32 research outputs found
Distinct cell proliferation events during abstinence after alcohol dependence: Microglia proliferation precedes neurogenesis
Excessive alcohol intake characteristic of Alcohol Use Disorders (AUDs) produces neurodegeneration that may recover with abstinence. The mechanism of regeneration is unclear, however neurogenesis from neural stem/progenitor cells is a feasible mechanism of structural plasticity. Therefore, a timecourse of cell proliferation was examined in a rat model of an AUD and showed a striking burst in cell proliferation at 2 days of abstinence preceding the previously reported neurogenic proliferation at 7 days. New cells at 2 days, assessed by Bromo-deoxy-Uridine incorporation and endogenous markers, were observed throughout hippocampus and cortex. Although the majority of these new cells did not become neurons, neurogenesis was not altered at this specific timepoint. These new cells expressed a microglia specific marker, Iba-1, and survived at least 2 months. This first report of microglia proliferation in a model of an AUD suggests that microgliosis could contribute to volume recovery in non-neurogenic regions during abstinence
Long-term suppression of forebrain neurogenesis and loss of neuronal progenitor cells following prolonged alcohol dependence in rats.
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
LONG-LASTING SUPPRESSION OF SUBVENTRICULAR ZONE NEUROGENESIS FOLLOWING A HISTORY OF ETHANOL DEPENDENCE
Exposure to repeated cycles of ethanol intoxication and withdrawal results in a well characterized persistent post-dependent increase in excessive voluntary ethanol consumption and behavioral sensitivity to stress. We have previously described some molecular neuroadaptations that contribute to these behavioral traits. Formation of new neurons in the adult brain, or adult neurogenesis, is related to stress responsiveness, and previous work has established that it is modulated by ethanol intoxication and withdrawal. Here, we asked
whether adult neurogenesis is altered in the post-dependent state, in a manner that could contribute to the functional phenotype observed in this condition. To this end, we studied cell proliferation and neurogenesis in the subgranular zone of the
dentate gyrus (SGZ) and in the subventricular zone lining the lateral ventricle (SVZ) in rats over a period of 3 weeks following a previously described 7 week intermittent ethanol vapor
exposure to induce dependence, and compared to controls without a history of ethanol exposure. A single dose of 5-bromo-2-deoxyuridine (BrdU, 200 mg/kg, i.p.) was administered
4-5 h prior to euthanasia on day 0, 3, 7 and 21 post induction of dependence (abstinence days). Proliferating precursor cells incorporate the mitotic marker BrdU and were identified using immunohistochemistry in SVZ and SGZ. In agreement with prior work, ethanol exposure decreased density and number of proliferating cells by 70 % in both the SVZ
(p<0.001) and SGZ (p<0.05), followed by a 2- fold rebound burst in proliferation on day 3 (p<0.001) of abstinence. In the SGZ, proliferation returned to normal levels within one week.
However, the density of proliferating cells in the SVZ remained significantly decreased on day 7 (36%, p<0.01) and day 21 (35%, p<0.05) of abstinence. These changes were paralleled by
decreased doublecortin expression, a neuronal marker expressed shortly after neuronal cell fate determination.
Our data indicate a long-lasting suppression of neurogenesis in the SVZ of post-dependent rats, potentially leading to reduced neuronal turnover in the olfactory bulb and possibly also in
prefrontal cortex circuitry. Although, the functional correlates of SVZ suppression are unknown, loss of olfactory discrimination is common in alcoholics and correlates with loss of executive function
Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and toll-like receptors in the adult prefrontal cortex
Adolescence is a critical developmental stage of life during which the prefrontal cortex (PFC) matures, and binge drinking and alcohol abuse are common. Recent studies have found that ethanol increases neuroinflammation via upregulated high-mobility group box 1 (HMGB1) signaling through Toll-like receptors (TLRs). HMGB1/TLR ‘danger signaling’ induces multiple brain innate immune genes that could alter brain function. To determine whether adolescent binge drinking persistently increases innate immune gene expression in the PFC, rats (P25–P55) were exposed to adolescent intermittent ethanol (AIE [5.0 g/kg, 2-day on/2-day off schedule]). On P56, HMGB1/TLR danger signaling was assessed using immunohistochemistry (i.e., +immunoreactivity [+IR]). In a separate group of subjects, spatial and reversal learning on the Barnes maze was assessed in early adulthood (P64–P75), and HMGB1/TLR danger signaling was measured using immunohistochemistry for +IR and RT-PCR for mRNA in adulthood (P80). Immunohistochemical assessment at P56 and 24 days later at P80 revealed increased frontal cortical HMGB1, TLR4, and TLR3 in the AIE-treated rats. Adolescent intermittent ethanol treatment did not alter adult spatial learning on the Barnes maze, but did cause reversal learning deficits and increased perseverative behavior. Barnes maze deficits correlated with the expression of danger signal receptors in the PFC. Taken together, these findings provide evidence that adolescent binge drinking leads to persistent upregulation of innate immune danger signaling in the adult PFC that correlates with adult neurocognitive dysfunction
Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat
The brain continues to develop through adolescence when excessive alcohol consumption is prevalent in humans. We hypothesized that binge drinking doses of ethanol during adolescence will cause changes in brain ethanol responses that persist into adulthood. To test this hypothesis Wistar rats were treated with an adolescent intermittent ethanol (AIE; 5 g/kg, i.g. 2 days on–2 days off; P25–P54) model of underage drinking followed by 25 days of abstinence during maturation to young adulthood (P80). Using markers of neuronal activation c-Fos, EGR1, and phophorylated extracellar signal regulated kinase (pERK1/2), adult responses to a moderate and binge drinking ethanol challenge, e.g., 2 or 4 g/kg, were determined. Adult rats showed dose dependent increases in neuronal activation markers in multiple brain regions during ethanol challenge. Brain regional responses correlated are consistent with anatomical connections. AIE led to marked decreases in adult ethanol PFC (prefrontal cortex) and blunted responses in the amygdala. Binge drinking doses led to the nucleus accumbens (NAc) activation that correlated with the ventral tegmental area (VTA) activation. In contrast to other brain regions, AIE enhanced the adult NAc response to binge drinking doses. These studies suggest that adolescent alcohol exposure causes long-lasting changes in brain responses to alcohol that persist into adulthood
Induction of innate immune genes in brain create the neurobiology of addiction
Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy