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. Author manuscript; available in PMC: 2015 Oct 3.
Published in final edited form as: Prog Neuropsychopharmacol Biol Psychiatry. 2014 May 17;0:103–113. doi: 10.1016/j.pnpbp.2014.05.003

Alcohol and adult hippocampal neurogenesis: Promiscuous drug, wanton effects

Chelsea R Geil 1, Dayna M Hayes 1, Justin A McClain 1, Daniel J Liput 1, S Alex Marshall 1, Kevin Y Chen 1, Kimberly Nixon 1
PMCID: PMC4134968  NIHMSID: NIHMS605590  PMID: 24842804

Abstract

Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology. Alcohol is a pharmacologically promiscuous drug capable of interfering with adult neurogenesis through multiple mechanisms. This review will discuss the primary mechanisms underlying alcohol-induced changes in adult hippocampal neurogenesis including alcohol's effects on neurotransmitters, CREB and its downstream effectors, and the neurogenic niche.

1. Introduction

Alcohol use disorders (AUDs), more commonly referred to as alcoholism, include alcohol abuse or alcohol dependence, the diagnostic terms for uncontrollable, excessive alcohol intake despite negative consequences. AUDs are major social and economic problems. With nearly 8.5% of the U.S. population meeting the diagnostic criteria for an AUD on any given day, it is not surprising that the economic burden was estimated to be $223.5 billion dollars in 2006 alone (Bouchery et al., 2011; Grant et al., 2004). Further, excessive alcohol consumption is the third leading cause of preventable death in the United States (Mokdad et al., 2004). Despite these tolls, both the incidence of AUDs and the number of new users have increased in past decades (Grant et al., 2004). AUDs are a significant problem across much of the lifespan as experimentation with alcohol begins in adolescence. Indeed, disturbingly similar rates of AUDs exist between adolescents and adults (Clark et al., 2002). Although there are many theories about the development of AUDs, all involve the fact that repeated bouts of excessive alcohol intake change the brain in a way that drives a loss of control over consumption (Koob and Le Moal, 1997). This loss of control may be driven by hijacked learning processes, impairments in behavioral control, and/or impaired decision-making (Crews, 1999; Noel et al., 2013). All of these processes involve, at least partially, the contribution of an intact hippocampus, and a wide variety of studies have shown that excessive alcohol intake impacts the structure and function of hippocampal circuitry.

Alcohol (ethanol) is a small, highly lipid soluble and pharmacologically promiscuous drug capable of penetrating virtually every organ system including the brain. Excessive alcohol consumption has widespread deleterious effects on many of these organ systems, but central nervous system injury is a critical consequence as 50 to 75% of alcohol-dependent adults show permanent cognitive impairment (Eckardt and Martin, 1986). These impairments are thought to be due to both structural and functional changes resulting from excessive alcohol consumption (Crews, 1999; Sullivan and Pfefferbaum, 2005). Alcohol appears to target some brain regions more than others with a critical cluster of alcohol-induced impairments in behavioral control, learning, memory, mood, and decision-making attributed, at least in part, to the integrity of the hippocampus (Mechtcheriakov et al., 2007). Because ethanol is so pharmacologically promiscuous, there are many reported and potential mechanisms of alcohol-induced effects on the hippocampus. This review focuses on the emerging role of adult hippocampal neurogenesis in alcoholic neuropathology and the various potential mechanisms involved in alcohol's effects on neural progenitor cells (NPCs) and the neurogenic niche.

2. The hippocampus and alcohol use disorders

Excessive alcohol consumption results in extensive deficits in neuropsychological functions, many of which are subserved by the hippocampus (Chanraud et al., 2007; Ozsoy et al., 2013; Parsons, 1993). As has been reviewed extensively elsewhere (Belujon and Grace, 2011; Eichenbaum, 2001; Gilbert and Kesner, 2006; Johnson et al., 2007), the hippocampus is especially critical for aspects of learning and memory and as such is implicated in the acquisition, consolidation, and expression of context-dependent drug memories (reviewed in Hyman et al., 2006; Nixon et al., 2011). However, many now postulate a role for the hippocampus in relapse and drug seeking as well (Belujon and Grace, 2011; Vorel et al., 2001). This expanded role has emerged from data demonstrating its broader role in cognitive functions, specifically through its interconnections with frontal cortices and reward systems. For example, glutamatergic efferents projecting from the hippocampus and terminating in the prefrontal cortex (PFC) are implicated in the proper processing of executive functions, working memory, and contextual information (Godsil et al., 2013). Therefore, disruptions in the structural integrity of the hippocampus may be an underling substrate for impairments in these functions. Certainly, long-lasting deficits in executive function and working memory are observed following excessive alcohol consumption (O'Daly et al., 2012; Stavro et al., 2012; Stephens and Duka, 2008) and it is hypothesized that compromised hippocampal integrity in alcoholics may contribute to these impairments. In support of this hypothesis, a correlation between deficits in executive function and hippocampal gray matter volume has been reported (Chanraud et al., 2007). Although correlation does not imply causation, increasing new evidence supports that hippocampal integrity influences a broader range of cognitive functions than classically considered.

With newer technology, more consistent reports of hippocampal pathology have emerged in the last several years (Beresford et al., 2006; Ozsoy et al., 2013) including grey matter loss (Mechtcheriakov et al., 2007). Historically, ongoing debate is evident in the literature over whether the hippocampus was impacted by excessive alcohol: whether the left, right, or both hippocampi are affected, whether degeneration is due to effects in white or gray matter, and/or the magnitude of this effect (Agartz et al., 1999; Laakso et al., 2000; Sullivan et al., 1995). Importantly, one commonality that has emerged is that differences in the study population may underlie these discrepancies. For example, early onset drinking has been shown to be associated with greater hippocampal volumetric deficits (Ozsoy et al., 2013) and adolescent AUDs consistently result in hippocampal volume loss (De Bellis et al., 2000; Nagel et al., 2005). However, on the other end of the age spectrum, greater anterior volume loss was reported in the hippocampi of older alcoholics (Sullivan et al., 1995).

