Limits...
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) exposure leads to long-term reductions of doublecortin-immunopositive (DCX + IR) cells in the dorsal and ventral hippocampal dentate gyrus. (A) Quantification of pixel density revealed a 33% (±4%) decrease of DCX + IR in the adolescent (postnatal [P]56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood (P220 [51 ± 6%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the dorsal hippocampus from young adult (P80) CON- and AIE-treated animals. (B) Quantification of pixel density revealed a 42% (±7%) decrease of DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the ventral hippocampus from young adult (P80) CON- and AIE-treated animals. Data are presented as mean ± SEM. *indicates p < 0.05; **indicates p < 0.01, relative to CON rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4325907&req=5

Figure 2: Adolescent intermittent ethanol (AIE) exposure leads to long-term reductions of doublecortin-immunopositive (DCX + IR) cells in the dorsal and ventral hippocampal dentate gyrus. (A) Quantification of pixel density revealed a 33% (±4%) decrease of DCX + IR in the adolescent (postnatal [P]56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood (P220 [51 ± 6%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the dorsal hippocampus from young adult (P80) CON- and AIE-treated animals. (B) Quantification of pixel density revealed a 42% (±7%) decrease of DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the ventral hippocampus from young adult (P80) CON- and AIE-treated animals. Data are presented as mean ± SEM. *indicates p < 0.05; **indicates p < 0.01, relative to CON rats.

Mentions: Doublecortin, a neuroprogenitor microtubule-associated protein expressed specifically by immature neurons (Brown et al., 2003), was assessed separately in the dorsal and ventral hippocampus following adolescent binge ethanol treatment. In our animal paradigm, human adolescent drinking is modeled using an intermittent administration schedule consistent with known patterns of heavy weekend binge drinking, but not daily drinking associated with alcoholism in adulthood. Tissue samples were collected from the dorsal and ventral hippocampus, and DCX + IR was assessed in animals sacrificed on P56 (24 h post-AIE treatment), P80 (25 days post-AIE treatment), and P220 (165 days post-AIE treatment). In CON- and AIE-treated subjects, DCX + IR in the dorsal and ventral hippocampus was characterized by darkly stained cell bodies and processes that innervated the granular cell layer of the hippocampal dentate gyrus, with less cell and process staining observed in the AIE-treated animals (see Figure 2). A 2 × 3 ANOVA (Treatment [CON vs. AIE] × Age [P56 vs. P80 vs. P220]) found that expression of DCX significantly declined with age from P55 to P220 in both the dorsal [main effect of Age: F(2, 39) = 51.5, p < 0.01] and ventral [main effect of Age: F(2, 39) = 25.1, p < 0.01] hippocampal dentate gyrus. Further, we found that relative to CONs, AIE treatment resulted in a 33% (±4%) decrease in DCX + IR in the adolescent (P56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood [P220 [51 ± 6%]; main effect of Treatment: F(1, 39) = 24.7, p < 0.01; see Figure 2A]. Since DCX labels both cell bodies and processes of immature neurons, we assessed DCX + IR cell bodies in the superior blade of the dorsal dentate gyrus of the P80 age group to verify the AIE-induced DCX reductions. We chose the superior blade because there were less overlapping DCX + IR cells in this region allowing for more precise quantification. We found that AIE treatment reduced the number of DCX + IR cells by 45% (±4%), relative to the CONs [One-Way ANOVA: F(1,15) = 56.3, p < 0.01]. Further, we found that DCX pixel density in the dorsal hippocampus was positively correlated with DCX cell counts (r = 0.78, N = 16, p < 0.01). Similar to the dorsal hippocampus, AIE treatment led to a 42% (±7%) decrease in DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to CONs [main effect of Treatment: F(1,39) = 25.3, p < 0.01; see Figure 2B]. There were no interactions of Treatment × Age in either analysis. Thus, these data reveal that adolescent binge ethanol exposure reduces DCX expression in the dorsal and ventral hippocampal dentate gyrus of the adolescent brain (P56) that follows the age-related decline in neurogenesis with AIE-induced deficits persisting into adulthood (P220), although the age-associated decline in DCX + IR obscures the AIE-induced differences, particularly within the dorsal hippocampal dentate gyrus, where it is largely diminished by 220 days of age.


