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Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.

Vetreno RP, Crews FT - Front Neurosci (2015)

Bottom Line: This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3).In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules.Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina Chapel Hill, NC, USA.

ABSTRACT
Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

No MeSH data available.


Related in: MedlinePlus

Adolescent intermittent ethanol (AIE) treatment leads to long-term reductions of Ki-67 immunoreactive (+IR) expression in the young adult hippocampus. Profile cell counts revealed a 35% (±5%) reduction of Ki-67 + IR cells in the dorsal hippocampal dentate gyrus of AIE-treated animals on postnatal day 80, relative to controls (CONs). Data are presented as mean ± SEM. **indicates p < 0.01, relative to CON rats. Included are representative photomicrographs of Ki-67 + IR cells in the dentate gyrus of the dorsal hippocampus from CON- and AIE-treated animals. Arrowheads highlight Ki-67+IR cells.
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Figure 3: Adolescent intermittent ethanol (AIE) treatment leads to long-term reductions of Ki-67 immunoreactive (+IR) expression in the young adult hippocampus. Profile cell counts revealed a 35% (±5%) reduction of Ki-67 + IR cells in the dorsal hippocampal dentate gyrus of AIE-treated animals on postnatal day 80, relative to controls (CONs). Data are presented as mean ± SEM. **indicates p < 0.01, relative to CON rats. Included are representative photomicrographs of Ki-67 + IR cells in the dentate gyrus of the dorsal hippocampus from CON- and AIE-treated animals. Arrowheads highlight Ki-67+IR cells.

Mentions: Our finding of AIE-induced diminution of DCX + IR in the hippocampus prompted us to assess whether a reduction in neural progenitor cell proliferation may have contributed to the effects of adolescent binge ethanol exposure on neurogenesis. We assessed expression of Ki-67, an endogenous nuclear protein expressed in dividing cells (Scholzen and Gerdes, 2000), in the young adult (P80) dorsal hippocampal dentate gyrus of CON- and AIE-treated animals. In CON- and AIE-treated subjects, Ki-67 + IR was characterized by darkly stained clusters of cell bodies that were localized within the subgranular zone of the dentate gyrus. Adolescent binge ethanol exposure reduced Ki-67 + IR cell populations by 35% (±5%), relative to CON subjects [One-Way ANOVA: F(1, 12) = 9.5, p < 0.01; see Figure 3]. These data suggest that diminished neural cell proliferation could contribute to the AIE-induced reduction in hippocampal neurogenesis.


Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.

Vetreno RP, Crews FT - Front Neurosci (2015)

Adolescent intermittent ethanol (AIE) treatment leads to long-term reductions of Ki-67 immunoreactive (+IR) expression in the young adult hippocampus. Profile cell counts revealed a 35% (±5%) reduction of Ki-67 + IR cells in the dorsal hippocampal dentate gyrus of AIE-treated animals on postnatal day 80, relative to controls (CONs). Data are presented as mean ± SEM. **indicates p < 0.01, relative to CON rats. Included are representative photomicrographs of Ki-67 + IR cells in the dentate gyrus of the dorsal hippocampus from CON- and AIE-treated animals. Arrowheads highlight Ki-67+IR cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325907&req=5

Figure 3: Adolescent intermittent ethanol (AIE) treatment leads to long-term reductions of Ki-67 immunoreactive (+IR) expression in the young adult hippocampus. Profile cell counts revealed a 35% (±5%) reduction of Ki-67 + IR cells in the dorsal hippocampal dentate gyrus of AIE-treated animals on postnatal day 80, relative to controls (CONs). Data are presented as mean ± SEM. **indicates p < 0.01, relative to CON rats. Included are representative photomicrographs of Ki-67 + IR cells in the dentate gyrus of the dorsal hippocampus from CON- and AIE-treated animals. Arrowheads highlight Ki-67+IR cells.
Mentions: Our finding of AIE-induced diminution of DCX + IR in the hippocampus prompted us to assess whether a reduction in neural progenitor cell proliferation may have contributed to the effects of adolescent binge ethanol exposure on neurogenesis. We assessed expression of Ki-67, an endogenous nuclear protein expressed in dividing cells (Scholzen and Gerdes, 2000), in the young adult (P80) dorsal hippocampal dentate gyrus of CON- and AIE-treated animals. In CON- and AIE-treated subjects, Ki-67 + IR was characterized by darkly stained clusters of cell bodies that were localized within the subgranular zone of the dentate gyrus. Adolescent binge ethanol exposure reduced Ki-67 + IR cell populations by 35% (±5%), relative to CON subjects [One-Way ANOVA: F(1, 12) = 9.5, p < 0.01; see Figure 3]. These data suggest that diminished neural cell proliferation could contribute to the AIE-induced reduction in hippocampal neurogenesis.

Bottom Line: This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3).In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules.Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina Chapel Hill, NC, USA.

ABSTRACT
Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

No MeSH data available.


Related in: MedlinePlus