Long-term suppression of forebrain neurogenesis and loss of neuronal progenitor cells following prolonged alcohol dependence in rats.
- Authors
- Hansson, Anita C; Nixon, Kimberly; Rimondini, Roberto; Damadzic, Ruslan; Sommer, Wolfgang H; Eskay, Robert; Crews, Fulton T; Heilig, Markus
- Year
- 2010
- Journal
- The international journal of neuropsychopharmacology
- PMID
- 20334723
- DOI
- 10.1017/S1461145710000246
- PMCID
- PMC4821191
Alcohol dependence leads to persistent neuroadaptations, potentially related to structural plasticity. Previous work has shown that hippocampal neurogenesis is modulated by alcohol, but effects of chronic alcohol on neurogenesis in the forebrain subventricular zone (SVZ) have not been reported. Effects in this region may be relevant for the impairments in olfactory discrimination present in alcoholism. Here, we examined the effects of prolonged alcohol dependence on neurogenesis. Rats were sacrificed directly after 7 wk of intermittent alcohol vapour exposure, or 3, 7 or 21 d into abstinence. Proliferation was assessed using BrdU and Ki67 immunoreactivity, newly differentiated neurons (neurogenesis) as doublecortin-immunoreactivity (DCX-IR), and neural stem cells using the SOX2 marker. In the dentate gyrus, chronic dependence resulted in a pattern similar to that previously reported for acute alcohol exposure: proliferation and neurogenesis were suppressed by the end of exposure, rebounded on day 3 of abstinence, and returned to control levels by days 7 and 21. In the SVZ, proliferation was also suppressed at the end of alcohol exposure, followed by a proliferation burst 3 d into abstinence. However, in this area, there was a trend for reduced proliferation on days 7 and 21 of abstinence, and this was accompanied by significant suppression of DCX-IR, indicating a long-term suppression of forebrain neurogenesis. Finally, a decrease in the SOX2 stem cell marker was detected at days 7 and 21, suggesting long-term reduction of the SVZ stem cell pool. While suppression of hippocampal neurogenesis by alcohol dependence is transient, the suppression in the forebrain SVZ appears long-lasting.
Hippocampal cell proliferation during protracted abstinence. (a) Top: schematic illustration of the sampled area (grey outline) for BrdU-immunoreactive (IR) cell counting of the dentate gyrus subgranular zone (SGZ) in a coronal rat section (adapted from Vaidya et al. 2007). Bottom: data showing the number of BrdU-IR positive cells/mm2 (mean±S.E.M.) in the SGZ at various time-points after the last intoxication cycle (■) and in alcohol-naive controls (□, n=16). The number of BrdU-positive cells varied as a function of time (p<0.0001), and was decreased immediately after alcohol exposure (day 0, n=9), followed by a rebound burst on day 3 (n=8), returning to normal levels on day 7 (n=8) and day 21 (n=3). (b) Illustrative brightfield photomicrographs showing clusters of BrdU-positive cells in the SGZ at the different time-intervals. Scale bar, 30 μm; Bregma level=−1.8 to −5.6 mm according to Paxinos & Watson (2005). (c) Data showing the number of Ki67-IR positive cells/mm2 (mean±S.E.M.) at the respective time-point after the last intoxication cycle [■, n=9 (day 0), n=8 (day 3), n=8 (day 7), n=3 (day 21)] and in alcohol-naive controls (□, n=16). ** p<0.01, *** p<0.001 vs. controls. (For detailed statistics, see Results section.)
