test for SAMR1 mice fed a safflower oil (A) or perilla oil diet (B). R+: Correct response to positive stimulus when mouse was given a pellet in response to lever pressing; R-: incorrect response to negative stimulus when no pellet was given; R+ + R-: total number of lever presses. Values are means ± SEM, n = 8 (safflower group) or 9 (perilla group). (A): The effect of training was significant (P = 0.001) as was the training x diet interaction (P = 0.0001). *P < 0.05, **P < 0.01 compared to R- response at each session. (B): The effect of training was significant (P = 0.0001) as was the training x diet interaction (P = 0.01). *P < 0.05, **P < 0.01 compared to R- response at each session. (C): Correct response ratio in the light and dark discrimination learning test. The correct response ratio, R+/(R+ + R-) x 100, was calculated from the data presented in A and B. The effect of training was significant (P = 0.0001), the training x diet interaction was not significant (P = 0.09).

View larger version (17K): [in this window] [in a new window]   Figure 3. Number of lever presses during the 19th session in the light and dark discrimination test for SAMR1 mice fed a safflower oil (A) or perilla oil (B) diet R+: response to positive stimulus when mouse was given a pellet in response to lever pressing until the 18th session, R-: response to negative stimulus when no pellet was given until the 18th session. Values are means ± SEM, n = 8 (safflower group) or 9 (perilla group). (A): The effect of training was significant (P = 0.0001), and the training x stimulus interaction was not significant (P = 0.46). *P < 0.05 compared to R- response at each session. (B): The effect of training was significant (P = 0.0001) as was the training x stimulus interaction (P = 0.03). *P < 0.05 compared to R- response at each session.

Food intake and body weights did not differ between the mice fed the safflower oil diet and those fed the perilla oil diet. Brain weights also did not differ and were 451.6 ± 17.3 mg (safflower oil group), 444.6 ± 16.7 mg (perilla oil group). Whole brain total phospholipid phosphorus concentrations were 61.8 ± 10.2 µmol/g in the safflower oil-fed group and 51.0 ± 2.3 µmol/g in the perilla oil-fed group (P > 0.05). The difference in the (n-6)/(n-3) ratio of the diets was reflected in the (n-6)/(n-3) fatty acid ratios in the brain phospholipids (Table 3 ).There was no significant difference in the proportions of (n-3) polyunsaturated fatty acid (PUFA) between the two diet groups, despite a marked difference in the proportions of -linolenate in the two diets (safflower oil, 0.3%; perilla oil, 58.5% of the total). On the other hand, the proportions of (n-6) PUFA in the brain phospholipids clearly reflected the difference in the (n-6)/(n-3) ratio of the diets. The proportions of total PUFA in the brain phospholipids was significantly higher in the safflower oil group than in the perilla oil group (P < 0.01), whereas the proportions of saturated fatty acids (SFA) and monounsaturated fatty acids in brain phosphatidylethanolamine (PE) were significantly higher in the perilla oil group than those in the safflower oil group (P < 0.05). The difference in the -linolenate/linoleate ratios of the diets reflected the differences in the proportions of (n-6) and (n-3) PUFA and the (n-3)/(n-6) ratios when expressed relative to total PUFA (Table 4 ).The relative lack of -linolenate in the safflower oil diet led to a major decline in 18:3(n-3), 18:4(n-3), 20:5(n-3), 22:5(n-3), 22:6(n-3) and total (n-3)PUFA in the total PUFA of brain PE and phosphatidylcholine (PC); however, there was a compensatory increase in 20:4(n-6), 22:4(n-6) and 22:5(n-6), three fatty acids that can be produced from linoleate. On the other hand, the proportion of 20:5(n-3), 22:5(n-3), 22:6(n-3) and total (n-3) PUFA in the total PUFA of brain PE and PC were higher in the perilla oil group than in the safflower oil group.

	DISCUSSION

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Measures of open field behavior are generally considered indicators of emotion in rodents (Archer 1973 ), assuming that decreased activity is related to increased emotion. Previous studies on behavioral arousal showed fewer episodes of wall-leaning (Lamptey and Walker 1976 ) and decreased exploratory activity in the open field in rats fed (n-3)-deficient diets (Enslen et al. 1991 ), but no change in motor activity compared with rats fed an -linolenate-rich diet (Bourre et al. 1989 ). Reportedly, significant increases in the open field activity of (n-3)-deficient mice indicate increased arousal (Wainwright et al. 1994 ). In SAMR1 mice, the locomotor activity in the open field decreased as the exploration time increased (Shimada et al. 1992 ), suggesting that emotion may have a positive relationship with activity. Locomotor activity during a 5-min period in the novel environment of an open field was significantly greater in SAMR1 mice fed safflower oil than in those fed perilla oil.