Imaging studies thus far, however, lack sufficient resolution to identify specific subregions of the hippocampus or cellular populations. Therefore, post-mortem studies in humans and experimental evidence in animal models have been necessary to offer insight into dentate gyrus specific effects and/or alcohol-induced neuronal loss. One study observed significant reductions in neuron number in all hippocampal subfields, including the dentate gyrus, in alcoholics less than 45 years of age (Bengochea and Gonzalo, 1990). However, a more rigorous stereological estimation failed to observe neuronal loss in any hippocampal subfield, though these subjects were older averaging 55 years of age (Harding et al., 1997). Although Harding et al. (1997) associated hippocampal volume deficits in alcoholic cases with white matter loss, others have proposed that astroglial loss underlies hippocampal neurodegeneration (Korbo, 1999). Nonetheless, animal models of chronic alcohol exposure have shown consistently that alcohol is toxic to hippocampal neurons, including the dentate gyrus granule cells (Cadete-Leite et al., 1988b; Lukoyanov et al., 2000; Walker et al., 1980). Furthermore, animal models allow researchers to examine the effect of dose, duration and/or pattern of exposure which led to the discovery that subtle evidence of damage in the hippocampus is apparent after as little as 24-48 hours of high dose, binge-like ethanol exposure (Hayes et al., 2013; Obernier et al., 2002b). In the four-day binge model of alcohol dependence, neurons are lost throughout the corticolimbic pathway with degenerating cells particularly evident in the entorhinal cortex and ventral dentate gyrus (Collins et al., 1996; Crews et al., 2000; Kelso et al., 2011; Obernier et al., 2002a; Obernier et al., 2002b). Importantly, these binge models mimic the high blood ethanol concentrations (BECs) experienced by binge drinking alcoholics, which is estimated to be 60% or more of the alcoholic population (Robin et al., 1998; Zeigler et al., 2005). Additionally, alcoholics who drink in a binge pattern are much more likely to have neurodegeneration (Hunt, 1993).

Some portion of alcohol-induced neurodegeneration and impairments in cognitive function can recover with abstinence from alcohol (Bartels et al., 2007; Carlen et al., 1978; Gazdzinski et al., 2005; Mann et al., 1999; Pfefferbaum et al., 1995). For the hippocampus, a host of plastic changes were originally thought to underlie this recovery, such as, dendritic expansion (Cadete-Leite et al., 1989; Cadete-Leite et al., 1988b) and spine density recovery (King et al., 1988); however, alcohol withdrawal may compromise some of these effects (Durand et al., 1989). Although it has long been hypothesized that this plasticity underlies recovery in hippocampal volume and/or function observed in animals (Lukoyanov et al., 2000) and humans (Bartels et al., 2007), the contribution of these mechanisms seems insufficient to overcome such a significant volume loss. Many of these theories, however, did not take in to consideration the newly accepted phenomena of adult neurogenesis in the dentate gyrus (Armstrong and Barker, 2001; Nixon, 2006).

3. Adult neurogenesis – a critical component of hippocampal integrity

Adult neurogenesis, the process by which new neurons are created in the postnatal brain, occurs constitutively in two brain regions, the subventricular zone of the walls of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (Altman and Das, 1965; Doetsch et al., 1999). Recent discoveries about the lack of newborn neurons in the adult human olfactory bulb (Bergmann et al., 2012) however, suggest a more critical role for adult neurogenesis in hippocampal structure and function. Although Altman and Das's (1965) seminal discovery of adult neurogenesis was not widely accepted until the late-1990s (Eriksson et al., 1998; Gross, 2000; Kaplan and Hinds, 1977; Palmer et al., 1997), the exponential increase in published work on adult neural stem cells and adult neurogenesis has fundamentally changed thinking about the hippocampus; specifically, how ongoing neuron generation and potential for regeneration impacts its function and dysfunction in neuropsychiatric disorders. In the hippocampus, new neurons are generated constitutively throughout life in a multi-step process from radial glia-like stem cells that reside along the SGZ of the dentate gyrus (described in Figure 1; see Zhao et al., 2008 for a detailed review of this process). Approximately 6% of the GCL is generated each month in the adult rodent (Cameron and McKay, 2001), even though not every cell that divides survives through incorporation into the GCL. Furthermore, baseline rates of proliferation, survival, and incorporation vary across species, strain, age, and sex that are additionally impacted by environment and experience (Kempermann, 2012; Kempermann and Gage, 2002; Zhao et al., 2008). Although this phenomenon is now accepted as a contributor to the structural integrity of the hippocampus (Imayoshi et al., 2008), the functional role of newborn neurons remains unclear. Early work relied upon correlation to implicate adult neurogenesis in many of the same functions of the hippocampus (van Praag et al., 1999). However, conditional and inducible transgenic animals have provided the most compelling evidence for the role of adult neurogenesis. These tools have allowed for the discovery that adult neurogenesis is critical for pattern separation, a process that acts to enhance differences between similar experiences so they can be distinguished from one another (Clelland et al., 2009; Nakashiba et al., 2012). These more specific knock-out methods have also helped resolve contradictory results across the hallmark of hippocampal function in rodents, spatial learning and memory. Well-controlled, genetic manipulations by inducible knockouts or lentiviral transgene delivery show, fairly consistently, impairments in spatial memory (reviewed in Marin-Burgin and Schinder, 2012). More importantly, of those that did not detect deficits with the classic test of spatial memory, the Morris water maze, several did report impairments in other hippocampus-dependent behavioral tasks such as, contextual fear conditioning (Saxe et al., 2006), trace fear conditioning (Shors et al., 2002), or place recognition (Madsen et al., 2003). Therefore, although there are some contradictory results, new technologies are helping to resolve these issues to strengthen the conclusion that decreases in adult neurogenesis result in some kind of deficit in hippocampal-dependent behavior (Marin-Burgin and Schinder, 2012; Zhao et al., 2008).

Figure 1.