Hippocampal neurogenesis during protracted abstinence. (a) Data showing the number of newly differentiated, doublecortin-immunoreactive (DCX-IR) cells/mm2 (mean±S.E.M.) in the subgranular zone (SGZ) at varying intervals after the last intoxication cycle (■) and alcohol-naive controls (□, n=16). The number of positive cells varied as a function of time (p<0.0001). DCX-IR cells were markedly decreased immediately following exposure (day 0, n=9), showed a trend level rebound (day 3, n=8), and then returned to levels that did not differ from controls (day 7, n=8; day 21, n=3). *** p<0.001 vs. controls. (For detailed statistics, see Results section.) (b) Illustrative brightfield photomicrographs of DCX-IR-labelled cells within the SGZ at the different time-intervals. Scale bar, 30 μm; Bregma level=−1.8 to −5.6 mm.
Cell proliferation in the subventricular zone (SVZ) during protracted abstinence. (a) Top: schematic illustration representing the sampled areas (■) within the SVZ (grey outline) for densitometric evaluation of 5′-bromo-2-deoxyuridine-immunoreactivity (BrdU-IR) in coronal rat sections (adapted from Vaidya et al. 2007). Bottom: data showing mean integrated optical densities (IOD; mean±S.E.M.) of BrdU-IR-positive cells in relation to alcohol-naive controls (□, n=16) at different time-points after the last intoxication cycle (■). BrdU-IR varied as a function of time (p<0.001). BrdU-IR cells were markedly suppressed immediately following exposure (day 0, n=8), followed by a rebound burst on day 3 (n=8), and finally a return to levels on day 7 (n=8) and 21 (n=3) that were numerically lower than controls, although the individual post-hoc comparisons failed to reach significance. ** p<0.01 vs. controls. (For detailed statistics, see Results section.) (b) Illustrative brightfield photomicrographs showing clusters of BrdU-IR-positive proliferating cells in the SVZ at the different time-points. Scale bar, 80 μm; Bregma level=+1.0 to +0.2 mm. (c) Data showing mean integrated optical densities (IOD; mean±S.E.M.) from Ki67-IR at various time-points after the last intoxication cycle (■, n=9 (day 0), n=8 (day 3), n=8 (day 7), n=3 (day 21)] and in alcohol-naive controls (□, n=16).
Neurogenesis in the subventricular zone (SVZ) during protracted abstinence. (a) Data showing doublecortin-immunoreactivity (DCX-IR) as normalized mean integrated optical density (IOD; mean±S.E.M.) in the SVZ at varying intervals after the last intoxication cycle (■) and in controls (□; absolute value 306±46, n=15). DCX-IR varied as a function of time (p<0.00001). It was suppressed immediately following exposure (day 0, n=8), rebounded to elevated levels on day 3 (n=8) and day 7 (n=8), and was again suppressed on day 21 (n=3). *** p<0.001 vs. controls. (For detailed statistics, see Results section.) (b) Illustrative brightfield photomicrographs of SVZ DCX-IR neurons at varying intervals following exposure. Scale bar, 80 μm; Bregma level=+1.0 to +0.2 mm.
Loss of SOX2-immunoreactive (IR)-labelled neural stem cells in the subventricular zone (SVZ) during protracted abstinence. (a) Data show mean integrated optical densities (IOD; mean±S.E.M.) of SOX2-IR-labelled neural stem cells at varying intervals following the last intoxication cycle (■) compared to control rats (□, n=16). SOX2-IR varied as a function of time (p<0.0001). Levels did not differ from controls on day 0 (n=8) and 3 (n=8), but were suppressed on day 7 (n=8), and remained suppressed on day 21 (n=3). ** p<0.01, *** p<0.001. (For detailed statistics, see Results section). (b) Illustrative brightfield photomicrographs of SOX2-IR-labelled neural stem cells in the SVZ at the different time-points. Scale bar, 80 μm; Bregma level=+1.0 to +0.
