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2 Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1 and 3 Department of Pharmacology and Toxicology and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724
* To whom correspondence should be addressed. E-mail: gyoung01{at}uoguelph.ca.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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Niacin was identified as a vitamin following years of devastation by the disease pellagra. Pellagra, the disease of niacin deficiency, is characterized by the 4 Ds of dermatitis, diarrhea, dementia, and death (1). The dementia of pellagra is similar to schizophrenia, in which patients show signs of depression and apprehension that progress to paranoia, delirium, hallucinations, and violent behavior as the disease worsens. Strikingly, the majority of psychological functioning is recovered within days when insane patients with pellagra are treated with niacin, which suggests that the dementia is caused by alterations in neural signaling pathways, rather than structural pathological changes (1).
Although the evidence from pellagra clearly indicates that niacin is involved in neural functioning, minimal investigation has considered the effects of either niacin deficiency or pharmacological niacin supplementation on cognitive abilities. Such investigations are warranted, as both clinical (12,13) and subclinical (14,15) niacin deficiencies continue to occur, and pharmacological treatment with nicotinamide has been investigated as a preventative treatment for type 1 diabetes in children (16–18). Additionally, although studies have shown that dietary niacin can modify NAD+ in various tissues (19–21), effects on cADPR are unknown. It was therefore the objective of our study to determine whether niacin deficiency and pharmacological nicotinamide supplementation have an effect on spatial learning ability in young male Long-Evans rats as assessed by the Morris Water Maze (MWM), and whether brain cADPR, like brain NAD+, is modified by dietary niacin intake.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Male weanling Long-Evans rats (initial weight; 35–40 g) (Charles River Canada) were housed singly in wire-bottomed cages with unrestricted access to water. Rats were fed between 1000 and 1200 each day, weighed biweekly, and maintained on a 12:12 light:dark cycle (light from 0600–1800) at 22 ± 2°C. The study was approved by the Animal Care Committee at the University of Guelph and adhered to the standards set forth by the Canadian Council on Animal Care. During the course of each experiment, any animal that demonstrated a >10% weight loss from the peak weight on 2 successive weighings was considered moribund and was euthanized.
Dietary manipulations
Rats were fed a nutritionally complete AIN-93 (22) diet with modifications as followed below.
Expt.1: Niacin deficiency vs. pair feeding. The niacin-deficient (ND) group was fed a diet containing 0 mg nicotinic acid/kg, whereas the pair-fed (PF) group was fed a control diet containing 30 mg nicotinic acid/kg diet (Table 1). There were 8 rats in each group, and each ND rat was weight-matched to a PF counterpart. The amount of food consumed by each ND rat was determined daily, and the same amount of food was given to its PF partner. The pair-feeding strategy was used to maintain equivalent food consumption between the 2 groups. In wk 5 of the experiment, 3 rats in the ND group became moribund and were euthanized along with their PF partners, leaving n = 5.
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Expt. 3: Niacin deficiency vs. niacin recovery. All rats were considered as 1 group for the first 25 d of the experiment and were variably maintained on a diet containing either 0 mg added nicotinic acid/kg diet, or 1 mg added nicotinic acid/kg diet, depending on body weight. The addition of 1 mg nicotinic acid · kg–1 · d–1 was implemented when rats showed a 5% weight loss. When weight stabilized, rats were placed back on the 0 mg added nicotinic acid/kg diet. There were 30 rats in total. On d 26, rats were randomized into 2 groups based on weight, with 15 rats being placed in the recovered (REC) group and 15 rats remaining in the ND group. Each ND rat was weight-matched to a REC counterpart. On d 26 and d 27, the REC group consumed a diet containing 1 g added nicotinamide/kg diet to allow for rapid replenishment of body tissues with niacin. On these days, REC rats consumed food ad libitum. On d 28, and continuing to d 33, the REC group was fed the regular control diet containing 30 mg added nicotinic acid/kg diet. REC rats were pair fed during this period. Initially, there were 15 rats in each group. In the 4th week of the experiment, 6 ND rats became moribund and were euthanized along with their corresponding REC partners, leaving n = 9 in both groups.