Figure 1

Schematic representation of adult neurogenesis and known ways in which alcohol affects this process. Adult hippocampal neurogenesis consists of multiple stages that cells progress or mature through: stem-like radial glia act as the neural stem cell (NSC) and proliferate into neural progenitor cells (NPCs). Type 1 radial-glia like neural stem cells divide asymmetrically and produce a progenitor (Type 2a) that can also divide and produce daughter progenitors (circular arrows indicate that the cell is capable of replicating). The NPC term is used throughout when it is not clear which cell type, the NSC or one of the progenitors, has been examined or if the distinction was not made. These subpopulations of progenitors have varying capacities for self-renewal and differentiation as NPCs may differentiate into a neuronal or glial phenotype (Bonaguidi et al., 2011; 2012; Dranovsky et al., 2011; Encinas et al., 2011). The maturation of these cells progress through Type 3 and immature neuroblast (I) as they migrate and integrate into the granule cell layer (GCL) where they finally become mature granule cells (M; green cells = granule cells; pink cells = SGZ; Gage, 2000; Zhao et al., 2008). Alcohol impacts these processes at multiple stages:
  1. Alcohol dependence may kill progenitor cells with long duration, chronic exposure (Richardson et al., 2009; Taffe et al., 2010).
  2. Alcohol intoxication reduces NPC proliferation whereas reactive increases in neurogenesis occur at one week in abstinence (Nixon and Crews, 2002; 2004). Alcohol also alters the cell cycle of NPCs (McClain et al., 2011a).
  3. Multiple ways in which alcohol may directly affect the neurogenic niche, notably alcohol produces reactive astrocytes and reactive microglia (Kelso et al., 2011; Marshall et al., 2013; McClain et al., 2011b).
  4. High peak blood ethanol concentrations are likely required to impact survival of new born cells (Herrera et al., 2003; Nixon and Crews, 2002).
  5. Chronic alcohol exposure blunted dendritic arborization in newborn cells (He et al., 2005), an effect that would have functional implications for new cells incorporation into hippocampal circuitry.
  6. Binge alcohol exposure kills entorhinal cortex cells that project to the hippocampal dentate gyrus (Collins et al., 1996; Kelso et al., 2011).

4. Alcohol and hippocampal neurogenesis

For over 30 years, scientists have known that a direct relationship exists between alcohol intake and disruptions in hippocampal integrity (Walker et al., 1980). Preliminary conjecture coupled with extensive literature revealing overt cell death following alcohol exposure in vivo led to the original assumption that cell loss in the hippocampus was due to dying neurons (Bengochea and Gonzalo, 1990; Collins et al., 1996; Walker et al., 1980). However, this theory failed to incorporate the then controversial idea that adult neurogenesis was an essential component of hippocampal structure and function (Zhao et al., 2008). In fact, more recent data utilizing adult and adolescent alcohol exposure models strongly suggest that alcoholic neuropathology is at least partially due to an attenuation of adult neurogenesis (Crews et al., 2006c; Morris et al., 2010; Nixon and Crews, 2002). In this same model, hippocampal integrity is impacted, resulting in an 8% loss of granule cells despite a lack of equivalent levels of cell death (Leasure and Nixon, 2010). Therefore, alcohol likely impairs hippocampal integrity, in part, through its effects on adult neurogenesis (Morris et al., 2010).

As described in figure 1, adult neurogenesis is a process comprised of four separate components: cell proliferation, differentiation, migration, and survival. Alcohol exposure can affect neurogenesis at any one of these individual phases or through a combination of effects at multiple stages (Figure 1). Indeed, the various phases are differentially affected by alcohol intoxication, alcohol dependence, and other sequelae that result from chronic alcohol exposure such as seizures and/or neurodegeneration. Therefore, the effects of alcohol intoxication versus alcohol withdrawal and abstinence are discussed separately.

The vast majority of in vivo studies have shown that alcohol intoxication leads to an overall decrease in neurogenesis through alcohol's effects on cell proliferation and cell survival (Crews and Nixon, 2009; Herrera et al., 2003; Nixon, 2006; Nixon and Crews, 2002; Richardson et al., 2009), while increased neurogenesis has been observed in abstinence following alcohol dependence (Nixon and Crews, 2004). Although a few studies showed no effect or an increase in proliferation resulting from 10 days (Rice et al., 2004), 2 weeks (Aberg et al., 2005), 6 weeks (Herrera et al., 2003), or 10 weeks (Aberg et al., 2005) of chronic alcohol exposure, these differences could result from the use of different animal models, the animal's BEC at time of sacrifice/analysis, the timing of analysis with respect to alcohol exposure, and methods used to label proliferating cells (Nixon, 2006). Despite all of these explanations, an interesting trend can be gleaned from these reports: ethanol intoxication appears to dose-dependently inhibit neural stem cell proliferation, an effect which has been shown in vivo with acute doses in adolescent rats (Crews et al., 2006b) and can be extrapolated from a similar correlation in mice (Contet et al., 2013). Determining or estimating the BEC at the time of sacrifice and labeling of the proliferating population continues to support the view that some level of significant intoxication, perhaps above 80 mg/dl, is necessary to inhibit proliferation (Aberg et al., 2005; Crews et al., 2006b; Nixon, 2006). Recent publications continue to support this point. For example, rats that were fed an ethanol containing liquid diet had an average BEC of 86.4 mg/dl (0.08%) and showed a 40% decrease in proliferation (Anderson et al., 2012). It is important to note that these BECs were obtained from animals at sacrifice, which is typically done during lights on, at the start of the sleeping period for rodents, and thus 12+ hours past when they would likely have had a drinking bout and BECs would have peaked. Therefore, alcohol may have reduced proliferation in some of these divergent studies, but the sacrifice time point missed the time of peak intoxication and therefore peak inhibition of cell proliferation. Alternatively, it is of note that the two studies that have observed an increase in proliferation have been in mice (Aberg et al., 2005; Pawlak et al., 2002). Mice metabolize ethanol much faster than rats (Livy et al., 2003), meaning withdrawal events will occur relatively earlier. Therefore, the timeline of these alcohol-induced neurogenesis events may be shifted in mice compared to rats.

