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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

Regeneration of brain is related to increased phosphorylated cAMP-responsive element-binding protein (pCREB). The 4-day rat BIBD model time line illustrates the relationship between alcohol-induced degeneration, abstinence-induced neurogenesis, and pCREB. The temporal relationship of binge-induced neurodegeneration and abstinence-induced cell genesis can be examined by pCREB immunohistochemical staining in the dentate gyrus. Immunohistochemical staining is a process of localizing proteins in cells of a tissue section using antibodies that bind to specific proteins, such as pCREB. More staining means more protein. In the dentate gyrus granule cells (GCs) of control subjects, most neuronal nuclei have some pCREB+ immunoreactivity (IR), with higher levels of staining in the subgranule zone (SGZ), where neurogenesis is active (control, upper left image). In the diagram, values below the x-axis reflect degeneration or loss of brain mass. Markers of neuronal death increase throughout the 4 days of intoxication. Neurogenesis decreases and pCREB+IR is low (middle image). Markers of neuronal death persist into abstinence, although they progressively decline and mostly disappear after 1 week of abstinence (dotted line). Regeneration is represented by the dashed line increasing above the x-axis, with stars indicating time points of measured neurogenesis and other cell genesis (Crews and Nixon 2008). After 4 days of binge alcohol treatment, pCREB staining is decreased when neurogenesis is inhibited and granule cells degenerate. However, after 72 hours of abstinence, a marked increase in pCREB staining (top photo [4 days alcohol/72 hours withdrawal]) coincides with increased neurogenesis and loss of degeneration markers (Bison and Crews 2003).NOTE: CREB is a transcription factor altered by alcohol. When CREB is activated, pCREB is formed. The dentate gyrus is part of the hippocampus.
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f6-arh-31-4-377: Regeneration of brain is related to increased phosphorylated cAMP-responsive element-binding protein (pCREB). The 4-day rat BIBD model time line illustrates the relationship between alcohol-induced degeneration, abstinence-induced neurogenesis, and pCREB. The temporal relationship of binge-induced neurodegeneration and abstinence-induced cell genesis can be examined by pCREB immunohistochemical staining in the dentate gyrus. Immunohistochemical staining is a process of localizing proteins in cells of a tissue section using antibodies that bind to specific proteins, such as pCREB. More staining means more protein. In the dentate gyrus granule cells (GCs) of control subjects, most neuronal nuclei have some pCREB+ immunoreactivity (IR), with higher levels of staining in the subgranule zone (SGZ), where neurogenesis is active (control, upper left image). In the diagram, values below the x-axis reflect degeneration or loss of brain mass. Markers of neuronal death increase throughout the 4 days of intoxication. Neurogenesis decreases and pCREB+IR is low (middle image). Markers of neuronal death persist into abstinence, although they progressively decline and mostly disappear after 1 week of abstinence (dotted line). Regeneration is represented by the dashed line increasing above the x-axis, with stars indicating time points of measured neurogenesis and other cell genesis (Crews and Nixon 2008). After 4 days of binge alcohol treatment, pCREB staining is decreased when neurogenesis is inhibited and granule cells degenerate. However, after 72 hours of abstinence, a marked increase in pCREB staining (top photo [4 days alcohol/72 hours withdrawal]) coincides with increased neurogenesis and loss of degeneration markers (Bison and Crews 2003).NOTE: CREB is a transcription factor altered by alcohol. When CREB is activated, pCREB is formed. The dentate gyrus is part of the hippocampus.

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)

Regeneration of brain is related to increased phosphorylated cAMP-responsive element-binding protein (pCREB). The 4-day rat BIBD model time line illustrates the relationship between alcohol-induced degeneration, abstinence-induced neurogenesis, and pCREB. The temporal relationship of binge-induced neurodegeneration and abstinence-induced cell genesis can be examined by pCREB immunohistochemical staining in the dentate gyrus. Immunohistochemical staining is a process of localizing proteins in cells of a tissue section using antibodies that bind to specific proteins, such as pCREB. More staining means more protein. In the dentate gyrus granule cells (GCs) of control subjects, most neuronal nuclei have some pCREB+ immunoreactivity (IR), with higher levels of staining in the subgranule zone (SGZ), where neurogenesis is active (control, upper left image). In the diagram, values below the x-axis reflect degeneration or loss of brain mass. Markers of neuronal death increase throughout the 4 days of intoxication. Neurogenesis decreases and pCREB+IR is low (middle image). Markers of neuronal death persist into abstinence, although they progressively decline and mostly disappear after 1 week of abstinence (dotted line). Regeneration is represented by the dashed line increasing above the x-axis, with stars indicating time points of measured neurogenesis and other cell genesis (Crews and Nixon 2008). After 4 days of binge alcohol treatment, pCREB staining is decreased when neurogenesis is inhibited and granule cells degenerate. However, after 72 hours of abstinence, a marked increase in pCREB staining (top photo [4 days alcohol/72 hours withdrawal]) coincides with increased neurogenesis and loss of degeneration markers (Bison and Crews 2003).NOTE: CREB is a transcription factor altered by alcohol. When CREB is activated, pCREB is formed. The dentate gyrus is part of the hippocampus.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f6-arh-31-4-377: Regeneration of brain is related to increased phosphorylated cAMP-responsive element-binding protein (pCREB). The 4-day rat BIBD model time line illustrates the relationship between alcohol-induced degeneration, abstinence-induced neurogenesis, and pCREB. The temporal relationship of binge-induced neurodegeneration and abstinence-induced cell genesis can be examined by pCREB immunohistochemical staining in the dentate gyrus. Immunohistochemical staining is a process of localizing proteins in cells of a tissue section using antibodies that bind to specific proteins, such as pCREB. More staining means more protein. In the dentate gyrus granule cells (GCs) of control subjects, most neuronal nuclei have some pCREB+ immunoreactivity (IR), with higher levels of staining in the subgranule zone (SGZ), where neurogenesis is active (control, upper left image). In the diagram, values below the x-axis reflect degeneration or loss of brain mass. Markers of neuronal death increase throughout the 4 days of intoxication. Neurogenesis decreases and pCREB+IR is low (middle image). Markers of neuronal death persist into abstinence, although they progressively decline and mostly disappear after 1 week of abstinence (dotted line). Regeneration is represented by the dashed line increasing above the x-axis, with stars indicating time points of measured neurogenesis and other cell genesis (Crews and Nixon 2008). After 4 days of binge alcohol treatment, pCREB staining is decreased when neurogenesis is inhibited and granule cells degenerate. However, after 72 hours of abstinence, a marked increase in pCREB staining (top photo [4 days alcohol/72 hours withdrawal]) coincides with increased neurogenesis and loss of degeneration markers (Bison and Crews 2003).NOTE: CREB is a transcription factor altered by alcohol. When CREB is activated, pCREB is formed. The dentate gyrus is part of the hippocampus.
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