Alcohol and adult neurogenesis: Roles in neurodegeneration and recovery in chronic alcoholism

Nixon, Kimberly

doi:10.1002/hipo.20162

Cited by 151 publications

(120 citation statements)

References 91 publications

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“…Although little is known about the factors that promote this comorbidity, converging evidence implicates reductions in hippocampal neurogenesis as a mechanism that may underlie pathologies associated with both alcoholism and depression (Nixon, 2006;Warner-Schmidt and Duman, 2006). In this study, we show that depression-like behavior is increased during abstinence following voluntary alcohol drinking in mice.…”

Section: Discussionmentioning

confidence: 56%

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Stevenson

Schroeder

Nixon

et al. 2008

Neuropsychopharmacol

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131

102

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Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing that abstinence from voluntary alcohol drinking leads to the emergence of depressionlike behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H 2 O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (ie behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.

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Section: Discussionmentioning

confidence: 56%

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Stevenson

Schroeder

Nixon

et al. 2008

Neuropsychopharmacol

Self Cite

131

102

View full text Add to dashboard Cite

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“…This pattern is in contrast with the cerebral cortex, which exhibited significant negative correlations with drinking at 6 and 12 months. Given the ability of hippocampal neurons to undergo morphological changes in response to stress (McEwen, 1999), and the accentuated role of adult neurogenesis in its maintenance (Nixon, 2006), it is possible that biological processes specific to the hippocampus underlie neuroadaptations occurring between 6 and 12 months of drinking. Alternatively, increased hippocampal volume following 6 months of drinking may reflect an inflammatory process associated with the continued exposure to alcohol (Crews and Nixon, 2009).…”

Section: Discussionmentioning

confidence: 99%

Monkeys that Voluntarily and Chronically Drink Alcohol Damage their Brains: a Longitudinal MRI Study

Kroenke

Rohlfing

Park

et al. 2013

Neuropsychopharmacol

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Neuroimaging has consistently documented reductions in the brain tissue of alcoholics. Inability to control comorbidity, environmental insult, and nutritional deficiency, however, confound the ability to assess whether ethanol itself is neurotoxic. Here we report monkey oral ethanol self-administration combined with MR imaging to characterize brain changes over 15 months in 18 well-nourished rhesus macaques. Significant brain volume shrinkage occurred in the cerebral cortices of monkeys drinkingX3 g/kg ethanol/day (12 alcoholic drinks) at 6 months, and this persisted throughout the period of continuous access to ethanol. Correlation analyses revealed a cerebral cortical volumetric loss of B0.11% of the intracranial vault for each daily drink (0.25 g/kg), and selective vulnerability of cortical and noncortical brain regions. These results demonstrate for the first time a direct relation between oral ethanol intake and measures of decreased brain gray matter volume in vivo in primates. Notably, greater volume shrinkage occurred in monkeys with younger drinking onset that ultimately became heavier drinkers than monkeys with older drinking onset. The pattern of volumetric changes observed in nonhuman primates following 15 months of drinking suggests that cerebral cortical gray matter changes are the first macroscopic manifestation of chronic ethanol exposure in the brain.

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“…Fortunately the developing brain is remarkably plastic and postnatal intervention with environmental enrichment (Hannigan et al, 2006), appropriate nutritional supplementation (Thomas et al, 2004) and motor training (Klintsova et al, 2000) can reverse some of the deficits caused by gestational ethanol exposure. In addition, the characterization of factors governing stem cell production during intoxication and repair may lead to regererative therapies (Nixon 2006). These interventions ultimately involve BDNF and may be augmented by BDNF peptidomimentics.…”

Section: Bdnf As a Therapeutic Target For Alcoholism?mentioning

confidence: 99%

Ethanol–BDNF interactions: Still more questions than answers

Davis

2008

Pharmacology & Therapeutics

127

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Brain Derived Neurotrophic Factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism.

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Alcohol and adult neurogenesis: Roles in neurodegeneration and recovery in chronic alcoholism

Cited by 151 publications

References 91 publications

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Monkeys that Voluntarily and Chronically Drink Alcohol Damage their Brains: a Longitudinal MRI Study

Ethanol–BDNF interactions: Still more questions than answers

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