Neuronal Loss in Hippocampus Induced by Prolonged Ethanol Consumption in Rats

Walker, David A.; Barnes, David; Zornetzer, Steven F.; Hunter, Bruce E.; Kubanis, Patricia

doi:10.1126/science.7394532

Cited by 378 publications

(117 citation statements)

References 17 publications

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“…Chronic alcoholics show a consistent pattern of cognitive deficits with noted impairments in spatial learning and memory, short term and declarative memory, and impulsivity, all of which suggest hippocampal dysfunction (Brandt et al, 1983;Parsons, 1993;Sullivan et al, 2000b). Observations of hippocampal neuropathology in human alcoholics (Bengochea and Gonzalo, 1990;Sullivan et al, 1995;Agartz et al, 1999;Laakso et al, 2000) are paralleled by descriptions of hippocampal cell loss and DG neurodegeneration in animal models (Walker et al, 1980;Collins et al, 1996;Obernier et al, 2002). Furthermore, alcohol intoxication decreases neurogenesis by inhibiting both NPC proliferation (Nixon and Crews, 2002;Rice et al, 2004) and newborn cell survival (Nixon and Crews, 2002;Herrera et al, 2003), effects that are consistent with cell loss in alcoholism.…”

Section: Introductionmentioning

confidence: 86%

Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol

Nixon¹,

Crews²

2004

J. Neurosci.

204

252

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Adult neurogenesis is a newly considered form of plasticity that could contribute to brain dysfunction in psychiatric disease. Chronic alcoholism, a disease affecting over 8% of the adult population, produces cognitive impairments and decreased brain volumes, both of which are partially reversed during abstinence. Clinical data and animal models implicate the hippocampus, a region important in learning and memory. In a model of alcohol dependence (chronic binge exposure for 4 d), we show that adult neurogenesis is inhibited during dependence with a pronounced increase in new hippocampal neuron formation after weeks of abstinence. This increase is attributable to a temporally and regionally specific fourfold increase in cell proliferation at day 7 of abstinence, with a majority of those cells surviving and differentiating at percentages similar to controls, effects that doubled the formation of new neurons. Although increases in cell proliferation correlated with alcohol withdrawal severity, proliferation remained increased when diazepam (10 mg/kg) was used to reduce withdrawal severity. Indeed, those animals with little withdrawal activity still show a twofold burst in cell proliferation at day 7 of abstinence. Thus, alcohol dependence and recovery from dependence continues to alter hippocampal plasticity during abstinence. Because neurogenesis may contribute to hippocampal function and/or learning, memory, and mood, compensatory neurogenesis and the return of normal neurogenesis may also have an impact on hippocampal structure and function. For the first time, these data provide a neurobiological mechanism that may underlie the return of human cognitive function and brain volume associated with recovery from addiction.

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Section: Introductionmentioning

confidence: 86%

Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol

Nixon¹,

Crews²

2004

J. Neurosci.

204

252

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“…The neuropathological correlate of the cognitive impairments accompanying alcoholism remains unclear (2)(3)(4). In animal models of alcoholism, a thinning of the granular layer of the dentate gyrus (DG) is attributed to neuronal loss (5). These findings, however, have been difficult to confirm in human brains (6) and have been contested in animal models as well (7).…”

mentioning

confidence: 87%

Selective impairment of hippocampal neurogenesis by chronic alcoholism: Protective effects of an antioxidant

Herrera

Yagüe²,

Johnsen-Soriano³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

243

159

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A major pathogenic mechanism of chronic alcoholism involves oxidative burden to liver and other cell types. We show that adult neurogenesis within the dentate gyrus of the hippocampus is selectively impaired in a rat model of alcoholism, and that it can be completely prevented by the antioxidant ebselen. Rats fed for 6 weeks with a liquid diet containing moderate doses of ethanol had a 66.3% decrease in the number of new neurons and a 227-279% increase in cell death in the dentate gyrus as compared with paired controls. Neurogenesis within the olfactory bulb was not affected by alcohol. Our studies indicate that alcohol abuse, even for a short duration, results in the death of newly formed neurons within the adult brain and that the underlying mechanism is related to oxidative or nitrosative stress. Moreover, these findings suggest that the impaired neurogenesis may be a mechanism mediating cognitive deficits observed in alcoholism.A lcohol dependence and abuse are among the most prevalent mental disorders in the United States, with Ϸ14% of the general population meeting criteria for alcohol dependence at some time in their lives and 7% having been dependent in the past year (1). Severe cognitive impairment consistently occurs in chronic alcoholism regardless of the presence of associated thiamine deficits (Korsakoff syndrome), and it includes progressive and severe anterograde learning deficits, implicating impairment in hippocampal circuits. However, no consistent pathological finding has yet been identified. The neuropathological correlate of the cognitive impairments accompanying alcoholism remains unclear (2-4). In animal models of alcoholism, a thinning of the granular layer of the dentate gyrus (DG) is attributed to neuronal loss (5). These findings, however, have been difficult to confirm in human brains (6) and have been contested in animal models as well (7). Human postmortem studies account for the duration of alcohol abuse but not the duration of abstinence before death. Interestingly, MRI studies demonstrate reduction of hippocampal volumes in alcoholics that are reversible after short periods of abstinence (8). The loss of hippocampal volume has been attributed to changes in white matter (6), but the incorporation of newly formed neurons to the DG could also be affected by alcohol. Similarly, hippocampaldependent cognitive functions have also shown reversibility after comparable periods of abstinence.Neurogenesis is primarily a developmental process that involves the proliferation, migration, and differentiation into neurons of primordial CNS stem cells (9, 10). Neurogenesis declines until it ceases in the young adult mammalian brain with two exceptions: the olfactory bulb (OB) and the hippocampus produce new neurons throughout adult life. In the subgranular cell layer of the DG, hippocampal progenitors proliferate and migrate a short distance into the granule cell layer, where they differentiate into hippocampal granule cells. Although multiple factors seem to regulate adult neurogenesis including...

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“…Much of the research on chronic ethanol and trophic factors has focused on the hippocampus and the neuronal loss and atrophy of cholinergic and GABAergic neurons in the septohippocampal pathway that are known to occur with chronic ethanol treatment (3,72,(99)(100)(101)(102). These neurons are known to require neurotrophins for normal function and survival.…”

Section: Neurotrophic Factorsmentioning

confidence: 99%

Alcohol and Neurodegeneration

Crews

1999

CNS Drug Reviews

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Neuronal Loss in Hippocampus Induced by Prolonged Ethanol Consumption in Rats

Cited by 378 publications

References 17 publications

Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol

Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol

Selective impairment of hippocampal neurogenesis by chronic alcoholism: Protective effects of an antioxidant

Alcohol and Neurodegeneration

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