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

Abstract

Binge-like exposure to ethanol early in development results in neurotoxic impairments throughout the brain, including the cerebellum and brainstem. Rats exposed to ethanol, during a period of time commensurate with the human third trimester, also show deficits in classical eyeblink conditioning (EBC), a cerebellar-dependent associative learning procedure. The relationship between ethanolmediated EBC deficits and the intensity of the unconditioned stimulus (US) was explored in the current study. Neonatal rats were intubated and infused with ethanol (EtOH rats), sham-intubated and given no ethanol (SI rats), or reared as unhandled controls (UC rats). As adults, all rats underwent 10 days of 350 ms delay eyeblink conditioning with a tone conditioned stimulus (CS) and one of three co-terminating periorbital shock US. The frequency and topography of the conditioned eyeblink response (CR) were impaired in EtOH rats relative to UC rats. EtOH rats produced fewer CRs, with longer onset latencies, at all US intensities. In contrast, CR amplitude was impaired in EtOH rats at the highest US intensity only. Following conditioning, the unconditioned eyeblink response (UR) was analyzed in subsets of rats from each treatment group at five US intensities. Early ethanol exposure did not impair UR peak amplitude. The deficits in CR production are proposed to result from ethanol-mediated damage within specific regions of the EBC neural circuit.

Neonatal binge alcohol exposure produces dose dependent deficits in interstimulus interval discrimination eyeblink conditioning in juvenile rats

“…The present data support and extend previous findings of impaired EBC in rats following heavy binge-like alcohol exposure over PD4-9 (Brown et al, 2007, 2008; Green et al, 2000; 2002a, b; Lindquist et al, 2007; Stanton and Goodlett, 1998; Tran et al, 2005, 2007). Consistent with a previous report from our laboratory (Brown et al, 2008), deficits are present in ISI discrimination EBC following PD4-9 exposure to an alcohol dose as low as 3 g/kg/day, suggesting that this task may display enhanced sensitivity to the effects of neonatal alcohol exposure relative to single-cue EBC paradigms (Goodlett et al, 2007; Stanton et al, 2000).…”

“…Binge-like alcohol exposure at high doses (5 g/kg/day or more) over PD4-9 impairs acquisition of EBC in post-weanling, juvenile, and adult rats (Brown et al, 2007, 2008; Green et al, 2000, 2002a, b; Lindquist et al, 2007; Stanton and Goodlett, 1998; Tran et al, 2005, 2007). These impairments appear to reflect deficits in learning rather than performance (Green et al, 2000; Stanton and Goodlett, 1998; Tran et al, 2007) and are correlated with cerebellar neuronal loss (Green et al, 2002b; Tran et al, 2005) and impaired cerebellar electrophysiological activity (Green et al, 2002a).…”

Associative and non-associative blinking in classically conditioned adult rats

“…To that end, we have previously examined CR acquisition at multiple US intensities in the adult rat [25]. In line with results in the rabbit [18], US intensity was found to be critically important for CR acquisition, with the rate and asymptote of conditioned responding greater in rats trained with a 2.0 than 1.0 mA periorbital shock US [25]. …”

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

“…Hippocampal CA1 unit activity showed a similar pattern across treatment groups. Importantly, no differences between ethanol-exposed and control rats in their responsiveness to the aversive US or in their performance during explicitly unpaired training have been reported (Green et al, 2000; Lindquist, 2013; Lindquist et al, 2007; Tran et al, 2007). Nor were significant differences in startle reactivity to the tone CS found in the current study between the various treatment groups, in agreement with other reports (e.g., Stanton and Goodlett, 1998).…”

“…Indeed, even a single ethanol dose administered on PD 4 is sufficient to produce Purkinje cell death when these cells are counted in rats sacrificed just 10 hours after exposure (Idrus and Napper, 2012). Ethanol exposure in early development is proposed to induce rapid apoptosis in the cerebellum (and associated brainstem structures), leading to long-lasting impairments in the acquisition of delay EBC in both juvenile and adult rats (Brown et al, 2007; Green et al, 2000; Lindquist et al, 2007; Stanton and Goodlett, 1998; Tran et al, 2007), although some differences in CR timing have been seen in ethanol-exposed rats across the 2 age groups with more complex forms of EBC (Brown et al, 2009; Brown et al, 2008). IP damage may preferentially affect delay EBC performance, with acquisition deficits — defined by percentage of CRs or the blink’s peak amplitude — significantly correlated to ethanol-induced IP cell loss (Green et al, 2002b; Young et al, 2010).…”