Observation of the circadian rhythm of SMA over a 48-h period revealed that SAMR1 mice fed safflower oil had significantly higher activity in the first and second dark periods than did the perill oil-fed group, despite indicating that the mice fed safflower oil adapted to a novel environment in the experimental box. These motor activity findings suggested that SAMR1 mice fed safflower oil normally showed hyperactive reactivity, while those fed perilla oil normally exhibited a low degree of activity.

Although the correct response ratios in the dietary groups did not differ in the light and dark discrimination learning tests, the two groups were not similar in their lever pressing performance. The number of incorrect responses (R-) in the perilla oil decreased markedly as the session continued, while those in the safflower oil group decreased only slightly (P < 0.10). That is, the mice fed perilla oil definitely acquired more discriminative learning ability than those fed safflower oil. On the other hand, in the 19th session, the perilla oil group promptly coped with the change in the situation more than did the safflower oil group. Those behavioral findings coincide with those in SAMP8 mice reported previously (Umezawa et al. 1995 ).

Despite the severity of the dietary treatments, the levels of (n-3) PUFA in the total fatty acids of brain PE and PC did not differ between the two groups. Our findings were not consistent with those in SAMP8 mice and previous works, in which the level of (n-3) PUFA in rodent brains reflected the ratio of dietary (n-3) to (n-6) PUFA (Bourre et al. 1984 , Galli et al. 1971 , Nakasima et al. 1993 , Umezawa et al. 1995 , Wainwright 1992 , Yamamoto et al. 1987 ). The differences between the SAMR1 mice and SAMP8 mice and other studies may be related to differences in experimental species, strains or feeding periods. The influences of dietary (n-3) PUFA deficiency were marked in rat brain phospholipids compared with mice brain phospholipids (Nakashima et al. 1993 , Yamamoto et al. 1987 ). The level of (n-3) PUFA in the brain phospholipids of SAMP8 mice fed safflower oil exhibited a more significant decrease than did those fed perilla oil, but the decrease was quantitatively low (Umezawa et al. 1995 ). The reduction of [22:6(n-3)] in brain phospholipids in dietary (n-3) PUFA-deficient rats was less with advanced age than young age (Delion et al. 1997 ). However, we thought that the dietary treatment in this study influenced the fatty acid compositions of phospholipid from brains of SAMR1 mice, because the (n-6)/(n-3) ratio of the diets reflected the (n-6) and (n-3) fatty acid composition of total PUFA in the brain phospholipids.

We conclude that the better learning performance previously observed in SAMP8 mice fed a perilla oil is associated with diet-induced effects on learning and memory ability and emotional reactivity, as in the SAMR1 mice fed perilla oil in this study. The reduced locomotor activity in the open field and circadian rhythm and a markedly lower number of lever press responses in the perilla oil-fed group were noted, although there were no significant differences in body weight or appearance between the safflower oil- and perilla oil-fed groups. Interpretation of the positive relationship between fatty acid composition in brain phospholipids, behavioral effects and learning ability is still unclear, so further studies are needed.

	ACKNOWLEDGMENTS

 
We thank Zhu Bing-Hua at Kyoto University for technical assistance.

	FOOTNOTES

 
¹ To whom correspondence should be addressed.

¹ Soybean protein isolate was a generous gift from the Fuji Oil Company, Osaka. This work was supported by a grant from the Ministry of Education, Science, Sports & Culture and the Ministry of Health and Welfare of Japan, and by a Special Research Grant from Koshien University.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked ''advertisement'' in accordance with 18 USC section 1734 solely to indicate this fact.

³ Abbreviations used: MUFA, monounsaturated fatty acids; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PUFA, polyunsaturated fatty acids; SAM, senescence-accerelated mouse; SMA, spontaneous motor activity.

Manuscript received April 22, 1998. Initial review completed June 15, 1998. Revision accepted November 4, 1998.

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