Ectopic hippocampal neurogenesis in adolescent male rats following alcohol dependence

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Addiction Biology (Impact Factor: 5.36). 07/2013; 19(4). DOI: 10.1111/adb.12075
Source: PubMed


The adolescent hippocampus is highly vulnerable to alcohol-induced damage, which could contribute to their increased susceptibility to alcohol use disorder. Altered adult hippocampal neurogenesis represents one potential mechanism by which alcohol (ethanol) affects hippocampal function. Based on the vulnerability of the adolescent hippocampus to alcohol-induced damage, and prior reports of long-term alcohol-induced effects on adult neurogenesis, we predicted adverse effects on adult neurogenesis in the adolescent brain following abstinence from alcohol dependence. Thus, we examined neurogenesis in adolescent male rats during abstinence following a 4-day binge model of alcohol dependence. Bromodeoxyuridine and Ki67 immunohistochemistry revealed a 2.2-fold increase in subgranular zone cell proliferation after 7 days of abstinence. Increased proliferation was followed by a 75% increase in doublecortin expression and a 56% increase in surviving bromodeoxyuridine-labeled cells 14 and 35 days post-ethanol exposure, respectively. The majority of newborn cells in ethanol and control groups co-localized with NeuN, indicating a neuronal phenotype and therefore a 1.6-fold increase in hippocampal neurogenesis during abstinence. Although these results mirror the magnitude of reactive neurogenesis described in adult rat studies, ectopic bromodeoxyuridine and doublecortin positive cells were detected in the molecular layer and hilus of adolescent rats displaying severe withdrawal symptoms, an effect that has not been described in adults. The presence of ectopic neuroblasts suggests that a potential defect exists in the functional incorporation of new neurons into the existing hippocampal circuitry for a subset of rats. Age-related differences in functional incorporation could contribute to the increased vulnerability of the adolescent hippocampus to ethanol.

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    • "However, in this study, many BrdU-labeled cells were present in the hilus, and nearly 80% of them died within weeks. We did not double label these cells, and therefore cannot confirm that they are neurons; however, others have reported an increase in the presence of young neurons during puberty, especially after seizures or alcohol withdrawal (McClain et al., 2013). Again, we did not confirm the neuronal identity of these new hilar cells, but it is nonetheless striking that so many of them were not only generated, but also rescued from death by learning. "
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    ABSTRACT: The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood.
    Frontiers in Neuroscience 04/2014; 8(8):70. DOI:10.3389/fnins.2014.00070 · 3.66 Impact Factor
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    • "Peripheral levels of BDNF reflected in serum will likely differ from central expression. Our results also differ from a recent study that reports no difference in BDNF expression in the adolescent brain between the ethanol and control group following a 4-day binge (McClain et al., 2013). A possible reason for these conflicting findings is that we measured BDNF expression after completion of behavioral testing while the recent study measured BDNF expression at different time points after alcohol administration. "
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    ABSTRACT: Here we investigated whether changes in neurogenesis and brain-derived neurotrophic factor (BDNF) expression are possible mechanisms involved in the depression-like symptom during the withdrawal/abstinence period after chronic binge-pattern alcohol consumption given the limited number of studies addressing the link between these factors in the adolescent brain. Forty-seven male Sprague-Dawley rats were used in the study and the experimental protocol started when rats were 25-days old. Rats were assigned to either: (a) ethanol or (b) control group. Animals in each group were further randomized to receive either: BDNF receptor agonist or vehicle. Rats were trained to self-administer ethanol and the binge protocol consisted of daily 30-min experimental sessions 4 h into the dark period for 12 days. Two days after the last drinking session, rats were tested in the sucrose preference test to evaluate anhedonia and the open field test after habituation to evaluate behavioral despair. Our data showed that: (1) self-administration of alcohol in a binge-like pattern causes inebriation as defined by the National Institute on Alcohol Abuse and Alcoholism and this pattern of alcohol exposure is associated with the development of a depression-like symptom; (2) no significant difference in blood alcohol levels between the two ethanol groups; and (3) chronic binge drinking resulted in the development of a depressive phenotype, decreased survival and neuronal differentiation of neural progenitor cells in the hippocampus, and decreased BDNF effect during the withdrawal period. But the most important finding in our study is that augmenting BDNF actions through the use of tyrosine kinase B (TrkB, a BDNF receptor) agonist restored neurogenesis and abolished the alcohol-induced anhedonia and despair behaviors seen during the withdrawal/abstinence period. Our results suggest that BDNF might be a molecule that can be targeted for interventions in alcoholism-depression co-incidence.
    Neuroscience 09/2013; 254. DOI:10.1016/j.neuroscience.2013.09.031 · 3.36 Impact Factor
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    ABSTRACT: The aim of the present study was to investigate if a novelty-seeking phenotype mediates the long-lasting consequences of intermittent EtOH intoxication during adolescence. The hole board test was employed to classify adolescent mice as High- or Low-Novelty Seekers. Subsequently, animals were administered ethanol (1.25 or 2.5 g/kg) on two consecutive days at 48-h intervals over a 14-day period. Anxiety levels - measured using the elevated plus maze- spontaneous motor activity and social interaction test were studied 3 weeks later. A different set of mice underwent the same procedure, but received only the 2.5 g/kg dose of ethanol. Three weeks later, in order to induce CPP, the same animals were administered 1 or 6 mg/kg of cocaine or 1 or 2.5 mg/kg MDMA. The results revealed a decrease in aggressive behaviors and an anxiolytic profile in HNS mice and longer latency to explore the novel object by LNS mice. Ethanol exposure enhanced the reinforcing effects of cocaine and MDMA in both groups when CPP was induced with a sub-threshold dose of the drugs. The extinguished cocaine-induced CPP (1 and 6 mg/kg) was reinstated after a priming dose in HNS animals only. Our results confirm that intermittent EtOH administration during adolescence induces long-lasting effects that are manifested in adult life, and that there is an association between these effects and the novelty-seeking phenotype.
    PLoS ONE 03/2014; 9(3):e92576. DOI:10.1371/journal.pone.0092576 · 3.23 Impact Factor
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