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Alcohol-related neurodegeneration and recovery: mechanisms from animal models.

Crews FT - Alcohol Res Health (2008)

Bottom Line: Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use.Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment.Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

ABSTRACT
Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addition, animal studies indicate that inhibition of the creation of neurons (i.e., neurogenesis) and other brain-cell genesis contributes to alcoholic neurodegeneration. Animal studies also suggest that neurodegeneration changes cognition, contributing to alcohol use disorders. Risk factors such as adolescent age and genetic predisposition toward alcohol consumption worsen neurodegeneration. Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment. Thus, animal studies suggest that heavy alcohol use contributes to neurodegeneration and the progressive loss of control over drinking. Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.

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Related in: MedlinePlus

Neurogenesis during abstinence following binge alcohol treatment. The protein doublecortin (DCX) is expressed in neuroprogenitors during differentiation into mature neurons (Brown et al. 2003). The images show DCX immunohistochemistry in control subjects and after 14 days of abstinence following a 4-day binge-drinking period. Note the prominent increase in new neurons (exhibited by dark staining) being formed after 2 weeks of abstinence (Nixon and Crews 2004).
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f5-arh-31-4-377: Neurogenesis during abstinence following binge alcohol treatment. The protein doublecortin (DCX) is expressed in neuroprogenitors during differentiation into mature neurons (Brown et al. 2003). The images show DCX immunohistochemistry in control subjects and after 14 days of abstinence following a 4-day binge-drinking period. Note the prominent increase in new neurons (exhibited by dark staining) being formed after 2 weeks of abstinence (Nixon and Crews 2004).

Mentions: Animal binge-drinking models investigating NSCs and neurogenesis have found that alcohol inhibits neurogenesis, with adolescents being particularly sensitive (Crews and Nixon 2008). Abstinence following binge-drinking treatment in rats results in increased NSC proliferation in multiple brain regions (Nixon and Crews 2004). NSC proliferation increases within 1 day of abstinence and continues for many days and weeks (He et al. 2008). During abstinence following alcohol dependence, hippocampal NSCs proliferate in bursts, with an expansion of cells leading to a progressive wave of cells differentiating from NSCs into immature new neurons. Specific proteins, such as doublecortin, are expressed only in developing new neurons. This allows researchers to use this protein to identify new neurons. As shown in figure 5, hippocampal neurogenesis is dramatically greater in rats 2 weeks after the last dose of alcohol in the 4-day binge model compared with age-matched controls not exposed to alcohol. The alcohol-abstinence–induced burst of cell proliferation occurs as the degeneration and fragments of dying neurons clear but also is associated with a marked increase in pCREB, likely caused by synaptic glutamate-activating trophic signals. Trophic, cell-strengthening signals increase through pCREB, as described in figure 6. Multiple broad areas of the brain show new progenitor cells at 1 and 2 months of abstinence. New cells in the hippocampus become neurons, whereas in many other brain regions they become microglia but do not appear to be activated proliferating microglia (Crews and Nixon 2008). Although microglial proliferation is a sign of proinflammatory microglial activation, the lack of a “bushy” or “ameboid” morphology suggests that proliferating progenitor cells become resting microglia. Although studies of humans have limited information on lifetime cycles of drinking and abstinence, the increase in microglia in abstinent rat brain is similar to the increased numbers of microglia found in human alcoholic brains (see figure 4).


Alcohol-related neurodegeneration and recovery: mechanisms from animal models.

Crews FT - Alcohol Res Health (2008)

Neurogenesis during abstinence following binge alcohol treatment. The protein doublecortin (DCX) is expressed in neuroprogenitors during differentiation into mature neurons (Brown et al. 2003). The images show DCX immunohistochemistry in control subjects and after 14 days of abstinence following a 4-day binge-drinking period. Note the prominent increase in new neurons (exhibited by dark staining) being formed after 2 weeks of abstinence (Nixon and Crews 2004).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860462&req=5

f5-arh-31-4-377: Neurogenesis during abstinence following binge alcohol treatment. The protein doublecortin (DCX) is expressed in neuroprogenitors during differentiation into mature neurons (Brown et al. 2003). The images show DCX immunohistochemistry in control subjects and after 14 days of abstinence following a 4-day binge-drinking period. Note the prominent increase in new neurons (exhibited by dark staining) being formed after 2 weeks of abstinence (Nixon and Crews 2004).
Mentions: Animal binge-drinking models investigating NSCs and neurogenesis have found that alcohol inhibits neurogenesis, with adolescents being particularly sensitive (Crews and Nixon 2008). Abstinence following binge-drinking treatment in rats results in increased NSC proliferation in multiple brain regions (Nixon and Crews 2004). NSC proliferation increases within 1 day of abstinence and continues for many days and weeks (He et al. 2008). During abstinence following alcohol dependence, hippocampal NSCs proliferate in bursts, with an expansion of cells leading to a progressive wave of cells differentiating from NSCs into immature new neurons. Specific proteins, such as doublecortin, are expressed only in developing new neurons. This allows researchers to use this protein to identify new neurons. As shown in figure 5, hippocampal neurogenesis is dramatically greater in rats 2 weeks after the last dose of alcohol in the 4-day binge model compared with age-matched controls not exposed to alcohol. The alcohol-abstinence–induced burst of cell proliferation occurs as the degeneration and fragments of dying neurons clear but also is associated with a marked increase in pCREB, likely caused by synaptic glutamate-activating trophic signals. Trophic, cell-strengthening signals increase through pCREB, as described in figure 6. Multiple broad areas of the brain show new progenitor cells at 1 and 2 months of abstinence. New cells in the hippocampus become neurons, whereas in many other brain regions they become microglia but do not appear to be activated proliferating microglia (Crews and Nixon 2008). Although microglial proliferation is a sign of proinflammatory microglial activation, the lack of a “bushy” or “ameboid” morphology suggests that proliferating progenitor cells become resting microglia. Although studies of humans have limited information on lifetime cycles of drinking and abstinence, the increase in microglia in abstinent rat brain is similar to the increased numbers of microglia found in human alcoholic brains (see figure 4).

Bottom Line: Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use.Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment.Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.

View Article: PubMed Central - PubMed

Affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

ABSTRACT
Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addition, animal studies indicate that inhibition of the creation of neurons (i.e., neurogenesis) and other brain-cell genesis contributes to alcoholic neurodegeneration. Animal studies also suggest that neurodegeneration changes cognition, contributing to alcohol use disorders. Risk factors such as adolescent age and genetic predisposition toward alcohol consumption worsen neurodegeneration. Mild impairment of executive functions similar to that found in humans occurs in animals following binge alcohol treatment. Thus, animal studies suggest that heavy alcohol use contributes to neurodegeneration and the progressive loss of control over drinking. Despite the negative consequences of heavy drinking, there is hope of recovery with abstinence, which in animal models can result in neural stem-cell proliferation and the formation of new neurons and other brain cells, indicative of brain growth.

Show MeSH
Related in: MedlinePlus