Expt. 4: Niacin supplementation vs. control. The niacin-supplemented (SUPP) group was fed a diet containing 4 g added nicotinamide/kg diet, whereas the control (CON) group was fed a diet containing 30 mg added nicotinic acid/kg diet (Table 1). There were 18 rats in the SUPP group and 15 rats in the CON group. All rats were fed the control diet ad libitum for a 2-d period prior to dietary manipulation. The amount of food eaten daily during this period by each rat was determined and correlated to body weight, allowing for an estimation of the mean amount of food eaten · d–1 · g–1 body wt. The amount of food was initially determined at 0.15 g/g body wt, and this value was used to calculate the amount of food provided on each day of the experimental period. This level of food provision was used throughout the experiment, insofar as the residual food per day suggested we allow ad libitum, or nearly ad libitum, feeding to all rats. This model allowed a more uniform food intake than the pair-feeding model used during niacin deficiency, and worked in this case because of the consistent food intake of these rats.
Morris Water Maze apparatus and procedures
The Morris Water Maze (MWM) apparatus was the same as previously described (23). In brief, the MWM consisted of a circular pool, 180 cm in diameter and 60 cm in height, with the interior painted white. The escape platform was made of clear plexiglass, 14 cm in diameter and 15 cm in height, and was located 
1 cm below the surface of the water. Visual cues were visible to the rats, including 4 geometric shapes that measured at least 20 cm in height and were positioned so that they were 15 cm above water level and remained distal to the rats at all times. The water was maintained at a temperature of 22 ± 2°C, and was made opaque by the addition of nontoxic white latex paint (Crayola). Movement of rats in the pool was analyzed by a digital tracking system (Columbus Instruments). The software used in analysis of behavior was Water Maze, version 4.20 (Columbus Instruments). The maximum trial time in each phase of the experiment was 90 s. If the time limit was exceeded, the animal was gently guided to the platform where it remained for 15 s. The starting location was varied in each trial, and the sequence of start locations was randomized across days. Following the completion of the trial, rats were allowed to warm and dry off under heat lamps in holding cages before being returned to their home cage. There were 3 trials/d with an intertrial interval of 2 h. Due to the time required to complete 3 trials, rats were tested during both the 1st and 2nd part of their light cycle.
In Expt. 1 and 2, testing in the MWM began on d 21 of the experiment; in Expt. 3, testing in the MWM began on d 20 of the experiment; and in Expt. 4, testing in the MWM began on d 15 of the experiment. In each experiment, there was an acquisition phase that lasted 6 d. In Expt. 3, there was also a reversal training phase, in which the platform was moved to a new location, that lasted 4 d. The platform was moved to the opposite quadrant of the pool and was placed 10 cm closer to the pool wall during reversal training. All other water maze procedures remained the same during this period. Reversal training in Expt. 3 began after 4 d of niacin refeeding, on d 30 of the experiment. During reversal training, the REC were fed a niacin-replete diet, whereas during acquisition they were fed a ND diet. Following completion of the last run of training in each experiment, a probe trial was run in which the platform was removed from the pool and the rats were allowed to swim freely for 30 s. The pool was divided into 4 quadrants of equal size, and the number of crossings of the target platform in the target quadrant were measured and compared against the number of crossings of the symmetrical platform locations in the other 3 quadrants of the pool.
For each trial, measures of cumulative error, measured in cm, were obtained. Cumulative error was the combined measure of the latency of swimming and how far the rat deviated from an ideal swim path, and it helped to eliminate the influence of swim speed on the results (24). The results of the 3 daily trials were averaged to give a mean value for each day of testing.
Schematic representations of the diet and water maze procedures in each of the 3 niacin deficiency experiments are shown in Figure 1.
