Interactions Between Chronic Ethanol Consumption and Thiamine Deficiency on Neural Plasticity, Spatial Memory, and Cognitive Flexibility

Abstract

Background Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology. A factor confounded with prolonged heavy alcohol consumption is poor nutrition and many alcoholics are thiamine deficient. Thus, thiamine deficiency (TD) has emerged as a key factor underlying alcohol–related brain damage (ARBD). TD in humans can lead to Wernicke Encephalitis that can progress into Wernicke–Korsakoff Syndrome and these disorders have a high prevalence among alcoholics. Animal models are critical for determining the exact contributions of ethanol- and TD-induced neurotoxicity, as well as the interactions of those factors to brain and cognitive dysfunction. Methods Adult rats were randomly assigned to one of six treatment conditions: Chronic ethanol treatment (CET) where rats consumed a 20% v/v solution of ethanol over 6 months; Severe pyrithiamine-induced TD (PTD-MAS); Moderate PTD (PTD-EAS); Moderate PTD followed by CET (PTD-CET); Moderate PTD during CET (CET-PTD); Pair-fed control (PF). After recovery from treatment, all rats were tested on spontaneous alternation and attentional set-shifting. After behavioral testing, brains were harvested for determination of mature brain-derived neurotrophic factor (BDNF) and thalamic pathology. Results Moderate TD combined with CET, regardless of treatment order, produced significant impairments in spatial memory, cognitive flexibility and reductions in brain plasticity as measured by BDNF levels in the frontal cortex and hippocampus. These alterations are greater than those seen in moderate TD alone and the synergistic effects of moderate TD with CET leads to a unique cognitive profile. However, CET did not exacerbate thalamic pathology seen after moderate TD. Conclusions These data support the emerging theory that subclinical TD during chronic heavy alcohol consumption is critical for the development of significant cognitive impairment associated with ARBD.

Chronic intermittent ethanol exposure leads to alterations in brain-derived neurotrophic factor within the frontal cortex and impaired behavioral flexibility in both adolescent and adult rats

“…Hippocampal tissue was diluted at a ratio of 1:4, while frontocortical was diluted at a ratio of 1:5 for appropriate detection within a standard curve. Protocol details can be found in Vedder et al, 2015. Homogenate samples (198) were run in duplicate across multiple days, therefore water i.g.…”

“…It has been shown that prenatal and adult chronic EtOH exposure alters levels of neurotrophin, such as brain derived neurotrophic factor (BDNF), in the frontal cortex and hippocampus (Miller et al, 2002; Davis, 2008; Nixon and McClain, 2010; Mooney and Miller, 2011; Vedder et al, 2015). However, few studies have assessed neurotrophin expression after adolescent CIE and the results are variable (Briones and Woods, 2013; McClain et al, 2014; Sakharkar et al, 2016).…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…However, thiamine deficiency resulting from chronic alcohol is also associated with general alcohol neurotoxicity and cerebellar degeneration without WKS (Martin et al, 1994). In addition, a subclinical thiamine deficiency during chronic heavy alcohol consumption can lead to significant cognitive impairments and reduced neuroplasticity (Vedder et al, 2015). The moderate association between a TPK1 SNP and alcohol dependence (Bierut et al, 2010), is supported by previous work showing a link between thiamine deficiency, neuropathology and associated cognitive impairments in cases of chronic alcohol consumption.…”

BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage

“…A rodent model of WKS, pyrithiamine-induced thiamine deficiency (PTD), recapitulates the diencephalic pathology observed in WKS patients, including damage to the mammillary bodies, anterior thalamic nuclei, and midline thalamic nuclei (Mair 1994;Langlais et al 1996). The PTD model also exhibits deficits in spatial working memory that persists for months after recovery from TD (Pitkin and Savage 2004;Vedder et al 2015).…”

“…There is a long-term decrease in hippocampal BDNF levels in the TD model (Vedder et al 2015;Hall and Savage 2016). Methods such as exercise and environmental enrichment that increase hippocampal BDNF levels have been demonstrated to improve hippocampal neural plasticity as well as learning and memory performance (Bekinschtein et al 2011;Chourbaji et al 2011).…”