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 functions