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For preparation of brain tissue isolated from rats in Expt. 1, rats were anesthetized with Isofluorane (Fisher Scientific) and the heads were then submerged in liquid nitrogen for 1 min. This method of termination was used to maintain brain energy metabolism, which requires freezing of the brain while oxygenated blood is still circulating (25,26). Heads were collected and returned immediately into liquid nitrogen and then stored at –80°C. Later, the brain was dissected out of the skull while still frozen and homogenized in a solution of ice cold 1 mol/L perchloric acid (PCA) at a concentration of 0.1 g of tissue to 1 mL PCA, using an electric homogenizer (Pro250, 10 mm head). Samples were centrifuged twice for 10 min, with the 1st at 1000 x g and the 2nd at 14000 x g. The aqueous layer was recovered from both centrifugations. For preparation of brain tissue isolated from rats in Expt. 2 and 4, anesthetized rats were decapitated with a guillotine and the brain was rapidly dissected out of the skull and placed immediately into liquid nitrogen and stored at –80°C. This method of termination was used after observing that NAD+ and cADPR levels did not differ significantly between rats that had undergone termination by submersion in liquid nitrogen and those that had been decapitated under anesthesia (unpublished observations). Frozen tissue was then treated in an identical manner to that described for Expt. 1.
Measurement of cADPR
The assay used to measure levels of cADPR was the cycling assay described in (27) with the modifications described in (28). Brain cADPR measurements were made on d 35 in Expt. 1, on d 33 in Expt. 3, and on d 21 in Expt. 4. There was no measurement of cADPR in Expt. 2.
Measurement of NAD+
Samples were diluted 5-fold in PCA from the initial concentration of 0.1 g of tissue to 1 mL of PCA. Upon thawing, all samples were neutralized to between pH 6.7 and 6.8 with 2 mol/L potassium hydroxide and analyzed for NAD+ content via the enzyme cycling of alcohol dehydrogenase (29). Brain NAD+ measurements were made on d 35 in Expt. 1, d 33 in Expt. 3, and d 21 in Expt. 4. There was no measurement of NAD+ in Expt. 2.
Statistical analysis
All statistical analyses were performed using SPSS, version 12.0 for Windows. Significance was determined at P 
0.05. A trend was defined as a P-value between 0.05 and 0.1. The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to evaluate normality. Because water maze data in each experiment showed an abnormal distribution on at least 1 experimental day, nonparametric tests were used to assess water maze performance. The Friedman test was performed to determine the within-subjects effect, and the Kruskal-Wallis test was performed to determine the between-subjects effect. The within-subjects factor was time (test day) and the between-subjects factor was diet. For probe trial analysis, 1-way ANOVA was used to compare the number of platform crossings at each of the 4 possible platform locations. Two-tailed independent t tests were used to compare mean swim speeds and brain nucleotides. Data were not transformed before analysis.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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0.001) (Fig. 2). ND rats swam faster than PF rats (P < 0.001) (Table 2). During the probe trial (90-s swim with platform removed) ND rats crossed platform 2 (the previous platform location) more times than the analogous positions in quadrants 1, 3, and 4 (P < 0.05). PF rats tended to cross platform 2 more times than platform 3 (P = 0.1). ND rats tended to cross the target platform more times than PF rats (P = 0.09) (data not shown). Brain NAD+ and cADPR (Table 3) concentrations were less in ND rats than in PF controls (P < 0.02).
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0.001) (Fig. 4). ND rats swam faster than PFR rats (P < 0.001) (Table 2). In the probe trial, ND and PFR rats crossed platform 2 (the previous platform location) more times than platforms 1, 3 and 4 (P < 0.05). ND and PFR rats did not differ in the number of crossings of the target platform (data not shown).
