Perinatal nutritional iron deficiency permanently impairs hippocampus-dependent trace fear conditioning in rats

Abstract

Many studies show that iron deficient (ID) children are at risk for poor cognitive development. This suggests that learning and cognitive centers in the brain, such as the hippocampus, may be compromised by developmental ID. The present study used a heart rate trace fear conditioning procedure in rats to show that perinatal nutritional ID impairs hippocampus-dependent learning. This procedure requires rats to associate a conditioned stimulus and a fearful unconditioned stimulus, which are separated by a trace interval. Rats were started on ID or control (CN) diets 10 days prior to birth, and learning was assessed on post natal day (PND)-28. The ID pups were impaired in trace fear coniditioning, but an ID control group was not impaired in a non-trace basic fear conditioning procedure that does not depend on the hippocampus. Another group was switched from ID to CN diet on PND-31, and this group also showed impairments in trace fear conditioning when tested during early adulthood (i.e. PND-63). Separate control tests show that ID may produce skeletal motor deficits. The ID-induced learning impairments in this study, however, were not due to altered motor activity because learning was assessed using non-motor heart rate responses.

Gestational and Neonatal Iron Deficiency Alters Apical Dendrite Structure of CA1 Pyramidal Neurons in Adult Rat Hippocampus

“…Although such data remain to be characterized in IDA rats, the changes in expression level might reflect the state of functional demands. Thus, it is possible that IDA-in- duced upregulation of RhoA and Rac1 at P7 reflects a compensation for a deficit in GTPases activity due to lower energy (GTP/ATP) availability in IDA rats [15] , while the changes at P65 may reflect reduced activity-dependent gene regulation [11,14,36] . The signaling and structural anomalies may account for the impaired electrophysiology (e.g.…”

“…The signaling and structural anomalies may account for the impaired electrophysiology (e.g. persistence of an immature LTP pattern and impaired PPF) and poorer learning documented during the period of iron deficiency in young rats [11,12,14] . The physiologic consequences likely stem from the reduced branching area as well as the thinner third-generation dendrite branches and the smaller spine head diameters observed in the ID animals at P15.…”

“…Gestational and early postnatal iron deficiency anemia (IDA) in humans results in concurrent [5] and persistent learning and memory deficits in later childhood [6][7][8] and adulthood [9,10] in spite of prompt treatment upon diagnosis. In rats, IDA from gestation through the period of rapid dendritogenesis between postnatal days (P) 15 and P25 impairs hippocampal development and function, including trace fear conditioning, long-term potentiation (LTP) and paired-pulse facilitation (PPF), microtubule associated protein-2 expression, neurometabolism and expression of genes involved in synaptic plasticity, such as postsynaptic density protein 95 and calcium calmodulin-dependent kinase II ␣ [11][12][13][14][15][16] . Nonetheless, neuronal dendrite and spine morphology and the potential molecular mechanisms underlying alterations in the dendrite arbor during development, that are key aspects in the development of synaptic efficacy, have not been assessed.…”

An Event-Related Potential Study of Attention and Recognition Memory in Infants With Iron-Deficiency Anemia

“…Moreover, studies in rodent models of gestational and/or lactational ID provide evidence of reduced neuronal metabolism (as indexed by cytochrome c oxidase activity 38 ) and altered dendritic structure in the hippocampus, 39 with associated poorer performance on spatial memory tasks 40,41 and on highly specific dorsal hippocampal tasks, such as trace conditioning. 42 One strength of ERP is its capacity to reveal subtle developmental differences in neurophysiologic processes underlying cognition that would not be detected by behavioral observation. Thus, the results of this study suggest a delay in cognitive development among infants with IDA in processing information about mother and stranger that was not clearly evident in their overt behavior.…”

Issues in the Timing of Integrated Early Interventions: Contributions from Nutrition, Neuroscience, and Psychological Research

“…Rodent models of gestational/lactational vs postnatal dietary iron deficiency reveal variable impairments in spatial navigation, trace fear conditioning, and procedural memory, all consistent with functional and structural abnormalities in the hippocampus and striatum, as well as abnormalities in myelin formation and monoamine regulation based on the timing of the deficiency. [31][32][33][34][35][36][37][38][39] A differential timing effect is also seen in rhesus monkeys, where late gestational iron deficiency results in a less fearful and more impulsive animal, while postnatal iron deficiency results in a more inhibited and anxious one. 40 …”