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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

Alcohol-induced persevering, compulsive relearning deficits mimic alcoholic cognitive dysfunction. Shown are the time lines of treatment and testing (upper box) as well as the behavior of two individual rats (bottom two circles), a control (left) and a binge alcohol–treated (right) rat. As indicated in the upper box time line, the 4-day binge alcohol treatment was followed by a 4.5-day abstinent withdrawal period. This model induces physical dependence that can include seizures during withdrawal. Physical withdrawal symptoms subside within 24 hours in this model. It was reasoned that long-term, perhaps permanent, changes in behavior attributed to binge-induced brain damage would be apparent in abstinence beyond withdrawal. After 5 days of abstinence, special reference memory tasks were tested for 1 week using the Morris water maze. The Morris water maze involves learning the location of a hidden platform just under the water using visual cues on the walls surrounding a round water tank 6 feet in diameter. Both control and binge alcohol–treated animals could swim equally well, had normal activity, and easily learned to find the platform. Learning (decreased time to find the platform) with repeated trials was not altered. There was no indication of a persistent binge alcohol treatment effect on learning. However, when relearning tasks were tested at almost 2 weeks of abstinence, a persistent cognitive change was found. Both control and abstinent binge-treated rats readily learned the old platform location. However, reversal learning was disrupted in binge-treated rats. Reversal learning was tested by moving the submerged platform from the original position in the water tank to a position in the quadrant opposite that in which it had been placed during the learning memory task (moved from northeast to southwest quadrant). A vertical view of the tracks taken by control (left) and alcohol (right)-treated rats during the reversal learning task is traced in the two circles representing the water tank. Note the path of the control rat. It first investigates the old learned platform location, reflects on the platform not being in the old location, and then searches and finds the new platform location. Note the persevering of circling behavior shown by the binge-treated animal with numerous reentries into the original goal quadrant. The binge-treated rat failed to reach the new platform location within the maximum time allowed and was removed. Thus, the trace ends in the water and not on the platform. The loss of executive function in the binge alcohol–treated rat is apparent in the repeated, compulsive searching in the old learned position and the lack of cognitive flexibility to search the other areas.SOURCE: Adapted from Obernier et al. 2002b.
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f3-arh-31-4-377: Alcohol-induced persevering, compulsive relearning deficits mimic alcoholic cognitive dysfunction. Shown are the time lines of treatment and testing (upper box) as well as the behavior of two individual rats (bottom two circles), a control (left) and a binge alcohol–treated (right) rat. As indicated in the upper box time line, the 4-day binge alcohol treatment was followed by a 4.5-day abstinent withdrawal period. This model induces physical dependence that can include seizures during withdrawal. Physical withdrawal symptoms subside within 24 hours in this model. It was reasoned that long-term, perhaps permanent, changes in behavior attributed to binge-induced brain damage would be apparent in abstinence beyond withdrawal. After 5 days of abstinence, special reference memory tasks were tested for 1 week using the Morris water maze. The Morris water maze involves learning the location of a hidden platform just under the water using visual cues on the walls surrounding a round water tank 6 feet in diameter. Both control and binge alcohol–treated animals could swim equally well, had normal activity, and easily learned to find the platform. Learning (decreased time to find the platform) with repeated trials was not altered. There was no indication of a persistent binge alcohol treatment effect on learning. However, when relearning tasks were tested at almost 2 weeks of abstinence, a persistent cognitive change was found. Both control and abstinent binge-treated rats readily learned the old platform location. However, reversal learning was disrupted in binge-treated rats. Reversal learning was tested by moving the submerged platform from the original position in the water tank to a position in the quadrant opposite that in which it had been placed during the learning memory task (moved from northeast to southwest quadrant). A vertical view of the tracks taken by control (left) and alcohol (right)-treated rats during the reversal learning task is traced in the two circles representing the water tank. Note the path of the control rat. It first investigates the old learned platform location, reflects on the platform not being in the old location, and then searches and finds the new platform location. Note the persevering of circling behavior shown by the binge-treated animal with numerous reentries into the original goal quadrant. The binge-treated rat failed to reach the new platform location within the maximum time allowed and was removed. Thus, the trace ends in the water and not on the platform. The loss of executive function in the binge alcohol–treated rat is apparent in the repeated, compulsive searching in the old learned position and the lack of cognitive flexibility to search the other areas.SOURCE: Adapted from Obernier et al. 2002b.

Mentions: Human studies (Harper and Kril 1990; Harper and Matsumoto 2005) using brain imaging or examining brains after death have found that alcoholics have smaller brains, particularly frontal cortical regions and white-matter brain regions that represent the wiring connecting the brain. In addition, alcoholics have larger fluid-filled areas (i.e., ventricles) of the brain and smaller overall brain matter. Functional deficits in alcoholics can relate to brain regional size deficits (see Rosenbloom and Pfefferbaum in this issue, pp. 362–376). Animal studies (Crews and Nixon 2008) indicate that alcohol can cause brain damage during intoxication (see figures 1 and 2). Further, alcohol-induced neurodegeneration in animals causes behavioral changes consistent with dysfunctional behavior found in human alcoholics (see figure 3). These studies suggest that alcoholic neurodegeneration could contribute to alcoholism.


