Chronic Alcohol Exposure is Associated with Decreased Neurogenesis, Aberrant Integration of Newborn Neurons, and Cognitive Dysfunction in Female Mice

Golub, Haleigh M.; Zhou, Qi; Zucker, Hannah; McMullen, Megan R.; Kokiko-Cochran, Olga N.; Ro, Eun Jeoung; Nagy, Laura E.; Suh, Hoonkyo

doi:10.1111/acer.12843

Cited by 55 publications

(52 citation statements)

References 50 publications

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“…At the cellular level, acute or chronic administration of drugs with addictive potential modifies hippocampal-dependent LTP (Kutlu and Gould, 2016;Lüscher and Malenka, 2011). Additionally, opioids, psychostimulants, and alcohol interfere with neurogenesis in the adult hippocampus (Eisch and Harburg, 2006;Golub et al, 2015), which may affect normal functioning.…”

Section: Hippocampus-dependent Learningmentioning

confidence: 99%

Learning and Memory in Addiction

Carmack

Koob

Anagnostaras³

2017

Learning and Memory: A Comprehensive Reference

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Section: Hippocampus-dependent Learningmentioning

confidence: 99%

Learning and Memory in Addiction

Carmack

Koob

Anagnostaras³

2017

Learning and Memory: A Comprehensive Reference

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“…AW increases the spine density of newborn DGCs. Our previous study showed that chronic alcohol exposure disrupted the synaptic connectivity of hippocampal newborn DGCs, dramatically reducing the density of dendritic spines of newborn DGCs (27). Here, we examined whether AW induces structural plasticity and impacts the function of newborn DGCs during a protracted abstinence.…”

Section: Resultsmentioning

confidence: 93%

“…As a result, both control and alcohol-fed mice consumed the same amount of calories during the experimental period (ref. 27 and Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.128770DS1). During the 4-week alcohol feeding period, mice consumed alcohol daily (20.2 ± 1.53 g/kg/day) and accumulated a significant amount of alcohol (545.0 ± 1.53 g/kg) (Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Activity of hippocampal adult-born neurons regulates alcohol withdrawal seizures

Lee¹,

Krishnan

Hai³

et al. 2019

JCI Insight

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Chronic alcohol exposure disrupts brain homeostasis and progressively transforms the brain into a state of alcohol dependence (1, 2). Abrupt alcohol withdrawal (AW) in alcohol-dependent individuals results in the emergence of a series of physiological and psychological symptoms that are collectively referred to as alcohol withdrawal syndrome (AWS) (3-7). Clinical features of AWS include alcoholic hallucinosis, cognitive and emotional impairments, delirium tremens, and brain hyperexcitability (8-12). More than 2 million Americans are estimated to develop AWS each year (13, 14). Despite such negative effects of alcohol on physical and mental function, its positive-reinforcing effects such as euphoria and pain reduction enhances susceptibility to relapse during a withdrawal period (abstinence), and the repeated cycles of alcohol consumption and withdrawal are ultimately thought to lead to alcohol addiction (15-18). To prevent enhanced vulnerability to relapse and perpetual alcohol use, it is imperative to understand the mechanisms underlying AWS. Generalized tonic-clonic seizures are the most dangerous and serious component of AWS, and they contribute to significant mortality of alcoholics (19-24). Alcohol is a well-known CNS depressant that facilitates and reduces inhibitory and excitatory signals, respectively, and chronic alcohol exposure induces prolonged and enhanced sedative effects (25). The brain attempts to counterbalance the depressant effect of alcohol by enhancing excitatory signals and decreasing inhibitory signals. However, continuous exposure to alcohol progressively dysregulates the neurophysiological system beyond normal homeostatic limits, and neuroadaptation that is masked by chronic exposure to alcohol is unveiled upon a sudden AW. This neuroadaptation, or brain allostatic state induced by chronic alcohol exposure, has been thought to underlie the emergence and expression of hyperexcitability of the brain and AW seizures when alcohol consumption ceases (6, 16, 17); however, the precise neural substrates that undergo neuroadaptation during alcohol exposure and withdrawal are not yet understood. Alcohol withdrawal (AW) after chronic alcohol exposure produces a series of symptoms, with AW-associated seizures being among the most serious and dangerous. However, the mechanism underlying AW seizures has yet to be established. In our mouse model, a sudden AW produced 2 waves of seizures: the first wave includes a surge of multiple seizures that occurs within hours to days of AW, and the second wave consists of sustained expression of epileptiform spikes and wave discharges (SWDs) during a protracted period of abstinence. We revealed that the structural and functional adaptations in newborn dentate granule cells (DGCs) in the hippocampus underlie the second wave of seizures but not the first wave. While the general morphology of newborn DGCs remained unchanged, AW increased the dendritic spine density of newborn DGCs, suggesting that AW induced synaptic connectivity of newborn DGCs with excitatory affere...

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“…Extensive literature has established that repeated administration of drugs of abuse, such as alcohol [52][53][54][55] , cocaine [56][57][58][59] , and opiates [60][61][62] , decreases adult hippocampal neurogenesis, as reviewed elsewhere [63][64][65] . However, therapeutic doses of amphetamines increase neurogenesis in at least one mouse model [66] .…”

Section: Drugs Of Abusementioning

confidence: 99%

The Contribution of Adult Hippocampal Neurogenesis to the Progression of Psychiatric Disorders

Kohman

Rhodes²

2017

Modern Trends in Psychiatry

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New neurons are continuously formed in the adult hippocampus of the human, nonhuman primate, and rodent throughout life though rates of neurogenesis precipitously decline with age to near zero levels at the end of the natural life span. Since its discovery in the 1960s, a large number of studies have documented numerous environmental and genetic factors which regulate adult neurogenesis. Chief among the positive regulators of neurogenesis are exercise and antidepressant drugs. Chief among the negative regulators of neurogenesis besides age are stress and inflammation. To the extent that many psychiatric disorders are comorbid with or causally related to stress and inflammation, decreased neurogenesis could be a partial contributor to the pathophysiology of the disorders. However, the functional significance of new neurons in behavior has yet to be established and is currently a hotly debated topic. Therefore, it is not clear whether changes in neurogenesis that occur alongside psychiatric illnesses are a cause or a consequence of the mediating factors such as stress, drug abuse, and inflammation, which are complexly involved in the disorders. It will be important moving forward to use modern technologies capable of instantaneously inactivating cohorts of new neurons to test their functional significance in behavior and the etiology of mental illnesses.

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Chronic Alcohol Exposure is Associated with Decreased Neurogenesis, Aberrant Integration of Newborn Neurons, and Cognitive Dysfunction in Female Mice

Cited by 55 publications

References 50 publications

Learning and Memory in Addiction

Learning and Memory in Addiction

Activity of hippocampal adult-born neurons regulates alcohol withdrawal seizures

The Contribution of Adult Hippocampal Neurogenesis to the Progression of Psychiatric Disorders

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