Postnatal nutritional iron deficiency impairs dopaminergic-mediated synaptic plasticity in the CA1 area of the hippocampus.

OBJECTIVES: Developmental iron deficiency (ID) has been shown to put children at risk for compromised learning and memory capacity, and it has also been shown to impair hippocampus-dependent forms of memory as well as hippocampal synaptic transmission. Catecholamines are known to play a pivotal role in memory consolidation, and studies have demonstrated that perinatal ID alters dopaminergic systems in various brain areas. It is not known, however, whether perinatal ID impairs dopaminergic synaptic plasticity in learning and memory structures such as the hippocampus. The objective of the present study was to examine dopaminergic-mediated synaptic efficacy in the hippocampus of mice subjected to an ID or control (CN) diet. METHODS: The present study used electrophysiological brain slice methods to examine dopaminergic-mediated synaptic efficacy in the hippocampus of mice subjected to an ID or CN diet from postnatal day (P) P0 through P20. Hippocampal brain slices were prepared in young (P26-30) and adult animals (P60-64). Synaptic efficacy was measured in CA1 neurons by examining population spike amplitude. Slices were treated with the dopaminergic agonist SKF-38393. RESULTS: Slices obtained from young and adult CN mice exhibited a long-lasting increase in synaptic efficacy as the result of SKF-38393 perfusion while the young and adult ID slices showed little or no increase. DISCUSSION: The present study demonstrates that postnatal ID produces long-lasting impairments in dopaminergic-dependent synaptic plasticity in the hippocampus. These impairments may play a role in the learning and memory deficits known to result from ID.

Altered eyeblink reflex conditioning in restless legs syndrome patients.

BACKGROUND: Restless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory-motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory-motor reflex conditioning task called differential eyeblink conditioning. METHODS: RLS subjects were washed out of treatment medication for 7 days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900 ms trace interval) and 60 CS- trials (i.e., a different auditory stimulus that was NOT paired with the US). RESULTS: Control subjects showed normal differential responding to the CS+ and CS-, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits. CONCLUSIONS: Together these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS.

Perinatal nutritional iron deficiency impairs noradrenergic-mediated synaptic efficacy in the CA1 area of rat hippocampus.

Many studies have shown that perinatal nutritional iron deficiency (ID) produces learning impairments in children. Research has also shown that catecholamines like epinephrine and norepinephrine play a pivotal role in the consolidation of memories. In this study, we sought to determine if perinatal ID impairs the following: 1) noradrenergic synaptic function in the hippocampus; and 2) several forms of hippocampus-dependent fear learning. Electrophysiological brain slice methods were used to examine noradrenergic-mediated synaptic efficacy in the CA1-hippocampus of rats that were subjected to perinatal ID or control (CN) diets. Rats were fed ID (3 mg Fe/kg) or CN (45 mg Fe/kg) diets on gestational d 14. These diets were maintained until postnatal d (P) 12 after which all rats were switched to the CN diet. Hippocampal slices were prepared between P26 and P30. The noradrenergic agonist isoproterenol (ISO) (1, 2, or 4 micromol) was used to induce modulatory increases in synaptic efficacy in the hippocampal slices. CN slices showed a long-lasting increase in synaptic efficacy as the result of ISO perfusion in the slice bath, whereas ID slices did not show increases in synaptic efficacy as the result of ISO perfusion. ID and CN groups did not differ when ISO was perfused through slices from adult rats (P61). Both young and adult ID rats showed reduced levels of hippocampus-dependent fear learning compared with the young and adult CN rats. Together, these findings suggest that ID may impair early forms of noradrenergic-mediated synaptic plasticity, which may in turn play a role in adult learning deficits.

Perinatal nutritional iron deficiency impairs hippocampus-dependent trace eyeblink conditioning in rats.

Studies show that iron deficient (ID) children are at risk for poor cognitive development. Research also shows that ID may impair the development of the skeletal motor abilities. The present study sought to determine if perinatal ID in rats impairs a motor learning task called eyeblink conditioning. This task used a hippocampus-dependent trace version or non-hippocampus-dependent delay version. Rats were placed on ID or control diets from gestational day (G) 12 to postnatal day (P) 12. Young rats (P32-29) subjected to perinatal ID showed severe impairments in trace eyeblink conditioning but only minor impairments in delay eyeblink conditioning. A young moderate ID group (ID from G12 to P2) was also impaired in trace eyeblink conditioning. The ID rats that became adults (P64-69) showed only minor impairments in trace eyeblink conditioning. Young ID rats showed no deficits in motoric ability on a separate rotorod learning test. This study suggests that perinatal ID impairs motoric learning by altering higher-order learning centers like the hippocampus more so than by altering the skeletal motor system.

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

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.

Single neurons in the dentate gyrus and CA1 of the hippocampus exhibit inverse patterns of encoding during trace fear conditioning.

