Eyeblink Classical Conditioning and Interpositus Nucleus Activity Are Disrupted in Adult Rats Exposed to Ethanol as Neonates

Abstract

Neonatal exposure to ethanol in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent cell loss in the cerebellum and deficits in coordinated motor performance. These rats are also impaired in eyeblink conditioning as weanlings and as adults. The current study examined single-unit neural activity in the interpositus nucleus of the cerebellum in adults following neonatal binge ethanol exposure. Group Ethanol received alcohol doses of 5.25 g/kg/day on postnatal days 4-9. Group Sham Intubated underwent acute intragastric intubation on postnatal days 4-9 but did not receive any infusions. Group Unintubated Control (from separate litters) did not receive any intubations. When rats were 3-7 mo old, pairs of extracellular microelectrodes were implanted in the region of the interpositus nucleus. Beginning 1 wk later, the rats were given either 100 paired or 190 unpaired trials per day for 10 d followed by 4 d of 100 conditioned stimulus (CS)-alone trials per day. As in our previous study, conditioned response acquisition in Group Ethanol rats was impaired. In addition, by session 5 of paired acquisition, Group Sham Intubated and Group Unintubated Control showed significant increases in interpositus nucleus activity, relative to baseline, in the CS-unconditioned stimulus interval. In contrast, Group Ethanol failed to show significant changes in interpositus nucleus activity until later in training. These results indicate that the disruption in eyeblink conditioning after early exposure to ethanol is reflected in alterations in interpositus nucleus activity.Early exposure to alcohol in humans is known to produce a variety of behavioral and neural abnormalities (for reviews, see Mattson and Riley 1998;Roebuck et al. 1998;Streissguth and O'Malley 2000). In some cases of heavy prenatal exposure to alcohol, fetal alcohol syndrome (FAS) can be diagnosed by the presence of the constellation of facial dysmorphology, growth deficiency, and central nervous system damage in the affected child. The development of animal models of FAS has been essential in understanding, at a detailed level, some of the behavioral and neural abnormalities associated with early exposure to alcohol (Hannigan 1996;Goodlett and Johnson 1999). This research has revealed that cortical, hippocampal, basal gangliar, and cerebellar areas are particularly vulnerable to the teratogenic effects of alcohol, and that the vulnerability of specific brain structures changes over stages of development.Much recent research has concentrated on cerebellar abnormalities that occur in conjunction with early exposure to alcohol. The use of a neonatal rat model of binge alcohol exposure during the period of brain development comparable to that of the human third trimester has been critical to this research. This model involves exposing neonatal rats to high doses of alcohol over a short period of time via either a chronic (Diaz and Samson 1980;West 1993) or an acute (Sonderegger et al. 1982;Light et...

Ethanol-exposed neonatal rats are impaired as adults in classical eyeblink conditioning at multiple unconditioned stimulus intensities

“…Rat pups exposed to binge-like levels of ethanol across PD 4-9 are impaired in eyeblink conditioning, both as weanlings (Stanton and Goodlett, 1998;Tran et al, 2005) and adult rats (Green et al, 2002a;Green et al, 2002b;Green et al, 2000). In addition to their behavioral deficits, adult rats exposed as neonates to alcohol have up to 50% fewer cerebellar deep nuclear neurons (Green et al, 2002b), as well as a corresponding reduction in learning-related neural activity in the IP (Green et al, 2002a).…”

“…In addition to their behavioral deficits, adult rats exposed as neonates to alcohol have up to 50% fewer cerebellar deep nuclear neurons (Green et al, 2002b), as well as a corresponding reduction in learning-related neural activity in the IP (Green et al, 2002a). One issue that makes interpretation of these results potentially problematic, however, is that the intensity of the periorbital shock US was independently titrated for each subject in order to produce a defined conditioned responsemaking it difficult to establish if US intensity was a major factor in determining the ethanolmediated conditioning deficits.…”

Eyeblink classical conditioning in the preweanling lamb.

“…Developmental alcohol-induced structural damage to the cerebellum and correlated deficits in acquisition of eyeblink conditioning were first demonstrated in rats following binge-like exposure to alcohol during the "brain growth spurt" of the early postnatal period (Green, 2004;Green, Johnson, Goodlett, & Steinmetz, 2002;Green, Rogers, Goodlett, & Steinmetz, 2000;Green, Tran, Steinmetz, & Goodlett, 2002;Stanton & Goodlett, 1998;Tran, Stanton, & Goodlett, 2007 , 1997). Taken together, these findings suggest that cerebellar damage and deficits in cerebellar-dependent learning may be a common phenotype of the fetal alcohol spectrum disorder (FASD) that results from heavy prenatal alcohol exposure (Riley & McGee, 2005).…”

“…For acquisition of trace conditioning and other higher-order procedural variants, the hippocampus and related forebrain structures are additionally required (Ivkovich & Stanton, 2001;McGlinchey-Berroth, Carrillo, Gabrieli, Brawn, & Disterhoft, 1997;Solomon, Vander Schaaf, Thompson, & Weisz, 1986;Weiss, Bouwmeester, Power, & Disterhoft, 1999). The developmental emergence of eyeblink conditioning has been characterized in rodents and humans (Claflin, Stanton, Herbert, Greer, & Eckerman, 2002;Freeman, Carter, & Stanton, 1995;Freeman, Barone, & Stanton, 1995;Ivkovich, Paczkowski, & Stanton, 2000, Freeman, Spencer, Skelton, & Stanton, 1993Stanton, Freeman, & Skelton, 1992), including characterization of correlated developmental changes in structure and function of identified eyeblink conditioning neural circuits (Freeman & Muckler, 2003;Freeman & Nicholson, 2000a, 2000b, suggesting that eyeblink conditioning may be a useful tool as an early indicator of prenatal brain damage in translational research.Developmental alcohol-induced structural damage to the cerebellum and correlated deficits in acquisition of eyeblink conditioning were first demonstrated in rats following binge-like exposure to alcohol during the "brain growth spurt" of the early postnatal period (Green, 2004;Green, Johnson, Goodlett, & Steinmetz, 2002;Green, Rogers, Goodlett, & Steinmetz, 2000;Green, Tran, Steinmetz, & Goodlett, 2002;Stanton & Goodlett, 1998;Tran, Stanton, & Goodlett, 2007 , 1997). Taken together, these findings suggest that cerebellar damage and deficits in cerebellar-dependent learning may be a common phenotype of the fetal alcohol spectrum disorder (FASD) that results from heavy prenatal alcohol exposure (Riley & McGee, 2005).…”

99HRT Prenatal Alcohol Exposure Damages Brain Signal Transduction Systems

“…Impaired contextual conditioning, Identification of a learning/memory deficit in adult offspring demonstrates that the mouse, as well as the previously described rat, FAE model produces learning and memory impairments which persist into adulthood, similar to the clinical course of FASD in humans. It is interesting to note that Green et al (2002) reported that eyeblink delay conditioning is impaired in rats that were exposed to alcohol as neonates, approximating the human third trimester period. Thus, FAE-induced deficits in associative learning measured using delay conditioning paradigms are reproducible across species and appear to be a useful behavioral endpoint for the study of the effects of therapeutic interventions on FAE-induced learning and memory deficits.…”