Alcohol-related amnesia and dementia: animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

Abstract

Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models--from repeated and chronic ethanol exposure to thiamine deficiency--is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone.

Figure 1

A schematic outlining the similarities and differences of the chronic ethanol exposure and thiamine deficiency affects on brain structure and behavior in animal models. Bulleted points represent factors that can modify the degree of dysfunction. Although there is considerable overlap between the two etiological variables, thiamine deficiency is unique in producing lesions within the diencephalon.

Figure 2

Neuronal specific nuclear protein (NeuN) stained slides comparing the thalamus and mammillary bodies of PF and PTD rats (from Anzalone et al, 2010). The top row (A and B) reveal the anterior thalamic nuclei in both PF and PTD rats. In PTD rats there is selective cell loss in the anteroventral ventrolateral (AVVL) with relative sparing of the anteroventral dorsal medial (AVDM) and anterodorsal nuclei (AD). The middle row (C and D) are images of midline and intralaminar thalamic structures. There is significant cell loss in the intralaminar nuclei (central medial (CM), paracentral (PC) and centrolateral (CL) nuclei) as well as the posterior thalamic nucleus (Po). However, the medial dorsal (MD) nucleus is spared—with the exception of the most ventral tip. The bottom row (E and F) are examples of the hypothalamus including the mammillothalamic tract (mt), medial mammillary nucleus (MM), lateral medial mammillary nucleus (ML) lateral mammillary nucleus (LM) and the supramammillary nucleus (SuM). There is significant cell loss medial mammillary ncuclei (MM, ML) and within the SuM.

Figure 3

Mean (± SEM) changes in ACh efflux (relative to baseline) before (B1-3), during (M1-3) and after (A1-3) training on hippocampal-dependent tasks in different memory-related brain structures in both PF (squares) and PTD (circles) rats. The greatest reductions were seen in the medial frontal cortex (A) prefrontal cortex (B), and hippocampus (C) followed by a moderate decrease in the retrosplenial [area 29ab] cortex (D). In contrast, no impairments in ACh efflux were observed in the amygdala (F) or dorsal striatum (F).

Figure 4

Acetylcholinesterase inhibors (AChEIs) acutely infused into the hippocampus (A: 40 ng, ●=0.97), medial septum (B: 5 μg,●=0.99) and medial frontal cortex (C: 1 μg,●=3.14) all significantly increased spontaneous alternation performance in PTD rats. NOTE: Dose response curves for all AChEIs were conducted for behavior and ACh efflux. Only the maximum effective dose is shown for each drug condition. *= significant difference between control and treatment conditions in PTD rats; ^ =Drug recovery in PTD rats is still reduced relative to PF saline score; ns= Recovery in PTD rats is equal to PF control score. For comparisons across studies, Cohen’s effect size (●) was reported.

Figure 5

(A) Basal brain derived neurotropic factor (BDNF) levels in PF (open bars) and PTD rats (black bars). (B) There is a strong positive correlation between BDNF levels in the hippocampus and frontal cortex.