A handful of studies have observed persistent decreases in proliferation despite animals being days to weeks past their last exposure and therefore no longer significantly intoxicated. Bromodeoxyuridine-labeled cells and other endogenous measures remain decreased in these reports, but it is of note that the majority of these reports were from long-term chronic exposure models with weeks or months of ethanol exposure (Contet et al., 2013; Hansson et al., 2010; Richardson et al., 2009; Taffe et al., 2010). Therefore, the duration (i.e. number of days, whether repeated binge-like or chronic) may impact the number of proliferating progenitors.

Although hippocampal NPC proliferation is decreased during alcohol intoxication, the percentage of newly born cells that differentiate into neurons or glia appears unchanged. No studies have examined differentiation specifically. Several intriguing reports on alcohol-induced effects in human neural stem cells (NSCs) within the context of Fetal Alcohol Spectrum Disorders (Vangipuram and Lyman, 2010; Zhou et al., 2011) suggest that this might be a potential area for discovery in AUD models. NPC/neuroblast survival is generally decreased in alcohol exposure models, but again, this effect is heavily dose-dependent, i.e., higher doses of alcohol produce greater decreases in new cell survival (Nixon and Crews, 2002; Richardson et al., 2009). Alcohol also potentially kills NSCs and/or NPCs according to long-term alcohol dependence models, again highlighting that dose and duration of exposure may be critical factors in understanding the mechanism of alcohol's effects on NSCs, NPCs, and adult neurogenesis (Contet et al., 2013; Hansson et al., 2010; Nixon and Crews, 2002; Richardson et al., 2009; Taffe et al., 2010). This dose and duration dependency is not surprising as alcohol-induced neuronal cell death, in general, is also hypothesized to be dose and duration dependent. Several groups, including ours, speculate that sustained BECs greater than 200 mg/dl (0.20%) are necessary to produce neurodegeneration (Collins et al., 1996). In support of this idea, a single 5 g/kg dose of alcohol, which only transiently produces >0.20% BEC, does not inhibit survival of hippocampal NPCs (Nixon and Crews, 2002).

Although chronic alcohol intoxication inhibits multiple aspects of adult neurogenesis, a different set of effects on adult neurogenesis are observed in abstinence after intoxication. The most distinct change involves a large, transient increase in NPC proliferation well after the cessation of alcohol exposure. Specifically, in a four-day binge model of alcohol dependence, a burst in NPC proliferation occurs after one week of abstinence, leading to an increased number of newly formed mature neurons four weeks later (Nixon and Crews, 2004). Notably, proliferation returns to control levels by at least two weeks following the last ethanol dose, which emphasizes the short-lived nature of the reactive neurogenesis response (Nixon et al., 2008). Similar increases in NPC proliferation and neurogenesis in abstinence have been described in alcohol-preferring rats subjected to a seven-week two-bottle choice paradigm and in rats exposed chronically to ethanol via vapor chambers (Hansson et al., 2010; He et al., 2009). In contrast, Taffe and colleagues reported a decrease in NPC proliferation and neurogenesis after two months of abstinence in adolescent rhesus macaques given alcohol chronically for 11 months (Taffe et al., 2010). This discrepancy may involve several factors related to the vastly different models: binge versus chronic, species of animals, the time in abstinence analyzed, and possibly even the age of the animals. In adolescents with AUDs, hippocampal neurodegeneration is more consistently reported than it is in adults (Harding et al., 1997; Nagel et al., 2005). Plus, the adolescent brain is more susceptible to negative consequences of ethanol, including degeneration in some cortical regions (Crews et al., 2000). This suggests that the NPC population in the adolescent brain may be more susceptible to alcohol-induced neurotoxicity. NPCs in the adolescent brain have shown different reactions to alcohol versus adults, such as a shortened cell cycle during alcohol-dependence (McClain et al., 2011a). In addition, given the transient nature of reactive neurogenesis observed early in abstinence in rodent models of alcohol exposure, it is possible that a similar transient change occurred but was missed due to the timing of analysis (which was months into abstinence). Importantly, if a short-lived increase in neurogenesis was missed, the subsequent return to an overall decrease in neurogenesis represents a potential barrier to full recovery of hippocampal structure and function. For this reason, understanding the full timeline of alcohol's effects on the progenitor population and the mechanisms responsible for reactive neurogenesis may be important for designing strategies aimed at sustaining neurogenesis at normal levels after long-term abstinence (Mandyam and Koob, 2012).

The specific components and the degree to which each stage of adult neurogenesis is affected by alcohol depend upon the dose, duration, and pattern of alcohol exposure as well as the age of the organism (Goodlett et al., 2005; Nixon, 2006). The mechanisms of alcohol-induced effects on neurogenesis have yet to be described and remain a critical gap in understanding the role of alcohol-induced brain damage in AUDs. In the following section, select plausible interactions are discussed through which alcohol may exert its effects on adult neurogenesis.

5. Potential mechanisms of alcohol's effects on adult neurogenesis

Excessive consumption of alcohol results in behavioral and neurochemical changes that are difficult to isolate due to the promiscuous pharmacology of ethanol on the brain. Ethanol's effects range from direct modulation of many neurotransmitter systems to indirect outcomes that are caused by or are comorbid with alcohol dependence. Alcohol's effects also vary depending on dose and duration of exposure, especially noting that a variety of neuroadaptations occur with the development of dependence (Vengeliene et al., 2008). Here, we focus on direct effects of ethanol on neurotransmission, cell signaling, and ethanol's cellular effects on the neurogenic niche. However, all of these events likely interact with each other as well as the host of indirect effects/comorbidities to generate the net effect alcohol has on the components of hippocampal adult neurogenesis.

