Eyeblink Classical Conditioning in Alcoholism and Fetal Alcohol Spectrum Disorders

Abstract

Alcoholism is a debilitating disorder that can take a significant toll on health and professional and personal relationships. Excessive alcohol consumption can have a serious impact on both drinkers and developing fetuses, leading to long-term learning impairments. Decades of research in laboratory animals and humans have demonstrated the value of eyeblink classical conditioning (EBC) as a well-characterized model system to study the neural mechanisms underlying associative learning. Behavioral EBC studies in adults with alcohol use disorders and in children with fetal alcohol spectrum disorders report a clear learning deficit in these two patient populations, suggesting alcohol-related damage to the cerebellum and associated structures. Insight into the neural mechanisms underlying these learning impairments has largely stemmed from laboratory animal studies. In this mini-review, we present and discuss exemplary animal findings and data from patient and neuroimaging studies. An improved understanding of the neural mechanisms underlying learning deficits in EBC related to alcoholism and prenatal alcohol exposure has the potential to advance the diagnoses, treatment, and prevention of these and other pediatric and adult disorders.

Neonatal ethanol exposure impairs long-term context memory formation and prefrontal immediate early gene expression in adolescent rats

“…Fetal alcohol spectrum disorders (FASDs) are the result of the teratogenic effects of alcohol on the developing nervous system, resulting in effects that range from decreases in cortical thickness [5,6], brain volume and neural activity [6][7][8][9][10][11], to impaired development of brain regions such as the basal ganglia, cerebellum, hippocampus, and prefrontal cortex [7,8,12,13], to disruptions in learning and memory associated with mild developmental alcohol exposure [14]. In addition to impaired performance in school or on academic achievement tests, prenatal alcohol exposure impairs performance on laboratory tasks, including eyeblink conditioning [15][16][17], spatial recognition, and working memory [10,[18][19][20]. Recent conservative estimates of FASD prevalence place it as high as 5% in diverse US communities, which underscores it as a serious and unanswered societal problem [4].…”

“…Animal models of FASD have been instrumental in isolating the neural and behavioral disruptions caused by developmental alcohol exposure because of the ability to manipulate multiple factors such as exposure window, pattern, and dosage [21]. In rats, neonatal ethanol exposure during the brain growth spurt (i.e., PD4-9, roughly equivalent to the third trimester of human pregnancy) captures many aspects of impaired brain and behavior similar to the human condition [2,15,21,22]. Indeed, binge-like ethanol exposure during this period severely disrupts neuronal and molecular signaling in the hippocampus in a manner that cannot be fully attributed to CA1 pyramidal cell loss [23][24][25][26][27].…”

Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis

“…Cerebella were cut from the forebrain and kept in 4% paraformaldehyde for 48 hours and then stored in phosphate buffered saline (PBS), all at 4 C. Each cerebellar vermis was blocked and sectioned at 50 µm thickness in the parasagittal plane using a vibrating tissue slicer (Vibratome 1000, The Vibratrome Company, St. Louis, MO). We chose to focus on the cerebellar vermis because studies indicate that this area is an important target of developmental ethanol exposure [7]. Fifteen consecutive sections of the vermis (see Fig 1 for representative images) were mounted sequentially on Superfrost plus slides (VWR Micro Slides, Radnor, PA), incubated for 20 min with 4',6-diamidino-2-phenylindole (DAPI; 1:4000 in PBS), washed with PBS 5 times, with each wash lasting 5 minutes, coverslipped with Vectashield mounting media (Vector Laboratories, Burlingame, CA), and sealed with clear nail polish.…”

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

“…In mice, prenatal alcohol exposure causes a PC loss and damages to GRs and PF-PC synapses. 62 Although these associated abnormalities may concur to alter the EBCC pattern, the PC is the final common pathway channeling information to DCN, so that reducing the PCs is equivalent to weakening the whole cortical output to DCNs. Indeed, pharmacological blockage of PCs in rabbits caused a higher uniform DCN activity during EBCC, due to the lack of inhibition from the cortex 32,63 , which perfectly agrees with the alterations of neural activity in our model.…”