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) exposure leads to long-term reductions of doublecortin-immunopositive (DCX + IR) cells in the dorsal and ventral hippocampal dentate gyrus. (A) Quantification of pixel density revealed a 33% (±4%) decrease of DCX + IR in the adolescent (postnatal [P]56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood (P220 [51 ± 6%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the dorsal hippocampus from young adult (P80) CON- and AIE-treated animals. (B) Quantification of pixel density revealed a 42% (±7%) decrease of DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the ventral hippocampus from young adult (P80) CON- and AIE-treated animals. Data are presented as mean ± SEM. *indicates p < 0.05; **indicates p < 0.01, relative to CON rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Adolescent intermittent ethanol (AIE) exposure leads to long-term reductions of doublecortin-immunopositive (DCX + IR) cells in the dorsal and ventral hippocampal dentate gyrus. (A) Quantification of pixel density revealed a 33% (±4%) decrease of DCX + IR in the adolescent (postnatal [P]56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood (P220 [51 ± 6%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the dorsal hippocampus from young adult (P80) CON- and AIE-treated animals. (B) Quantification of pixel density revealed a 42% (±7%) decrease of DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to controls (CONs). Included are representative photomicrographs of DCX + IR cells in the dentate gyrus of the ventral hippocampus from young adult (P80) CON- and AIE-treated animals. Data are presented as mean ± SEM. *indicates p < 0.05; **indicates p < 0.01, relative to CON rats.
Mentions: Doublecortin, a neuroprogenitor microtubule-associated protein expressed specifically by immature neurons (Brown et al., 2003), was assessed separately in the dorsal and ventral hippocampus following adolescent binge ethanol treatment. In our animal paradigm, human adolescent drinking is modeled using an intermittent administration schedule consistent with known patterns of heavy weekend binge drinking, but not daily drinking associated with alcoholism in adulthood. Tissue samples were collected from the dorsal and ventral hippocampus, and DCX + IR was assessed in animals sacrificed on P56 (24 h post-AIE treatment), P80 (25 days post-AIE treatment), and P220 (165 days post-AIE treatment). In CON- and AIE-treated subjects, DCX + IR in the dorsal and ventral hippocampus was characterized by darkly stained cell bodies and processes that innervated the granular cell layer of the hippocampal dentate gyrus, with less cell and process staining observed in the AIE-treated animals (see Figure 2). A 2 × 3 ANOVA (Treatment [CON vs. AIE] × Age [P56 vs. P80 vs. P220]) found that expression of DCX significantly declined with age from P55 to P220 in both the dorsal [main effect of Age: F(2, 39) = 51.5, p < 0.01] and ventral [main effect of Age: F(2, 39) = 25.1, p < 0.01] hippocampal dentate gyrus. Further, we found that relative to CONs, AIE treatment resulted in a 33% (±4%) decrease in DCX + IR in the adolescent (P56) dorsal hippocampal dentate gyrus that persisted from young adulthood (P80 [48 ± 7%]) into adulthood [P220 [51 ± 6%]; main effect of Treatment: F(1, 39) = 24.7, p < 0.01; see Figure 2A]. Since DCX labels both cell bodies and processes of immature neurons, we assessed DCX + IR cell bodies in the superior blade of the dorsal dentate gyrus of the P80 age group to verify the AIE-induced DCX reductions. We chose the superior blade because there were less overlapping DCX + IR cells in this region allowing for more precise quantification. We found that AIE treatment reduced the number of DCX + IR cells by 45% (±4%), relative to the CONs [One-Way ANOVA: F(1,15) = 56.3, p < 0.01]. Further, we found that DCX pixel density in the dorsal hippocampus was positively correlated with DCX cell counts (r = 0.78, N = 16, p < 0.01). Similar to the dorsal hippocampus, AIE treatment led to a 42% (±7%) decrease in DCX + IR in the adolescent (P56) ventral hippocampal dentate gyrus that persisted from young adulthood (P80 [46 ± 9%]) into adulthood (P220 [63 ± 7%]), relative to CONs [main effect of Treatment: F(1,39) = 25.3, p < 0.01; see Figure 2B]. There were no interactions of Treatment × Age in either analysis. Thus, these data reveal that adolescent binge ethanol exposure reduces DCX expression in the dorsal and ventral hippocampal dentate gyrus of the adolescent brain (P56) that follows the age-related decline in neurogenesis with AIE-induced deficits persisting into adulthood (P220), although the age-associated decline in DCX + IR obscures the AIE-induced differences, particularly within the dorsal hippocampal dentate gyrus, where it is largely diminished by 220 days of age.

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