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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

Graphical representation of the adolescent intermittent ethanol (AIE) exposure protocol and experimental design. (A) Rats were treated with either ethanol (5.0 g/kg, 20% ethanol w/v, i.g.) or a comparable volume of water on a 2-day on/2-day off administration schedule from postnatal day (P) 25 to P55. Blood ethanol concentrations (BECs) were assessed 1 h after ethanol exposure on P38 and P54 (mg/dL). Late adolescent rats were sacrificed on P56 (24 h post-AIE treatment). Subjects in the early adulthood group were sacrificed on P80 (25 days post-AIE treatment). A subset of subjects in the early adulthood group were treated with lipopolysaccharide (LPS; 1.0 mg/kg, i.p.) on P70 and sacrificed on P80. Subjects in the adulthood group were behaviorally tested on the novel object recognition memory task from P163 to P165, and were sacrificed on P220 (165 days post-AIE treatment). (B) Depicted are coronal sections of the dorsal and ventral hippocampus between Bregma –2.12 mm and –6.72 mm according to the atlas of Paxinos and Watson (1998) used for quantitative analysis of doublecortin-immunopositive cells.
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Figure 1: Graphical representation of the adolescent intermittent ethanol (AIE) exposure protocol and experimental design. (A) Rats were treated with either ethanol (5.0 g/kg, 20% ethanol w/v, i.g.) or a comparable volume of water on a 2-day on/2-day off administration schedule from postnatal day (P) 25 to P55. Blood ethanol concentrations (BECs) were assessed 1 h after ethanol exposure on P38 and P54 (mg/dL). Late adolescent rats were sacrificed on P56 (24 h post-AIE treatment). Subjects in the early adulthood group were sacrificed on P80 (25 days post-AIE treatment). A subset of subjects in the early adulthood group were treated with lipopolysaccharide (LPS; 1.0 mg/kg, i.p.) on P70 and sacrificed on P80. Subjects in the adulthood group were behaviorally tested on the novel object recognition memory task from P163 to P165, and were sacrificed on P220 (165 days post-AIE treatment). (B) Depicted are coronal sections of the dorsal and ventral hippocampus between Bregma –2.12 mm and –6.72 mm according to the atlas of Paxinos and Watson (1998) used for quantitative analysis of doublecortin-immunopositive cells.

Mentions: On P21, male Wistar rats were randomly assigned to either (i) AIE or (ii) water control (CON) groups. From P25 to P55, AIE animals received a single daily intragastric (i.g.) administration of ethanol (5.0 g/kg, 20% ethanol w/v) on a 2-day on/2-day off schedule and CON subjects received comparable volumes. Tail blood was collected to assess blood ethanol content (BEC) 1 h after ethanol administration as we previously found that BECs in the adolescent rat peak at approximately 60 min after i.p. ethanol administration (Crews et al., 2006b). Further, BECs were assessed at the midpoint of AIE treatment (P38) and again at the conclusion of AIE treatment (P54), and were quantitated using a GM7 Analyzer (Analox; London, UK). On P38 and P54, mean BECs (± SEM) were 189 ± 5 mg/dL and 190 ± 8 mg/dL, respectively, and did not differ across experiments (all p ≥ 0.2). Subjects were sacrificed at three different time points to assess the persistent effects of AIE treatment on neurogenesis in the dorsal and ventral hippocampus (see Figure 1A). Subjects were sacrificed on P56 (24 h post-AIE treatment) to determine the acute effects of AIE treatment on neurogenesis in the late adolescent hippocampus. A separate group of subjects were sacrificed on P80 (25 days post-AIE treatment) to assess the effects of AIE on neurogenesis in the young adult hippocampus and to ensure that neurogenesis is persistently reduced following AIE treatment (see Broadwater et al., 2014). Finally, subjects were sacrificed on P220 (165 days post-AIE treatment) to assess the long-term, persistent effects of AIE treatment on neurogenesis in the adult hippocampus. For the duration of AIE exposure, subjects evidenced dramatic increases in body weight that did not differ as a function of treatment during AIE exposure (all p's > 0.05, P25: CON = 73 ± 1 g, AIE = 73 ± 1 g; P55: CON = 304 ± 6 g, AIE = 286 ± 6 g; P80: 405 ± 8 g, AIE = 389 ± 7 g). Although body weights were unaffected by AIE treatment, there was an 11% (±3%) reduction in body weight of AIE-treated animals by P220 (CON = 622 ± 18 g, AIE = 553 ± 17 g [One-Way ANOVA: F = 7.9, p < 0.05]).


