Deficits in trace fear conditioning in a rat model of fetal alcohol exposure: dose–response and timing effects

In humans, prenatal alcohol exposure can result in significant impairments in several types of learning and memory, including declarative and spatial memory. Animal models have been useful for confirming that many of the observed effects are the result of alcohol exposure, and not secondary to poor maternal nutrition or adverse home environments. Wagner and Hunt (2006) reported that rats exposed to ethanol during the neonatal period (postnatal days [PDs] 4–9) exhibited impaired trace fear conditioning when trained as adolescents, but were unaffected in delay fear conditioning. The present series of three experiments represent a more detailed analysis of ethanol-induced deficits in trace conditioning. In Experiment 1, the dose of ethanol given to neonates was varied (3.0, 4.0, or 5.0 g/kg/day). There was a dose-dependent reduction in trace conditioning, with the poorest performance observed in animals treated with the highest dose. In Experiment 2, it was found that the impairment in trace conditioning resulting from neonatal ethanol exposure was dependent on the duration of the trace interval used for training; less learning was evident in ethanol-exposed animals trained with longer trace interval durations. These results confirm other reports of delay-dependent memory deficits. Finally, Experiment 3 determined that ethanol exposure limited to the first half of the neonatal period (PDs 4–6) was more detrimental to later trace conditioning than exposure during the second half (PDs 7–9). These results support the hypothesis that trace-conditioning impairments resulting from early ethanol exposure are due to the drug's teratogenic effects on the developing hippocampus, as the findings parallel those observed in animals with discrete hippocampal lesions. Comparisons between delay and trace fear-conditioning performance in animals exposed to ethanol during the brain growth spurt provide a model system to study both selective learning impairments and possible treatment approaches for humans with fetal alcohol spectrum disorders.     

Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats

Exposure to ethanol in neonatal rats results in reduced neuronal numbers in the cerebellar cortex and deep nuclei of juvenile and adult animals. This reduction in cell numbers is correlated with impaired delay eyeblink conditioning (EBC), a simple motor learning task in which a neutral conditioned stimulus (CS; tone) is repeatedly paired with a co-terminating unconditioned stimulus (US; periorbital shock). Across training, cell populations in the interpositus (IP) nucleus model the temporal form of the eyeblink-conditioned response (CR). The hippocampus, though not required for delay EBC, also shows learning-dependent increases in CA1 and CA3 unit activity. In the present study, rat pups were exposed to 0, 3, 4, or 5 mg/kg/day of ethanol during postnatal days (PD) 4–9. As adults, CR acquisition and timing were assessed during 6 training sessions of delay EBC with a short (280 ms) interstimulus interval (ISI; time from CS onset to US onset) followed by another 6 sessions with a long (880 ms) ISI. Neuronal activity was recorded in the IP and area CA1 during all 12 sessions. The high-dose rats learned the most slowly and, with the moderate-dose rats, produced the longest CR peak latencies over training to the short ISI. The low dose of alcohol impaired CR performance to the long ISI only. The 3E (3 mg/kg/day of ethanol) and 5E (5 mg/kg/day of ethanol) rats also showed slower-than-normal increases in learning-dependent excitatory unit activity in the IP and CA1. The 4E (4 mg/kg/day of ethanol) rats showed a higher rate of CR production to the long ISI and enhanced IP and CA1 activation when compared to the 3E and 5E rats. The results indicate that binge-like ethanol exposure in neonatal rats induces long-lasting, dose-dependent deficits in CR acquisition and timing and diminishes conditioning-related neuronal excitation in both the cerebellum and hippocampus.     

Long-term effects of prenatal alcohol exposure on the size of the whisker representation in juvenile and adult rat barrel cortex.

Children of mothers who abused alcohol during pregnancy are often reported to suffer from growth retardation and central nervous system (CNS) abnormalities. The use of prenatal alcohol exposed (PAE) animal models has revealed reductions in body and brain weights as well as regional specific brain deficits in neonatal pups. Recently, we and others reported reductions in the size of the posteromedial barrel subfield (PMBSF) in first somatosensory cortex (SI) associated with the representation of the large mystacial vibrissae in neonatal rats and mice that were exposed to alcohol at various times during gestation. While these reductions in barrel field size were reported in neonates, it was unclear whether similar reductions persisted later in life or whether some catch-up might take place in older animals. In the present study, we examined the effect of PAE on measures of barrel field size in juvenile (6 weeks of age) and adult (7 months of age) rats; body and brain weights were also measured. Pregnant rats (Sprague-Dawley) were intragastrically gavaged during gestational days 1-20 with alcohol (6 g/kg) to simulate a binge-like pattern of alcohol consumption (Alc); 6 g/kg alcohol produced blood alcohol levels ranging between 207.4 and 478.6 mg/dl. Chow-fed (CF), pair-fed (PF), and cross-foster (XF) groups served as normal, nutritional/stress, and maternal controls, respectively, for juvenile rats; an XF group was not included for adult rats. The major findings in the present study are (i) PAE significantly reduced the size of the total barrel field in Alc juvenile rats (13%) and adult rats (9%) compared to CF controls, (ii) PAE significantly reduced the total averaged sizes of individual PMBSF barrels in juvenile (14%) and adult (13%) rats, (iii) PAE did not significantly alter the septal area between barrels or the barrel pattern, (iv) PAE significantly reduced body weight of juvenile rats but only in comparison to PF controls (18%), (v) PAE significantly reduced whole brain (8%) and forebrain (7%) weights of juvenile rats but not adult rats, (vi) no differences were observed in forebrain/PMBSF body ratios nor was forebrain weight correlated with PMBSF area, and (vii) PAE resulted in a greater reduction in anterior barrels compared to posterior barrels. These results suggest that the effects of PAE previously reported in neonate PMBSF areas persist into adulthood.