Abstract
Abstinence after alcohol dependence leads to structural and functional recovery in many regions of the brain, especially the hippocampus. Significant increases in neural stem cell (NSC) proliferation and subsequent “reactive neurogenesis” coincides with structural recovery in hippocampal dentate gyrus (DG). However, whether these reactively born neurons are integrated appropriately into neural circuits remains unknown. Therefore, adult male rats were exposed to a binge model of alcohol dependence. On day 7 of abstinence, the peak of reactive NSC proliferation, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. After six weeks, rats underwent Morris Water Maze (MWM) training then were sacrificed ninety minutes after the final training session. Using fluorescent immunohistochemistry for c-Fos (neuronal activation), BrdU, and Neuronal Nuclei (NeuN), we investigated whether neurons born during reactive neurogenesis were incorporated into a newly learned MWM neuronal ensemble. Prior alcohol exposure increased the number of BrdU+ cells and newborn neurons (BrdU+/NeuN+ cells) in the DG versus controls. However, prior ethanol exposure had no significant impact on MWM-induced c-Fos expression. Despite increased BrdU+ neurons, no difference in the number of activated newborn neurons (BrdU+/c-Fos+/NeuN+) was observed. These data suggest that neurons born during alcohol-induced reactive neurogenesis are functionally integrated into hippocampal circuitry.
Highlights
Alcohol misuse remains a concerning public health crisis as a leading cause of preventable death due to the harmful impact it has on individuals and society [1,2,3]
This study focuses on adult hippocampal neurogenesis due to hippocampal pathology in alcohol use disorder (AUD) and that adult neurogenesis has been observed in the hippocampus of all mammals including humans, a debate that was recently resolved [53,54,55]
Newborn cells that were labeled with BrdU during reactive neurogenesis, survived six weeks, and expressed a mature neuronal marker (NeuN), and were activated in response to a hippocampal-dependent task (c-Fos; Morris Water Maze (MWM)) become triplelabeled, which suggested that these newborn neurons were integrated into the hippocampal circuitry necessary for learning and memory performance [57,93]
Summary
Alcohol misuse remains a concerning public health crisis as a leading cause of preventable death due to the harmful impact it has on individuals and society [1,2,3]. While excessive alcohol use impacts a wide array of organ systems within the body, brain damage by alcohol can lead to permanent cognitive impairments [7,8,9]. The hippocampus, an area of the brain important for learning and memory, is known to be more sensitive to the damaging effects of alcohol [18,19,20,21,22,23], for review see [24]. Excessive alcohol consumption is associated with impaired hippocampal-based learning and memory in humans [13,31,32,33] as well as in animal models [30,34]. The brain, especially the hippocampus, recovers with abstinence, though the mechanism of this recovery is not known [35,36,37,38,39,40,41,42]
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