| Name | Type |
|---|---|
| 4-d binge intoxication model local | cohort |
| abstinence | phenotype |
| acamprosate | drug |
| Adult rat brain local | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| alcohol-exposed animals local | cohort |
| Alcohol-exposed animals local | cohort |
| alcohol-exposed group | cohort |
| alcoholism | phenotype |
| alcohol preference | phenotype |
| alcohol self-administration | phenotype |
| Alcohol Use | phenotype |
| alcohol use disorders | phenotype |
| alcohol vapour local | drug |
| Alcohol vapour exposure local | drug |
| antidepressants | drug |
| anxiety | phenotype |
| astroglia | anatomy |
| Basal circulating glucocorticoids local | phenotype |
| Behavioral sensitivity to stress local | phenotype |
| Behavioural stress reactivity local | phenotype |
| Binge-like dependence model local | phenotype |
| blood alcohol concentration (BAC) | phenotype |
| blood alcohol levels | phenotype |
| brain | anatomy |
| BrdU | drug |
| BrdU-IR local | phenotype |
| BrdU-IR cells local | phenotype |
| cell cycle | phenotype |
| cell proliferation | phenotype |
| cell survival | phenotype |
| Chronic alcohol dependence local | phenotype |
| chronic alcoholism | phenotype |
| cognition | phenotype |
| control animals | cohort |
| control group | cohort |
| controls | cohort |
| DCX local | drug |
| DCX | gene |
| DCX-IR local | drug |
| DCX-IR local | phenotype |
| dentate gyrus | anatomy |
| Dentate gyrus subgranular zone local | anatomy |
| dependence | phenotype |
| depression | phenotype |
| Differentiation of progenitors into neuronal phenotypes local | phenotype |
| DXC-IR local | phenotype |
| Ethylene glycol | drug |
| executive function | phenotype |
| Exposed animals local | cohort |
| fluoxetine | drug |
| forebrain | anatomy |
| forebrain SVZ local | anatomy |
| GFAP | gene |
| glycerol | drug |
| hippocampal dentate gyrus | anatomy |
| hippocampus | anatomy |
| human | cohort |
| human alcoholics | phenotype |
| humans | cohort |
| Ki67 | drug |
| Ki67-IR local | phenotype |
| Ki67-IR cells local | phenotype |
| mice | cohort |
| Microglia increase local | phenotype |
| Morphological maturation of newborn neurons local | phenotype |
| NAD/NADPH-spectrophotometric assay kit local | drug |
| negative affect | phenotype |
| Neural precursor cell proliferation local | phenotype |
| neural progenitors | phenotype |
| neural stem cells | cohort |
| neurogenesis | phenotype |
| neuronal differentiation | phenotype |
| newly differentiated neurons local | phenotype |
| Newly differentiated neurons local | phenotype |
| Non-dependent rats local | cohort |
| NTRK2 | gene |
| olfactory bulb | anatomy |
| Olfactory discrimination local | phenotype |
| Olfactory sensitivity local | phenotype |
| paraformaldehyde | drug |
| pentobarbital | drug |
| Phosphate buffer local | drug |
| phosphate-buffered saline | drug |
| Piloerection local | phenotype |
| Post-dependent animals local | cohort |
| prefrontal cortex | anatomy |
| proliferation rates local | phenotype |
| Prolonged brain alcohol dependence local | phenotype |
| protracted abstinence | phenotype |
| rats | cohort |
| relapse | phenotype |
| rodents | cohort |
| saccharin | drug |
| Sox2 | gene |
| SOX2 local | drug |
| Stem cell populations local | phenotype |
| stress | phenotype |
| stress response | phenotype |
| Subgranular zone | anatomy |
| subventricular zone | anatomy |
| Survival of newly generated cells local | phenotype |
| SVZ | anatomy |
| Tail stiffness local | phenotype |
| unexposed controls | cohort |
| Vapour inhalation local | phenotype |
| voluntary alcohol consumption | phenotype |
| voluntary ethanol consumption | phenotype |
| Voluntary self-administration local | phenotype |
| Wistar rats | cohort |
| withdrawal | phenotype |
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In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Bioinformatic Analysis of DNA Methylation in Neural Progenitor Cell Models of Alcohol Abuse. | 2016 | 27774408 |
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