Combined Deficiency of Iron and (n-3) Fatty Acids in Male Rats Disrupts Brain Monoamine Metabolism and Produces Greater Memory Deficits Than Iron Deficiency or (n-3) Fatty Acid Deficiency Alone

Abstract

Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (by measuring monoamines and related gene expression) and spatial working and reference memory (by Morris water maze testing). Using a 2 × 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change = -1.33; P < 0.05). ID and (n-3)FAD significantly impaired working memory performance and the impairment positively correlated with DA concentrations in FC (r = 0.39; P = 0.026). Reference memory was impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r = -0.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brain monoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone.

Providing male rats deficient in iron and n-3 fatty acids with iron and alpha-linolenic acid alone affects brain serotonin and cognition differently from combined provision

“…This is consistent with several previous studies reporting decreased food intake associated with poor growth in rats suffering from ID anaemia [12,28-30]. However, previous depletion studies showed that severe ID decreased relative weight gain (g weight gain per g food intake) [12,28], while in the current study, relative weight gain was the same in rats repleted with Fe and remaining ID. Since neurotransmitters, including DA and 5-HT, are involved in the regulation of food intake [31], it is possible that the reduced food intake of ID rats is related to alterations in monoaminergic neurotransmission.…”

“…We previously showed that the provision of an ID + n-3 FAD diet for 5 weeks post-weaning resulted in an additive 1- to 2-fold increase in DA concentrations in the OB and Str, and decreased 5-HT concentrations relative to controls in the OB at PND 56 [12]. In the current study, at PND 91, rats that remained ID + n-3 FAD had significantly higher DA concentrations than controls (+189%) in the FC.…”

“…Brain regions were homogenized and digested with nitric acid according to Erikson et al [54], and total Fe concentrations measured using graphite furnace atomic absorption spectrometry (AAS; Perkin Elmer AA400, Beaconsfield, Bucks, UK) as described previously [12]. …”

“…We have recently shown in male rats that ID and n-3 FAD in combination impairs monoaminergic neurotransmission and reference memory in the Morris water maze (MWM) to a greater extent than ID or n-3 FAD alone [12]. In a subsequent study we repleted double-deficient rats with Fe and a mixture of DHA and EPA, alone and in combination, for a period of 5 weeks.…”

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“…Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids that maintain membrane fluidity (Simopoulos, 1991); serve as substrates in the biosynthesis of inflammatory eicosanoids (Simopoulos, 2002a; b); modulate dopaminergic neurotransmission (Chalon, 2006; Dervola et al , 2012; Baumgartner et al , 2012), and support other cellular functions. There are three omega-3 fatty acids relevant to human physiology: eicosapentanoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA).…”