Impaired trace fear conditioning and diminished ERK1/2 phosphorylation in the dorsal hippocampus of adult rats administered alcohol as neonates.

Abstract

Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N-methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec.

Neonatal Ethanol Exposure Impairs Trace Fear Conditioning and Alters NMDA Receptor Subunit Expression in Adult Male and Female Rats

“…Previous research from our laboratory demonstrated no differences in CS-evoked freezing behavior between control and 5E treatment groups during the TFC session (DuPont et al, 2014), indicating intact sensory/motor responding and associative learning for both groups. The current study expands on our previous results by comparing SI and 5E freezing percentages during the 15-second tone CS and, following its offset, the 30-second TI.…”

“…Rats were weaned on PD 21, same-sex group housed until PD 60 and, consistent with our previous studies, individually housed until sacrificed (DuPont et al, 2014;Goodfellow and Lindquist, 2014). Testing occurred between PD 65 to 75 around midday (~1100 to 1500) during the light phase (12-hour light/dark cyclelights on at 0600).…”

“…Testing occurred between PD 65 to 75 around midday (~1100 to 1500) during the light phase (12-hour light/dark cyclelights on at 0600). Prior work has demonstrated that SI and unhandled/unintubated control rats exhibit similar patterns of freezing behavior during TFC and retention testing with TIs ranging from 5 to 30-seconds (DuPont et al, 2014;Hunt et al, 2009). Considering SI rats are the critical comparison group for 5E rats (Schreiber and Hunt, 2013), and to conserve animals, only SI and 5E rats were used in the current study.…”

“…We recently reported significant learning and memory deficits in PD 4 to 9 EtOH-exposed (5E) rats, when tested as adults (DuPont et al, 2014). Relative to controls, adult 5E rats were impaired in auditory trace fear conditioning (TFC), in which a 15-second tone conditioned stimulus (CS) was followed, 30 seconds later, by a footshock unconditioned stimulus (US).…”

Yes-associated protein in the liver: Regulation of hepatic development, repair, cell fate determination and tumorigenesis

“…Detailed reviews of these upstream YAP regulators can be found elsewhere [80,81]. Serum-derived small molecules sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are particularly interesting because they are the first extracellular diffusible factors regulating YAP activity [82,83].…”