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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

Exposure to lipopolysaccharide (LPS) mimics the loss of doublecortin-immunoreactive (DCX + IR) cells associated with adolescent intermittent ethanol (AIE) exposure. (A) Pixel density quantification in the dentate gyrus of the dorsal hippocampus of young adult rats (postnatal [P]80) revealed a significant reduction of DCX + IR in AIE- (48 ± 5%), CON + LPS (41 ± 7%), and AIE + LPS-exposed (42 ± 15%) rats, relative to CONs. (B) Pixel density quantification in the dentate gyrus of the ventral hippocampus of young adult rats (P80) revealed a significant reduction of DCX + IR in AIE- (46 ± 9%), CON + LPS (41 ± 9%), and AIE + LPS-exposed (41 ± 13%) rats, relative to CONs. * indicates p < 0.05 and ** indicates p < 0.01, relative to CON/SAL rats. Data are presented as mean ± SEM.
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Figure 5: Exposure to lipopolysaccharide (LPS) mimics the loss of doublecortin-immunoreactive (DCX + IR) cells associated with adolescent intermittent ethanol (AIE) exposure. (A) Pixel density quantification in the dentate gyrus of the dorsal hippocampus of young adult rats (postnatal [P]80) revealed a significant reduction of DCX + IR in AIE- (48 ± 5%), CON + LPS (41 ± 7%), and AIE + LPS-exposed (42 ± 15%) rats, relative to CONs. (B) Pixel density quantification in the dentate gyrus of the ventral hippocampus of young adult rats (P80) revealed a significant reduction of DCX + IR in AIE- (46 ± 9%), CON + LPS (41 ± 9%), and AIE + LPS-exposed (41 ± 13%) rats, relative to CONs. * indicates p < 0.05 and ** indicates p < 0.01, relative to CON/SAL rats. Data are presented as mean ± SEM.

Mentions: Our laboratory previously found that adolescent binge ethanol exposure persistently upregulates neuroimmune signaling molecules and Toll-like receptor 4 (TLR4) expression in the brain (Vetreno and Crews, 2012; Vetreno et al., 2013). To determine if neuroimmune activation contributes to the reduction of hippocampal neurogenesis, CON- and AIE-exposed animals received a single dose of LPS (1.0 mg/kg, i.p.) on P70, and DCX + IR was assessed in the dorsal and ventral hippocampal dentate gyrus on P80. Lipopolysaccharide (LPS) is a gram-negative endotoxin agonist at TLR4 whose activation leads to proinflammatory cytokine and oxidase induction in brain (Qin et al., 2007). Expression of DCX in the dorsal and ventral hippocampal dentate gyrus was analyzed using separate 2 × 2 ANOVAs (Treatment [CON vs. AIE] × Drug [LPS vs. SAL]). Within the dorsal hippocampal dentate gyrus, AIE treatment significantly reduced DCX + IR relative to CONs [main effect of Treatment: F(1, 28) = 6.2, p < 0.05]. Although there was no main effect of Drug (p > 0.05), there was a significant Treatment × Drug interaction [F(1, 28) = 5.7, p < 0.05]. Post-hoc analysis revealed that, relative to CONs, DCX + IR was significantly reduced in the AIE (48% [±5%]; p < 0.01), CON + LPS (41% [±7%]; p < 0.05), and AIE + LPS (42% [±13%]; p < 0.05) treatment groups (see Figure 5A). Analysis of the ventral hippocampal dentate gyrus revealed a significant main effect of Treatment [F(1, 28) = 4.3, p < 0.05; see Figure 5B]. There were no other main effects or interactions. Thus, these data reveal that LPS treatment induces a similar reduction of DCX + IR in the CONs that was observed in AIE-treated animals.


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)

Exposure to lipopolysaccharide (LPS) mimics the loss of doublecortin-immunoreactive (DCX + IR) cells associated with adolescent intermittent ethanol (AIE) exposure. (A) Pixel density quantification in the dentate gyrus of the dorsal hippocampus of young adult rats (postnatal [P]80) revealed a significant reduction of DCX + IR in AIE- (48 ± 5%), CON + LPS (41 ± 7%), and AIE + LPS-exposed (42 ± 15%) rats, relative to CONs. (B) Pixel density quantification in the dentate gyrus of the ventral hippocampus of young adult rats (P80) revealed a significant reduction of DCX + IR in AIE- (46 ± 9%), CON + LPS (41 ± 9%), and AIE + LPS-exposed (41 ± 13%) rats, relative to CONs. * indicates p < 0.05 and ** indicates p < 0.01, relative to CON/SAL rats. Data are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Exposure to lipopolysaccharide (LPS) mimics the loss of doublecortin-immunoreactive (DCX + IR) cells associated with adolescent intermittent ethanol (AIE) exposure. (A) Pixel density quantification in the dentate gyrus of the dorsal hippocampus of young adult rats (postnatal [P]80) revealed a significant reduction of DCX + IR in AIE- (48 ± 5%), CON + LPS (41 ± 7%), and AIE + LPS-exposed (42 ± 15%) rats, relative to CONs. (B) Pixel density quantification in the dentate gyrus of the ventral hippocampus of young adult rats (P80) revealed a significant reduction of DCX + IR in AIE- (46 ± 9%), CON + LPS (41 ± 9%), and AIE + LPS-exposed (41 ± 13%) rats, relative to CONs. * indicates p < 0.05 and ** indicates p < 0.01, relative to CON/SAL rats. Data are presented as mean ± SEM.
Mentions: Our laboratory previously found that adolescent binge ethanol exposure persistently upregulates neuroimmune signaling molecules and Toll-like receptor 4 (TLR4) expression in the brain (Vetreno and Crews, 2012; Vetreno et al., 2013). To determine if neuroimmune activation contributes to the reduction of hippocampal neurogenesis, CON- and AIE-exposed animals received a single dose of LPS (1.0 mg/kg, i.p.) on P70, and DCX + IR was assessed in the dorsal and ventral hippocampal dentate gyrus on P80. Lipopolysaccharide (LPS) is a gram-negative endotoxin agonist at TLR4 whose activation leads to proinflammatory cytokine and oxidase induction in brain (Qin et al., 2007). Expression of DCX in the dorsal and ventral hippocampal dentate gyrus was analyzed using separate 2 × 2 ANOVAs (Treatment [CON vs. AIE] × Drug [LPS vs. SAL]). Within the dorsal hippocampal dentate gyrus, AIE treatment significantly reduced DCX + IR relative to CONs [main effect of Treatment: F(1, 28) = 6.2, p < 0.05]. Although there was no main effect of Drug (p > 0.05), there was a significant Treatment × Drug interaction [F(1, 28) = 5.7, p < 0.05]. Post-hoc analysis revealed that, relative to CONs, DCX + IR was significantly reduced in the AIE (48% [±5%]; p < 0.01), CON + LPS (41% [±7%]; p < 0.05), and AIE + LPS (42% [±13%]; p < 0.05) treatment groups (see Figure 5A). Analysis of the ventral hippocampal dentate gyrus revealed a significant main effect of Treatment [F(1, 28) = 4.3, p < 0.05; see Figure 5B]. There were no other main effects or interactions. Thus, these data reveal that LPS treatment induces a similar reduction of DCX + IR in the CONs that was observed in AIE-treated animals.

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