5.1. Altered neurotransmission

Ethanol affects virtually every neurotransmitter system in the central nervous system (CNS; reviewed in Vengeliene et al., 2008). For example, concentrations of alcohol that reflect those seen in human consumption, may directly interact with a host of neurotransmitters, receptors and ion channels including acetylcholine, endocannabinoids, neuropeptide Y (NPY), gamma-aminobutyric acid (GABA) receptors, n-methyl-d-aspartate (NMDA) type glutamate receptors, and serotonin receptors along with G-protein-activated inwardly rectifying K+ channels (Arnone et al., 1997; Fadda and Rossetti, 1998; Grobin et al., 2001; Lewohl et al., 1999; Lovinger, 1999; Lovinger et al., 1989; Vengeliene et al., 2008). This list notably overlaps with the neurotransmitter systems that regulate adult hippocampal neurogenesis, including acetylcholine, endocannabinoids, GABA, glutamate, norepinephrine, NPY, and serotonin to name a few (Aguado et al., 2005; Bruel-Jungerman et al., 2011; Cameron et al., 1998; Conover and Notti, 2008; Gray, 2008). As many of these have been reviewed previously (Crews and Nixon, 2003; Nixon et al., 2010; Nixon et al., 2011), only primary targets GABA and glutamate as well as new insights into endocannabinoid signaling are discussed below.

The process of adult neurogenesis and maturation of newly born neurons involves two neurotransmitter systems that are also considered the primary pharmacodynamic targets of ethanol, GABA and glutamate. GABAA receptors are present on newly born neurons in the SGZ and GABA acts as an excitatory neurotransmitter during the first two-four weeks of new neuron development (Esposito et al., 2005; Ge et al., 2006; Overstreet Wadiche et al., 2005). Around this time, the neuron begins to express NMDA receptors and undergoes a switch from GABA being excitatory to inhibitory and NMDA being excitatory, recapitulating that seen in development (Nacher et al., 2007; Zhao et al., 2008). Previous studies show that treatment with a GABAA agonist results in decreased SGZ NPC proliferation while antagonist treatment yielded the opposite effect (Tozuka et al., 2005). However, treatment with a GABAA agonist was shown to enhance activity-dependent neuronal differentiation (Tozuka et al., 2005). Since ethanol is a positive allosteric modulator of the GABAA receptor it is possible that this receptor could be one avenue through which alcohol acts to alter neurogenesis. These findings also suggest that alcohol could have very specific effects on NPCs and developing neuroblasts depending on their state of ontogeny, especially when GABA is initially excitatory. However, no one has explored this potential relationship or whether alcohol affects the maturation of neuroblasts in the dentate gyrus.

The role of NMDA receptors in adult neurogenesis is complex. Several studies have shown that NMDA receptor activation inhibits adult hippocampal neurogenesis (Cameron et al., 1995; Maekawa et al., 2009; Nacher et al., 2001; Pava and Woodward, 2012); whereas NMDA receptor antagonism increases adult neurogenesis (Cameron et al., 1995; Petrus et al., 2009). Acutely, ethanol intoxication inhibits NMDA receptors (Lovinger et al., 1989) which indicates that NMDA receptors are not likely the mechanism by which ethanol intoxication decreases adult neurogenesis (Nixon and Crews, 2002). Prolonged ethanol exposure and the development of dependence, however, augments NMDA function and enhances glutamate release, both of which contribute to neuronal hyperexcitability associated with the ethanol withdrawal syndrome (Hoffman, 2003). Increased neurogenesis is observed after four days of ethanol inhibition of NMDA receptors, which is consistent with an NMDA antagonist similarly increasing neurogenesis (Cameron et al., 1995). Furthermore, ethanol withdrawal-induced hyperexcitability increases activation of granule cell neurons as measured by c-fos immunoreactivity (Knapp et al., 1998; Matsumoto et al., 1993). Although hyperexcitability associated with ethanol withdrawal typically subsides within 24 hours (Matsumoto et al., 1993), previous studies demonstrate that the effects of granule cell excitation on neurogenesis can be delayed by several days (Bruel-Jungerman et al., 2006; Stone et al., 2011). Additional studies are needed, but the delayed neurogenic effects associated with activity-dependent neurogenesis fits the temporal profile for reactive neurogenesis that occurs after a four-day binge ethanol exposure (Nixon and Crews, 2004). Altogether, these findings suggest that altered glutamatergic neurotransmission could serve a central role regulating the reactive adult neurogenesis response observed during early abstinence.

Hippocampal NPCs express a functional endocannabinoid system, including plasma membrane expression of CB1 and CB2 receptors and cytoplasmic expression of fatty acid amide hydrolase (FAAH) which catabolizes the endocannabinoid anandamide (Aguado et al., 2005). Deficits in adult neurogenesis occur in CB1−/− and CB2−/− mice, to confirm that engagement of the endocannabinoid system helps to maintain basal neurogenesis (Jin et al., 2004; Kim et al., 2006; Palazuelos et al., 2006). In addition, in vitro cell culture experiments demonstrate that cannabinoid receptor activation or FAAH inhibition promote NPC proliferation and neurosphere formation, while receptor blockade has the opposite effect (Aguado et al., 2005; Palazuelos et al., 2006). Activation of CB1 receptors reverses diminished neurogenesis in aged rodents and mediates exercise-induced increases in NPC proliferation (Hill et al., 2010; Marchalant et al., 2009). Furthermore, genetic ablation of CB1 or CB2 receptors blunts the increase in NPC proliferation and neurogenesis that follows kainic acid-induced excitotoxicity, directly implicating the endocannabinoid system in reactive hippocampal neurogenesis (Aguado et al., 2007; Palazuelos et al., 2012). Although direct evidence connecting the endocannabinoid system with ethanol-induced reactive neurogenesis is lacking, the well-characterized increase in NMDA receptor expression associated with chronic ethanol consumption depends on CB1 receptor activity (Warnault et al., 2007). This indicates that the endocannabinoid system regulates ethanol-induced neuroadaptations in the hippocampus. In addition, hippocampal CB1 and endocannabinoid levels are increased during abstinence in models of alcohol dependence (Mitrirattanakul et al., 2007), suggesting an increase in endocannabinoid signaling may occur during reactive neurogenesis.

