Prenatal Iron Deficiency in Guinea Pigs Increases Locomotor Activity but Does Not Influence Learning and Memory

Fiset, Catherine; Surette, Marc E.; Fiset, Sylvain

doi:10.1371/journal.pone.0133168

Cited by 10 publications

(9 citation statements)

References 67 publications

(123 reference statements)

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“…An investigation into the effects of iron deficiency and iron deficiency anemia in young Zanzibari children demonstrated lower motor activity scores and less time in locomotion in affected children (54). However, there is evidence that early dietary iron deficiency can result in either reduced or increased locomotion (55, 56). To date, NCB5OR (or Cyb5R4) gene mutations have not been reported in patients with neurological diseases.…”

Section: Discussion and Summarymentioning

confidence: 99%

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. 59Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 weeks and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

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Section: Discussion and Summarymentioning

confidence: 99%

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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“…The weight difference became apparent starting from the third week of age and lasted until the end of the experiment, although iron deficiency treatment had ended at ~5 weeks of age. As we chose to group-house our piglets, we could not measure individual food intake, which ideally should be taken into account in nutritional studies that include growth performance as a read-oud parameter (e.g., Fiset et al, 2015 ). However, iron deficiency is well-known to impair growth and cause reduced appetite in both rats (Beard et al, 1995 ) and piglets (Ishaya, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…Because of developmental differences and differences in brain morphology between rodents and humans, more and better suited animal models are needed to study the long-term cognitive effects of iron deficiency in a controlled manner. Other animal models for studying cognitive effects of iron deficiency have been suggested that more resemble the early development of humans, including guinea-pigs (Fiset et al, 2015 ), pigs (Rytych et al, 2012 ), and primates (Golub et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Pre-weaning dietary iron deficiency impairs spatial learning and memory in the cognitive holeboard task in piglets

Antonides

Schoonderwoerd

Scholz

et al. 2015

Front. Behav. Neurosci.

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Iron deficiency is the most common nutritional deficiency in humans, affecting more than two billion people worldwide. Early-life iron deficiency can lead to irreversible deficits in learning and memory. The pig represents a promising model animal for studying such deficits, because of its similarities to humans during early development. We investigated the effects of pre-weaning dietary iron deficiency in piglets on growth, blood parameters, cognitive performance, and brain histology later in life. Four to six days after birth, 10 male sibling pairs of piglets were taken from 10 different sows. One piglet of each pair was given a 200 mg iron dextran injection and fed a control milk diet for 28 days (88 mg Fe/kg), whereas the other sibling was given a saline injection and fed an iron deficient (ID) milk diet (21 mg Fe/kg). Due to severely retarded growth of two of the ID piglets, only eight ID piglets were tested behaviorally. After dietary treatment, all piglets were fed a balanced commercial pig diet (190–240 mg Fe/kg). Starting at 7.5 weeks of age, piglets were tested in a spatial cognitive holeboard task. In this task, 4 of 16 holes contain a hidden food reward, allowing measurement of working (short-term) memory and reference (long-term) memory (RM) simultaneously. All piglets received 40–60 acquisition trials, followed by a 16-trial reversal phase. ID piglets showed permanently retarded growth and a strong decrease in blood iron parameters during dietary treatment. After treatment, ID piglets' blood iron values restored to normal levels. In the holeboard task, ID piglets showed impaired RM learning during acquisition and reversal. Iron staining at necropsy at 12 weeks of age showed that ID piglets had fewer iron-containing cells in hippocampal regions CA1 and dentate gyrus (DG). The number of iron-containing cells in CA3 correlated positively with the average RM score during acquisition across all animals. Our results support the hypothesis that early-life iron deficiency leads to lasting cognitive deficits. The piglet as a model animal, tested in the holeboard, can be useful in future research for assessing long-term cognitive effects of early-life diets or diet-induced deficiencies.

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“…On days 4 and 5, when clinical symptoms became more obvious in the NEC pigs, the difference in activity level between the 2 groups disappeared. This may relate to increased anxiety and pain in the NEC pigs along with the progression of more severe intestinal lesions [17]. Due to the unspecific nature of physical movements, and lacking knowledge about clinically relevant decreases in physical activity, more studies are required to enable precise estimates of sensitivity and specificity for physical activity as a predictor for NEC.…”

Section: Discussionmentioning

confidence: 99%

Physical Activity and Gastric Residuals as Biomarkers for Region-Specific NEC Lesions in Preterm Neonates

Cao

Andersen²,

Li³

et al. 2016

Neonatology

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Background: Necrotizing enterocolitis (NEC) is a serious feeding-related inflammatory gut disease with high mortality. Early clinical markers of NEC are of great importance for optimizing preventive interventions. Objective: Using preterm pigs as models, we hypothesized that an early postnatal onset of NEC can be predicted by decreased physical activity during the first few days after birth. Methods: Cesarean-delivered preterm pigs were fed parenteral nutrition and increasing amounts of formula for 5 days after birth (n = 120). Their physical activity was quantified by a continuous camera surveillance system and they were evaluated twice daily for clinical signs of apathy, discoloration, respiratory distress, abdominal distension and diarrhea. The volume of gastric residuals and the presence of macroscopic NEC-like lesions in the stomach, intestine and colon were recorded at euthanasia on day 5. Results: Half of the pigs (48%) showed clear NEC-like lesions on day 5, and these individuals had more adverse clinical symptoms from day 3 but decreased physical activity already from day 2 relative to the unaffected pigs (both p < 0.05). Only animals with NEC lesions in the small intestine had lower physical activity on days 2 and 3, and the increased volume of gastric residuals was specifically related to colon lesions (both p < 0.05). Conclusions: Decreased physical activity precedes the clinical symptoms of NEC in the small intestine of preterm pigs, and increased gastric residuals predict NEC lesions in the colon. Physical activity and gastric residuals may function as clinical biomarkers for region-specific NEC lesions in preterm neonates.

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Prenatal Iron Deficiency in Guinea Pigs Increases Locomotor Activity but Does Not Influence Learning and Memory

Cited by 10 publications

References 67 publications

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Pre-weaning dietary iron deficiency impairs spatial learning and memory in the cognitive holeboard task in piglets

Physical Activity and Gastric Residuals as Biomarkers for Region-Specific NEC Lesions in Preterm Neonates

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