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0.001) (Fig. 5). ND rats swam faster than REC rats (P < 0.001) during reversal training but not in a retrospective analysis of swim speed during acquisition, when both groups were still deficient (Table 2). ND and REC rats crossed platform 3 (the target platform) more times than platform 1, 2, and 4 (P < 0.05) and did not differ in the number of crossings of the target platform (data not shown). Brain NAD+ and cADPR (Table 3) concentrations in ND rats were less than in REC controls (P 0.001).
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0.001) (Fig. 6). SUPP rats swam faster than CON rats (P = 0.001) (Table 2). SUPP rats crossed platform 2 (the target platform) more times than platforms 3 and 4 (P < 0.01), and tended to cross platform 2 more times than platform 1 (P = 0.07). Similarly, CON rats crossed platform 2 more times than platforms 1, 3, and 4 (P < 0.01). SUPP and CON rats did not differ in the number of crossings of the target platform (data not shown). Brain NAD+ and cADPR (Table 3) concentrations in SUPP rats were higher than in CON controls (P < 0.02).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Niacin deficiency positively affected spatial learning ability in each of the 3 niacin deficiency experiments. In the 1st experiment, control rats were pair fed a diet containing 30 mg added nicotinic acid/kg diet throughout the duration of the experiment. This level is considered adequate to fully meet the needs of rats and is found in AIN93 formulations and most commercial rat chows. The pair-feeding model was used to control for differences in feed intake between niacin-deficient and control rats, insofar as a deficiency of niacin, like most micronutrients, causes anorexia (1). In the water maze, niacin-deficient rats showed superior spatial learning ability during acquisition and a trend for higher spatial accuracy in a probe test. However, we were concerned that rats voluntarily restricting their food intake due to anorexia may be different from rats being forcibly feed restricted and that the effect of hunger in the latter condition may have physiological consequences, at least in terms of cognitive function. To eliminate this effect, we used a modified pair-feeding model in Expt. 2 that we called partially restricted feeding. We pair fed the control group for the 1st 16 d of the experiment, and then fed them ad libitum for 4 d before and during the entire period of water maze testing. Our goal was to reduce hunger during the period of behavioral testing while minimizing the developmental differences that would result between niacin-deficient rats and rats fed ad libitum throughout the experiment. In the water maze, we observed that niacin-deficient rats again showed superior spatial learning ability, although the spatial accuracy of the 2 groups was comparable in a probe test. The food intake and body weight of the 2 groups diverged greatly once the control group was placed on ad libitum feeding. Whereas the reduced feed intake in Expt. 1 may have been a confounding variable, due to the effect of hunger on spatial learning ability, the increased feed intake in Expt. 2 may have been a similar confounding variable. Although the control rats were no longer hungry, they were consuming significantly more macro- and micronutrients than the niacin-deficient group, which would have an effect on a vast number of metabolic and developmental processes. So, in the 3rd niacin deficiency experiment, we used a recovery model in which all rats were maintained on a niacin-deficient diet during the 1st phase of water maze testing, and then half were recovered from the deficiency through niacin refeeding during the 2nd phase of water maze testing. Nicotinamide was used because it is the preferred substrate for NAD+ in most tissues, including the brain (30), and should therefore allow for a more rapid replenishment of niacin metabolites. The 4-d period of niacin refeeding prior to the 2nd phase of water maze testing was designed to mimic the period of nutritional rehabilitation typically required for resolution of the symptoms of pellagrous dementia (1). During the 1st phase of water maze testing, when all rats were niacin deficient, a retrospective analysis of performance revealed no significant differences between the 2 groups. However, during the 2nd phase of water maze testing, when the recovered rats were being refed niacin, niacin-deficient rats showed superior spatial learning ability, with comparable spatial accuracy in the probe test. It is important to note that during the 2nd phase of testing, rats were no longer naïve and had already undergone extensive water maze training, so the sensitivity of the test to detect subtle differences in spatial learning ability would be reduced. If hunger associated with pair feeding is, in fact, a confounding variable, it might be expected to affect the results in this experiment in the same way as in Expt. 1, because REC rats were pair fed to ND rats during the period of behavioral testing. However, we found that niacin-deficient rats require a number of days to fully recover their appetite, so the recovery group was not likely faced with the same hunger issues of the earlier pair-fed rats. The swim speed of ND rats in all 3 experiments was increased relative to each control group.