5.2. CREB and its downstream effectors

The cyclic adenosine monophosphate (cAMP) signal transduction cascade and its most notorious transcription factor, the cAMP-responsive element binding (CREB) protein, are involved in a diverse array of physiological functions that include adult neurogenesis. Specifically, the activated, phosphorylated form of CREB (pCREB) has been shown consistently to be present in the SGZ with more recent evidence indicating that pCREB is predominantly localized in immature neurons (Mantamadiotis et al., 2012; Meshi et al., 2006; Nakagawa et al., 2002a). Further, systemic delivery of Rolipram, an agent known to increase CREB signaling, led to enhanced proliferation, survival, and dendritic branching of neuroblasts in the SGZ while retroviral inhibition of CREB signaling reduced cell survival and dendrite extension (Buffo et al., 2008; Crews, 2012; Nakagawa et al., 2002b). Importantly, alcohol is a known modulator of this pathway and some of its target effectors such as NPY and brain-derived neurotrophic factor (BDNF) allow for the possibility that alcohol-induced inhibition of neurogenesis may result from these interactions (Moonat et al., 2010; Pava and Woodward, 2012; Tateno and Saito, 2008).

Although both NPY and BDNF have been shown consistently to play a role in alcohol-related behaviors (Davis, 2008; Miller et al., 1996; Thiele et al., 1998), more recent data has identified NPY and BDNF as promoters of adult hippocampal neurogenesis (Koo and Duman, 2008; Malva et al., 2012). Specifically, in the dentate gyrus, a subpopulation of GABAergic hilar interneurons express NPY, while SGZ NPCs express the Y1 receptor (Sperk et al., 2007). Mice lacking NPY exhibit a significant reduction in cell proliferation while exogenous NPY administration both stimulates cell proliferation and promotes differentiation toward a neuronal phenotype (Hauser et al., 2011; Hensler et al., 2003). Furthermore, modulation of the NPY system could be involved in regulation of alcohol-induced reactive neurogenesis. For example, neurotoxin-induced reactive neurogenesis can be enhanced with exogenous NPY treatment (Corvino et al., 2012), while seizure-induced neurogenesis is attenuated in NPY knockout mice (Howell et al., 2007). Importantly, alcohols effects on NPY mirror its effects on adult neurogenesis observed following alcohol dependence. In the four-day binge ethanol model, hilar NPY expression decreases during intoxication but rebounds and increases more than 30-fold compared to controls after three days of abstinence (Bison and Crews, 2003). Ethanol's effects on hippocampal NPY expression closely parallel effects on NPC proliferation, which also decreases during ethanol intoxication and transiently increases during abstinence (He et al., 2009; Jang et al., 2002; Nixon and Crews, 2002; 2004). The increase in NPY during abstinence precedes the start of reactive neurogenesis by four days, similar to the delayed neurogenic response following exogenous NPY administration (Decressac et al., 2011).

In addition to NPY, reports from a variety of disease states and models demonstrate a relationship between BDNF levels and adult hippocampal neurogenesis (Kalkman, 2009; Martinotti et al., 2012; Post, 2007; Schmidt and Duman, 2007). BDNF augments neurogenesis via an enhancement of cell birth, survival, and maturation within the hippocampal SGZ (Koo and Duman, 2008; Lee et al., 2002). Heterozygous BDNF (knockdown) mice show decreases in adult neurogenesis (Lee et al., 2002). Indeed, alcohol-dependent humans have decreased serum BDNF concentrations; however, once alcohol consumption ceased there was a general increase in BDNF levels (Costa et al., 2011; Köhler et al., 2013). Several rodent studies have shown a similar pattern: chronic alcohol administration reduces BDNF expression in the rat hippocampus, cortex, and hypothalamus (MacLennan et al., 1995; Pandey et al., 1999; TapiaArancibia et al., 2001) whereas BDNF mRNA increases post-withdrawal (Tapia-Arancibia et al., 2001; see also Davis, 2008 for review). Decreases in hippocampal BDNF have also been linked with greater depression-like behavior following alcohol exposure (Briones and Woods, 2013; Hauser et al., 2011). Studies show that administration of antidepressants following alcohol exposure can help mitigate depression-like behavior seen in rodents as well as alcohol-induced effects on some components of adult neurogenesis (Hauser et al., 2011; Stevenson et al., 2009). Furthermore, an agonist for the BDNF receptor, the tropomyosin-related kinase receptor (trkB), reduced depression-like symptoms associated with alcohol withdrawal/abstinence and also restored neurogenesis during this period (Briones and Woods, 2013). Therefore, since alcohol exposure leads to deficits in NPY and BDNF in the brain and decreases in these factors attenuate measures of neurogenesis, it is increasingly possible that alcohol could be altering neurogenesis via its effect on NPY and BDNF and/or CREB. These findings are particularly noteworthy because of the significant comorbidity between AUDs and mood disorders coupled with this striking overlap in the pathophysiology of AUDs and mood (Kalkman, 2009; Martinotti et al., 2012; Post, 2007; Schmidt and Duman, 2007; Schuckit and Monteiro, 1988). However, results of BDNF studies vary widely, some have found no change in hippocampal BDNF (Okamoto et al., 2006; Miller at al., 2002) or an increase in BDNF in the cortex (Baek et al., 1996). These disparities may be related to the animal model, age, or the time course of neurobiological events with regard to whether the animal is intoxicated, dependent, and/or dependent but in abstinence. For example, examining BDNF and adult neurogenesis after alcohol withdrawal suggests a very different role from what may happen during alcohol intoxication. Based on the role of BDNF in ectopic adult neurogenesis in seizures and the development of epilepsy, we examined BDNF expression during abstinence following a four-day model of alcohol dependence in adolescent rats. In this short-term model of alcohol dependence, which results in withdrawal seizure-like behavior in some animals, no changes were observed in BDNF protein expression and BDNF expression did not correlate to withdrawal severity (McClain et al., in press). Importantly, this same study reported ectopic or aberrant neurogenesis, an effect that has been linked to hyper-BDNF signaling in models of epilepsy (e.g. Scharfman et al., 2005) and schizophrenia (Kalkman, 2009). Remarkable inconsistencies in the BDNF literature, detailed in a thorough review by Davis (2008), coupled with what appears to be very diverse roles of BDNF on the different aspects of alcohol intoxication and/or dependence make it difficult to definitively conclude the role of BDNF in alcohol-induced effects on adult neurogenesis, let alone alcohol use disorders. However, BDNF plays a critical and well-established role in the pathophysiology of other psychiatric disorders and notably ones with significant comorbidity to AUDs (Martinotti et al., 2012; Post, 2007; Schuckit and Monteiro, 1988). Thus, this is an area of work that is ripe for discovery but needs a critical eye for the peculiarities of not only BDNF's role in the different aspects of adult neurogenesis but also the various phases of alcohol dependence.

