Many alcoholics display moderate to severe cognitive dysfunction accompanied by brain pathology including cell loss and tissue shrinkage. A factor confounded with alcohol-related behaviors and alcohol consumption is poor nutrition. Specifically, many alcoholics are thiamine deficient. Thiamine is a vital nutrient that is criticalfor normal brain health and functioning. Thus, thiamine deficiency has emerged as a key factor underlying alcohol-induced brain damage. Thiamine deficiency in humans can lead to Wernicke encephalitis that can progress into Wernicke-Korsakoff syndrome and these disorders have a high prevalence among alcoholics. However, these disorders are commonly misdiagnosed, particularly in alcoholics. It is difficult, if not impossible, to disentangle the neurotoxic effecs of chronic alcohol consumption and thiamine deficiency in human patients. Therefore, animal models are critical for determining the exact contribution of alcohol- and thiamine deficiency-induced neurotoxicity, as well as the synergistic interaction of those factors, to brain and behavioral dysfunction. However, few such models have been developed, particularly pertaining to forebrain pathology and cortical-dependent behaviors. In this proposal, we use our recently developed translational animal model of chronic ethanol treatment (CET) combined with thiamine deficiency (TD) to determine both the independent actions of CET and TD as well as how these factors synergistically interact to affect neurotrophin adaptation, cognitive functioning and activation of the fronto-cortico-limbic network (AIM 1). We will determine whether basal forebrain cholinergic cell loss, altered cortical cellular structure and dysfunctional acetylcholin (ACh) release are critical mediators of alcohol-related cognitive impairment. Furthermore, we will determine whether exercise can restore behavior, cholinergic innervation, and behaviorally stimulated ACh efflux across the hippocampus and frontal cortex (AIM 2).
The final AIM (3) will determine whether a moderate TD episode during CET leads to greater disruption of cytogenesis (neurogenesis in the hippocampus and gliogenesis in the frontal cortex). In addition, we will examine alternations in oligodendrocyte differentiation and myelin related proteins as a function of alcohol-related disease progression. This critical pre-clinical informatin is needed to improve the diagnostic criteria for alcohol-related neurological disorders and to develop therapeutic strategies that are effective for the recovery of cognitive functions after chronic alcohol addiction.
Just behind Alzheimer's disease, chronic alcoholism is a leading cause of dementia and cognitive dysfunction. Over 50% of detoxified alcoholics display some degree of cognitive impairment and 75% of autopsied chronic alcoholics have significant brain damage. However, the relative contribution of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment remains elusive. These studies will increase our understanding of the factors that lead to brain pathology in alcohol-related disorders. This critical pre-clinical information is needed to improve the diagnostic criteria for alcohol-related neurological disorders and develop therapeutic strategies that are effective for the recovery of cognitive functions after chronic alcohol/drug addiction.
|Fernandez, Gina M; Savage, Lisa M (2017) Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex. Neuroscience 361:129-143|
|Fernandez, Gina M; Lew, Brandon J; Vedder, Lindsey C et al. (2017) 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. Neuroscience 348:324-334|
|Vedder, Lindsey C; Savage, Lisa M (2017) BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage. Learn Mem 24:81-85|
|Fernandez, Gina M; Stewart, William N; Savage, Lisa M (2016) Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure. PLoS One 11:e0149987|
|Hall, Joseph M; Savage, Lisa M (2016) Exercise leads to the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band and subsequent rescue of both hippocampal ACh efflux and spatial behavior. Exp Neurol 278:62-75|
|Vedder, Lindsey C; Hall, Joseph M; Jabrouin, Kimberly R et al. (2015) Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility. Alcohol Clin Exp Res 39:2143-53|
|Savage, Lisa M; Hall, Joseph M; Resende, Leticia S (2012) Translational rodent models of Korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery. Neuropsychol Rev 22:195-209|