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)

Graphical representation of the adolescent intermittent ethanol (AIE) exposure protocol and experimental design. (A) Rats were treated with either ethanol (5.0 g/kg, 20% ethanol w/v, i.g.) or a comparable volume of water on a 2-day on/2-day off administration schedule from postnatal day (P) 25 to P55. Blood ethanol concentrations (BECs) were assessed 1 h after ethanol exposure on P38 and P54 (mg/dL). Late adolescent rats were sacrificed on P56 (24 h post-AIE treatment). Subjects in the early adulthood group were sacrificed on P80 (25 days post-AIE treatment). A subset of subjects in the early adulthood group were treated with lipopolysaccharide (LPS; 1.0 mg/kg, i.p.) on P70 and sacrificed on P80. Subjects in the adulthood group were behaviorally tested on the novel object recognition memory task from P163 to P165, and were sacrificed on P220 (165 days post-AIE treatment). (B) Depicted are coronal sections of the dorsal and ventral hippocampus between Bregma –2.12 mm and –6.72 mm according to the atlas of Paxinos and Watson (1998) used for quantitative analysis of doublecortin-immunopositive cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Graphical representation of the adolescent intermittent ethanol (AIE) exposure protocol and experimental design. (A) Rats were treated with either ethanol (5.0 g/kg, 20% ethanol w/v, i.g.) or a comparable volume of water on a 2-day on/2-day off administration schedule from postnatal day (P) 25 to P55. Blood ethanol concentrations (BECs) were assessed 1 h after ethanol exposure on P38 and P54 (mg/dL). Late adolescent rats were sacrificed on P56 (24 h post-AIE treatment). Subjects in the early adulthood group were sacrificed on P80 (25 days post-AIE treatment). A subset of subjects in the early adulthood group were treated with lipopolysaccharide (LPS; 1.0 mg/kg, i.p.) on P70 and sacrificed on P80. Subjects in the adulthood group were behaviorally tested on the novel object recognition memory task from P163 to P165, and were sacrificed on P220 (165 days post-AIE treatment). (B) Depicted are coronal sections of the dorsal and ventral hippocampus between Bregma –2.12 mm and –6.72 mm according to the atlas of Paxinos and Watson (1998) used for quantitative analysis of doublecortin-immunopositive cells.
Mentions: On P21, male Wistar rats were randomly assigned to either (i) AIE or (ii) water control (CON) groups. From P25 to P55, AIE animals received a single daily intragastric (i.g.) administration of ethanol (5.0 g/kg, 20% ethanol w/v) on a 2-day on/2-day off schedule and CON subjects received comparable volumes. Tail blood was collected to assess blood ethanol content (BEC) 1 h after ethanol administration as we previously found that BECs in the adolescent rat peak at approximately 60 min after i.p. ethanol administration (Crews et al., 2006b). Further, BECs were assessed at the midpoint of AIE treatment (P38) and again at the conclusion of AIE treatment (P54), and were quantitated using a GM7 Analyzer (Analox; London, UK). On P38 and P54, mean BECs (± SEM) were 189 ± 5 mg/dL and 190 ± 8 mg/dL, respectively, and did not differ across experiments (all p ≥ 0.2). Subjects were sacrificed at three different time points to assess the persistent effects of AIE treatment on neurogenesis in the dorsal and ventral hippocampus (see Figure 1A). Subjects were sacrificed on P56 (24 h post-AIE treatment) to determine the acute effects of AIE treatment on neurogenesis in the late adolescent hippocampus. A separate group of subjects were sacrificed on P80 (25 days post-AIE treatment) to assess the effects of AIE on neurogenesis in the young adult hippocampus and to ensure that neurogenesis is persistently reduced following AIE treatment (see Broadwater et al., 2014). Finally, subjects were sacrificed on P220 (165 days post-AIE treatment) to assess the long-term, persistent effects of AIE treatment on neurogenesis in the adult hippocampus. For the duration of AIE exposure, subjects evidenced dramatic increases in body weight that did not differ as a function of treatment during AIE exposure (all p's > 0.05, P25: CON = 73 ± 1 g, AIE = 73 ± 1 g; P55: CON = 304 ± 6 g, AIE = 286 ± 6 g; P80: 405 ± 8 g, AIE = 389 ± 7 g). Although body weights were unaffected by AIE treatment, there was an 11% (±3%) reduction in body weight of AIE-treated animals by P220 (CON = 622 ± 18 g, AIE = 553 ± 17 g [One-Way ANOVA: F = 7.9, p < 0.05]).

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