5.3. Direct effects on the neurogenic niche

The neurogenic niche is the neurogenesis-permissive zone where stem cells have been retained from embryonic pools (for review see Taupin, 2006). The SGZ of the hippocampal dentate gyrus is one such region in the adult brain where adult neurogenesis from NSCs continues because of the permissiveness or instructiveness of the microenvironment of the SGZ. The important role of the niche in adult neurogenesis emerged from data that stem cells can be isolated from multiple locations of the brain (Morshead et al., 1994; Reynolds and Weiss, 1992), but adult neurogenesis is restricted to these two specific locations under normal, non-pathological conditions. This permissiveness, however, can be induced by damage (Magavi et al., 2000) though aspects of damage and disease may further impair the production of new neurons (Monje et al., 2003). The cytoarchitectural organization of the niche is thought to be the critical factor for maintaining stem cell populations, as niche cells regulate self-renewal, stem cell activation, and cell fate choice (reviewed in Conover and Notti, 2008). Critical components of the hippocampal niche include the vasculature (Palmer et al., 2000), astrocytes (Seri et al., 2001; Song et al., 2002), and their host of secreted factors and signals (Notch, bone morphogenic proteins, ephrins, sonic hedgehog; Alvarez-Buylla and Lim, 2004). Importantly, this means that astrocytes may not only be acting as the stem cells themselves, but that they also constitute a significant portion of the microenvironment that makes up the niche (Taupin, 2006).

Excessive alcohol exposure is detrimental to astrocytes. In the least, astrocytes are activated by alcohol and at worst astrocytes may be damaged by excessive alcohol exposure (Crews and Nixon, 2009; Kelso et al., 2011; Korbo, 1999). Therefore, understanding the effect of alcohol on astrocytes is critical to understanding how alcohol impacts the neurogenic niche. When astrocytes react, termed astrogliosis, various changes in morphology and gene expression coincide with changes in their functional role (Sofroniew, 2009). Astrogliosis occurs in response to a host of damaging, neurodegenerative, and inflammatory conditions, including several models of AUDs (Baydas and Tuzcu, 2005; Dalcik et al., 2009; Evrard et al., 2006; Franke, 1995; Kelso et al., 2011; Robel et al., 2011; Sofroniew, 2009; Tagliaferro et al., 2002; Udomuksorn et al., 2011). A hallmark of astrogliosis is the up-regulation of intermediate filament proteins such as glial fibrillary acidic protein (GFAP), nestin, and vimentin, with the latter two also widely used to identify progenitor cells (Pekny et al., 2007). Indeed, reactive astrocytes may be a potential source of stem cells (Buffo et al., 2008; Robel et al., 2011). Unfortunately, due to the similarity in markers used to identify stem cells and reactive astrocytes, it remains a challenge to tease apart effects on niche astrocytes versus niche stem cells in conditions with astrogliosis such as the AUDs (Kelso et al., 2011). Regardless, normal astrocytic functions would clearly be impacted in the AUDs, such as providing metabolic and trophic support, buffering ions, taking up excessive extracellular neurotransmitter (especially glutamate), and eliminating free radicals, all of which would have major effects on the niche and the production of new neurons.

Several studies include a role for microglia in the niche, especially activated microglia where their role as either being pro-neurogenic (Battista et al., 2006) or anti-neurogenic (Monje et al., 2003) is hotly debated (Whitney et al., 2009). Their role is intertwined within the discussion of neuroinflammation, as they are the macrophages of the CNS. Although astrocytes play a role in neuroinflammation, as they are a component of the blood brain barrier (BBB), we focus on the role of microglia as the primary cells of the brain's innate immune system.

Much like the discovery of adult neurogenesis, inflammation in the CNS originally was not believed (Murphy and Sturm, 1923). This historical belief grew from the idea that the CNS was immune privileged and segregated from systemic inflammation by the BBB (Pachter et al., 2003). However, with the discovery that microglia could act as macrophages within the CNS came the concept of an innate immune system within the brain (Neuwelt and Clark, 1978). Classical inflammation in the CNS has three cardinal hallmarks: microglial activation, BBB disruption, and lymphocytic infiltration (Colton and Wilcock, 2010; Graeber et al., 2011). Although “activated” microglia have been reported to be anything from beneficial to detrimental to the processes of adult neurogenesis, in retrospect it appears that only the pro-inflammatory, classically-activated phenotype of microglia inhibit or impair adult neurogenesis (Russo et al., 2011). Microglia exist in a continuum of activation states, or phenotypes (Town et al., 2005), such that it is now clear that it is the microglial phenotype, whether anti-inflammatory or pro-inflammatory, that predicts which cytokines and chemokines are secreted and therefore whether adult neurogenesis is promoted or inhibited (Ekdahl et al., 2009; Whitney et al., 2009). Thus, it is the fully or classically activated microglia that secrete pro-inflammatory cytokines that are associated with reductions in neurogenesis (Monje et al., 2003). Inflammation can affect various phases of adult neurogenesis. For example, pro-inflammatory cytokine interleukin 6 (IL-6), results in decreased proliferation (Vallieres et al., 2002); whereas other pro-inflammatory cytokines such as interferon-gamma (IFN-γ) can alter fate choices from neuronal to astrocytic (Walter et al., 2011).