Trace fear conditioning is a hippocampus-dependent learning task that requires the association of an auditory conditioned stimulus (CS) and a shock unconditioned stimulus (US) that are separated by a 20-s trace interval. Single-neuron activity was recorded simultaneously from the dentate gyrus (DG) and CA1 of rats during unpaired pseudoconditioning and subsequent trace fear conditioning. Single neurons in DG showed a progressive increase in learning-related activity to the CS and US across trace fear conditioning. Single neurons in CA1 showed an early increase in responding to the CS, which developed into a decrease in firing later in trace conditioning. Correlation analyses showed that DG and CA1 units exhibit inverse patterns of responding to the CS during trace fear conditioning.

Perinatal nutritional iron deficiency reduces hippocampal synaptic transmission but does not impair short- or long-term synaptic plasticity.

Studies show that perinatal nutritional iron deficiency (ID) produces learning and memory impairments in humans and animals. This suggests that the functional physiology of learning and cognitive centers in the brain, such as the hippocampus, may be compromised by developmental ID. The present study used electrophysiological brain slice methods to examine multiple measures of hippocampal synaptic efficacy from rats that were subjected to perinatal ID diets or control (CN) diets. Measures of synaptic efficacy were obtained from the first and last synaptic regions of the hippocampal tri-synaptic loop (i.e. the dentate gyrus (DG) and CA1). Rats were placed on ID or CN diets on gestational day 11, and hippocampal brain slices were prepared between postnatal day 25 and 37. Results show that ID slices were not impaired in short-term (i.e. paired-pulse facilitation (PPF)) or long-term measures (i.e. long-term potentiation (LTP)) of synaptic plasticity in either the DG or CA1 areas. Input-output (IO) measures showed that synaptic transmission was reduced in both of these areas in the ID slices when compared with the CN slices. This suggests that ID-induced learning deficits may be the result of reductions in synaptic transmission throughout the hippocampus, and possibly in other learning and memory centers.

Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning.

Trace fear conditioning is a learning task that requires the association of an auditory conditioned stimulus (CS) and a shock unconditioned stimulus (US) that are separated by a 20-s trace interval. Single neuron activity was recorded from the prelimbic and infralimbic areas of the medial prefrontal cortex in rats during trace fear conditioning or nonassociative unpaired training. Prelimbic neurons showed learning-related increases in activity to the CS and US, whereas infralimbic neurons showed learning-related decreases in activity to these stimuli. A subset of prelimbic neurons exhibited sustained increases in activity during the trace interval. These sustained prelimbic responses may provide a bridging code that allows for overlapping representations of CS and US information within the trace fear conditioning circuit.

Trace fear conditioning is reduced in the aging rat.

Auditory trace fear conditioning is a hippocampus-dependent learning task that requires animals to associate an auditory conditioned stimulus (CS) and a fear-producing shock-unconditioned stimulus (US) that are separated by an empty 20-s trace interval. Previous studies have shown that aging impairs learning performance on hippocampus-dependent tasks. This study measured heart rate (HR) and freezing fear responses to determine if aging impairs hippocampus-dependent auditory trace fear conditioning in freely moving rats. Aging and Young rats received one long-trace fear conditioning session (10 trials). Each trial consisted of a tone-CS (5 s) and a shock-US separated by an empty 20-s trace interval. The next day rats received CS-alone retention trials. Young rats showed significantly larger HR and freezing responses on the initial CS-alone retention trials compared to the Aging rats. A control group of aging rats received fear conditioning trials with a short 1-s trace interval separating the CS and US. The Aging Short-Trace Group showed HR and freezing responses on the initial CS alone retention trials that were similar to the Young Long-Trace Group, but greater than the Aging Long-Trace Group. A second aging control group received unpaired CSs and USs, and showed no HR or freezing responses on CS-alone retention trials. These data show that HR and freezing are effective measures for detecting aging-related deficits in trace fear conditioning.

Single neurons in CA1 hippocampus encode trace interval duration during trace heart rate (fear) conditioning in rabbit.

This study sought to determine whether CA1 hippocampal neurons encode the duration of the trace interval during trace fear conditioning. Single neurons were recorded extracellularly in the CA1 of rabbits during and after a single trace fear classical conditioning session. Trace fear conditioning trials consisted of an auditory conditioned stimulus (CS; 3 sec) and a fear-producing shock unconditioned stimulus (US; 0.5 sec) separated by a silent trace interval. One group of rabbits was trained using a 10 sec trace interval (n = 5), and another group was trained using a 20 sec trace interval (n = 4). These groups were compared with pseudoconditioning control rabbits (n = 5 and n = 4, respectively) that received unpaired CSs and USs. One day after trace and pseudo fear conditioning rabbits received a CS-alone retention session in which no USs were presented. The trace conditioned groups showed larger bradycardiac-fear responses on CS-alone trials compared with the pseudoconditioning groups. A significant percentage of CA1 neurons from the 10 and 20 sec trace groups (24 and 28%, respectively) showed maximal firing on CS-alone retention trials timed to 10 sec (+/-1.5 sec) and 20 sec (+/-2.0 sec) after CS offset, respectively. These latencies were similar to the duration of the trace interval used on previous CS-trace-US trials. Timed CA1 firing was not seen in pseudoconditioning control animals, suggesting that a subset of CA1 neurons encoded the trace interval duration. The percentage of neurons encoding trace duration was largest when rabbits exhibited significant fear responses to the CS, suggesting that trace encoding was related to the strength of the CS and US association.