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

Crews FT - Alcohol Res Health (2008)

Alcohol-induced persevering, compulsive relearning deficits mimic alcoholic cognitive dysfunction. Shown are the time lines of treatment and testing (upper box) as well as the behavior of two individual rats (bottom two circles), a control (left) and a binge alcohol–treated (right) rat. As indicated in the upper box time line, the 4-day binge alcohol treatment was followed by a 4.5-day abstinent withdrawal period. This model induces physical dependence that can include seizures during withdrawal. Physical withdrawal symptoms subside within 24 hours in this model. It was reasoned that long-term, perhaps permanent, changes in behavior attributed to binge-induced brain damage would be apparent in abstinence beyond withdrawal. After 5 days of abstinence, special reference memory tasks were tested for 1 week using the Morris water maze. The Morris water maze involves learning the location of a hidden platform just under the water using visual cues on the walls surrounding a round water tank 6 feet in diameter. Both control and binge alcohol–treated animals could swim equally well, had normal activity, and easily learned to find the platform. Learning (decreased time to find the platform) with repeated trials was not altered. There was no indication of a persistent binge alcohol treatment effect on learning. However, when relearning tasks were tested at almost 2 weeks of abstinence, a persistent cognitive change was found. Both control and abstinent binge-treated rats readily learned the old platform location. However, reversal learning was disrupted in binge-treated rats. Reversal learning was tested by moving the submerged platform from the original position in the water tank to a position in the quadrant opposite that in which it had been placed during the learning memory task (moved from northeast to southwest quadrant). A vertical view of the tracks taken by control (left) and alcohol (right)-treated rats during the reversal learning task is traced in the two circles representing the water tank. Note the path of the control rat. It first investigates the old learned platform location, reflects on the platform not being in the old location, and then searches and finds the new platform location. Note the persevering of circling behavior shown by the binge-treated animal with numerous reentries into the original goal quadrant. The binge-treated rat failed to reach the new platform location within the maximum time allowed and was removed. Thus, the trace ends in the water and not on the platform. The loss of executive function in the binge alcohol–treated rat is apparent in the repeated, compulsive searching in the old learned position and the lack of cognitive flexibility to search the other areas.SOURCE: Adapted from Obernier et al. 2002b.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f3-arh-31-4-377: Alcohol-induced persevering, compulsive relearning deficits mimic alcoholic cognitive dysfunction. Shown are the time lines of treatment and testing (upper box) as well as the behavior of two individual rats (bottom two circles), a control (left) and a binge alcohol–treated (right) rat. As indicated in the upper box time line, the 4-day binge alcohol treatment was followed by a 4.5-day abstinent withdrawal period. This model induces physical dependence that can include seizures during withdrawal. Physical withdrawal symptoms subside within 24 hours in this model. It was reasoned that long-term, perhaps permanent, changes in behavior attributed to binge-induced brain damage would be apparent in abstinence beyond withdrawal. After 5 days of abstinence, special reference memory tasks were tested for 1 week using the Morris water maze. The Morris water maze involves learning the location of a hidden platform just under the water using visual cues on the walls surrounding a round water tank 6 feet in diameter. Both control and binge alcohol–treated animals could swim equally well, had normal activity, and easily learned to find the platform. Learning (decreased time to find the platform) with repeated trials was not altered. There was no indication of a persistent binge alcohol treatment effect on learning. However, when relearning tasks were tested at almost 2 weeks of abstinence, a persistent cognitive change was found. Both control and abstinent binge-treated rats readily learned the old platform location. However, reversal learning was disrupted in binge-treated rats. Reversal learning was tested by moving the submerged platform from the original position in the water tank to a position in the quadrant opposite that in which it had been placed during the learning memory task (moved from northeast to southwest quadrant). A vertical view of the tracks taken by control (left) and alcohol (right)-treated rats during the reversal learning task is traced in the two circles representing the water tank. Note the path of the control rat. It first investigates the old learned platform location, reflects on the platform not being in the old location, and then searches and finds the new platform location. Note the persevering of circling behavior shown by the binge-treated animal with numerous reentries into the original goal quadrant. The binge-treated rat failed to reach the new platform location within the maximum time allowed and was removed. Thus, the trace ends in the water and not on the platform. The loss of executive function in the binge alcohol–treated rat is apparent in the repeated, compulsive searching in the old learned position and the lack of cognitive flexibility to search the other areas.SOURCE: Adapted from Obernier et al. 2002b.
Mentions: Human studies (Harper and Kril 1990; Harper and Matsumoto 2005) using brain imaging or examining brains after death have found that alcoholics have smaller brains, particularly frontal cortical regions and white-matter brain regions that represent the wiring connecting the brain. In addition, alcoholics have larger fluid-filled areas (i.e., ventricles) of the brain and smaller overall brain matter. Functional deficits in alcoholics can relate to brain regional size deficits (see Rosenbloom and Pfefferbaum in this issue, pp. 362–376). Animal studies (Crews and Nixon 2008) indicate that alcohol can cause brain damage during intoxication (see figures 1 and 2). Further, alcohol-induced neurodegeneration in animals causes behavioral changes consistent with dysfunctional behavior found in human alcoholics (see figure 3). These studies suggest that alcoholic neurodegeneration could contribute to alcoholism.

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