Whether inflammation occurs in AUDs and the extent to which it influences alcohol-induced neurodegeneration and the development of AUDs is a matter of current debate (Crews, 2012). That excessive alcohol consumption produces neuroinflammation has been inferred from observations of increased expression of pro-inflammatory genes and cytokines following alcohol exposure (Crews et al., 2006c; He and Crews, 2008; Knapp and Crews, 1999; Qin et al., 2008), while other groups have shown that peripheral inflammation promotes increased ethanol consumption (Agrawal et al., 2011; Blednov et al., 2011). Furthermore, in animal models of chronic alcohol intake, innate immune signaling cascades are induced by ethanol activation of the pro-inflammatory transcription factor, nuclear factor-kappa-B (Crews et al., 2006a; Crews et al., 2011; Valles et al., 2004). However, classical definitions of inflammation state that it is a “multicellular process characterized by changes in the vasculature and infiltration of mobile cells” (p. 3800, Graeber et al., 2011). Although studies have shown microglial activation in alcoholic brain (He and Crews, 2008), no studies to date in human tissue have shown inflammation according to these classical definitions. Moreover, in the four-day binge model of an AUD, the most damaging of the AUD models, microglia are activated but only towards a low grade or beneficial phenotype (Marshall et al., 2013). That is not to say that alcohol abuse is not producing a pro-inflammatory environment, but true inflammation according to definition, may not be occurring.

A few studies have attempted to show direct links between alcohol, pro-inflammatory factors, and adult neurogenesis. In theory, pro-inflammatory cytokines produced by activated microglia in models of AUDs could be involved in the inhibition of neurogenesis (Ekdahl et al., 2009). For example, interleukin 1β (IL-1β), which is enhanced in LPS and ethanol-treated mice (Qin et al., 2008), has been shown repeatedly in other models to inhibit various stages of neurogenesis including proliferation and maturation (Koo and Duman, 2008; Zunszain et al., 2012). A recent in vitro study, however, showed a more direct relationship between alcohol-induced pro-inflammatory events and alcohol-induced inhibition of neurogenesis. Blocking the alcohol-induced increase in IL-1β synthesis ameliorated the alcohol-induced decrease in both NPC proliferation and new cell survival (Zou and Crews, 2012). This finding further indicates that the other cytokines typical of classical microglial activation and seen during intoxication may play a role in alcohol-induced decreased neurogenesis.

Microglial activation may also be involved in reactive neurogenesis after damage (Deboy et al., 2006; Wainwright et al., 2009). In other neurodegenerative conditions, cytokines are key to promoting reactive neurogenesis. For example, in an adrenalectomy model of reactive neurogenesis, blocking transforming growth factor beta (TGF-β) receptors reduced neurogenesis (Battista et al., 2006) whereas increases in interleukin-10 (IL-10) enhanced neurogenesis (Kiyota et al., 2012). Similar trends have been observed in the four-day binge model: a significant increase in the anti-inflammatory cytokine IL-10 and low-grade activation of microglia (Marshall et al., 2013) precedes a reactive burst in NSC proliferation (Nixon and Crews, 2004). Many studies have reported that alcohol exposure induces a microglial response, however no reports to date have reported on the potential for anti-inflammatory microglia (Marshall et al., 2013; McClain et al., 2011b; Nixon et al., 2008). Although alcohol-induced changes in anti-inflammatory cytokines have not been directly linked to the reported burst in NPC proliferation, the coincidental timing of this striking, anti-inflammatory microglia response and reactive neurogenesis suggests that alcohol-activated microglia directly influence the neurogenic niche.

6. Conclusions

Countless studies have illustrated that AUDs result in damage to the central nervous system with the hippocampus as a central target of its neurotoxic effects. Recent preclinical studies have highlighted that alcohol's effects on the various components of adult neurogenesis are one way in which excessive alcohol intake produces hippocampal pathology. By impacting the structure and function of the dentate gyrus through inhibition of adult neurogenesis, alcohol has downstream effects on hippocampal circuitry and subsequently the host of behaviors controlled or influenced by the hippocampus. Ethanol is a pharmacologically promiscuous drug that acts on many targets, several of which are involved in adult neurogenesis. Alcohol pharmacodynamically alters several neurotransmitter systems such as glutamate and GABA that are also critically involved in the process of adult neurogenesis. Additionally, alcohol modulates the transcription factor CREB and its downstream effectors (including NPY and BDNF) which also have roles in hippocampal neurogenesis and new cell survival. Alcohol-induced changes in neurogenesis could result from any combination of these targets. In addition to these direct, pharmacological effects, alcohol has significant cellular effects that impact the hippocampal neurogenic niche. Specifically, excessive alcohol consumption results in activation and/or damage to astrocytes, which are the primary components of the niche, if not the stem cells themselves. Microglia are also activated by excessive alcohol consumption although their contribution to adult neurogenesis depends upon their phenotype and inflammatory state. New data emerging on alcohol's effects on glia strongly imply that excessive alcohol consumption may impact the neurogenic niche through these cellular effects.

Importantly, research has shown that some recovery is possible when alcoholics abstain from alcohol use (e.g. Carlen et al., 1978; Pfefferbaum et al., 1995). Although there are a host of plastic changes that occur with abstinence, one way that the hippocampus may recover in abstinence is through the repopulation of the dentate gyrus by adult neurogenesis. Although it has been reported that a compensatory increase in neurogenesis occurs in abstinence, it is still not known whether the new cells are functionally integrated correctly or the extent to which this process influences cognitive recovery. Despite observation of this potential mechanism of recovery in animal models, detectable cognitive impairments remain in over 50% of AUD cases (Eckardt and Martin, 1986; Parsons, 1993). Therefore important future questions should include understanding the contribution of these phenomena – alcohol-induced decreases to pathology and reactive neurogenesis to recovery – to hippocampal integrity and function in AUDs.

Highlights.

  • Alcoholism may result in hippocampal pathology through effects on adult neurogenesis.

  • Alcohol's pharmacological promiscuity impacts neurogenesis via multiple mechanisms.

  • Alcohol affects neuronal signaling and/or the neurogenic niche to alter neurogenesis.

Acknowledgments

The authors thank M. Ayumi Deeny for producing Figure 1 and the support of National Institute of Alcohol Abuse and Alcoholism grants R01AA016959, R21AA16307 and National Institute of Drug Abuse training grants T32DA016176 and T32DA007304 in conducting the work described herein.

Footnotes

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