In contrast to niacin deficiency, we found that niacin supplementation negatively affects spatial learning ability. In Expt. 4, the effect of pharmacological nicotinamide supplementation on spatial learning ability was investigated. The brain shows a preference for using nicotinamide in the synthesis of NAD+ over any other precursors, and there is an active mechanism for nicotinamide uptake into the brain, where it is distributed evenly (31). The level of nicotinamide used was comparable to the human consumption of 1–3 g of nicotinamide/d by children in the diabetes prevention trials (32). In the water maze, we observed that niacin-supplemented rats showed inferior spatial learning ability, whereas the spatial accuracy of the 2 groups was comparable in a probe test. To our knowledge, there is only 1 previously published report of the effect of oral nicotinamide supplementation on spatial learning ability (33). In that study, the dose of nicotinamide given was comparable to ours, but rats were tested immediately following nicotinamide administration rather than after an extended period of dietary manipulation. In adult rats, nicotinamide supplementation had no effect on spatial learning ability, but in aged rats, there was a significant learning impairment. The effect of nicotinamide supplementation in weanling rats was not investigated. The observation of impairments in spatial learning ability in young rats following nicotinamide supplementation may have implications for diabetes studies in which comparable doses of the vitamin are being investigated as a preventive agent for NIDDM in young children (16–18). Like in the ND rats, the swim speed of niacin-supplemented rats was increased relative to the control group. The finding of increased swim speed in both ND and SUPP rats suggests that swim speed cannot explain the effect of niacin intake on spatial learning ability.
Changes in levels of the NAD+ metabolite cADPR may be the link between spatial learning ability and diet. In this study, we demonstrated that brain NAD+ and cADPR were decreased significantly in niacin-deficient rats. In contrast, brain NAD+ and cADPR were increased significantly in niacin-supplemented rats. Like dietary niacin, brain NAD+ and cADPR therefore show an inverse relation to spatial learning ability, with improvements correlated with reduced nucleotides and impairments correlated with increased nucleotides. At this time, the association between brain cADPR and spatial learning ability is correlative, but there is considerable evidence that cADPR is involved in brain function (4–10), and levels of cADPR in the brain are higher than in many other organs (34). In the hippocampus, cADPR is required for a form of long-term depression (LTD) that involves nitric oxide as a retrograde messenger and activation of guanylyl cyclase (35,36). The site of action for cADPR is in the presynaptic neuron (37), and presynaptic modulation of LTD involves changes in neurotransmitter release, either through reductions in quantal size or frequency of transmission (38). Animals that show impaired LTD display improved spatial learning (39), whereas animals that show facilitated LTD display impaired spatial learning (40,41). Following this, we propose that, in niacin deficiency, there will be a decrease in systemic NAD+ that will subsequently decrease brain NAD+ and reduce the availability of the substrate for ADP-ribosyl cyclase enzymes to synthesize cADPR. Reduced cADPR will impair LTD, thereby facilitating LTP and improving spatial learning ability. Niacin supplementation will have the opposite effect of increasing NAD+ and cADPR and facilitating LTD, causing an impairment of spatial learning ability (Fig. 7).
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FOOTNOTES |
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4 Abbreviations used: cADPR, cyclic ADP-ribose; CON, control; LTD, long-term depression; MWM, Morris Water Maze; ND, niacin deficient; PCA, perchloric acid; PF, pair fed; PFR, partially feed restricted; REC, recovered; SUPP, supplemented.
Manuscript received 25 September 2006. Initial review completed 29 October 2006. Revision accepted 28 January 2007.
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