Background

Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge‐like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol‐preferring (P) rats.

Methods

Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self‐administered 0 to 200 mg% EtOH. Male P rats self‐administered 0 to 100 mg%.

Results

The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose–response curve for EtOH self‐administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex‐specific effects of AIE on gene expression; male only reduction in D3 receptors.

Conclusion

Binge‐like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Background

Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge‐like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol‐preferring (P) rats.

Methods

Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self‐administered 0 to 200 mg% EtOH. Male P rats self‐administered 0 to 100 mg%.

Results

The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose–response curve for EtOH self‐administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex‐specific effects of AIE on gene expression; male only reduction in D3 receptors.

Conclusion

Binge‐like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu₂) is a G_i/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu₂ function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu₂ function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu₂-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu₂-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu₂-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu₂ fully rescues mGlu₂-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu₂-LTD. We did not observe a reduction of mGlu₂ mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu₂ occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu₂ activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Chronic alcohol exposure is associated with increased reliance on behavioral strategies involving the dorsolateral striatum (DLS), including habitual or stimulus-response behaviors. Presynaptic G protein-coupled receptors (GPCRs) on cortical and thalamic inputs to the DLS inhibit glutamate release, and alcohol-induced disruption of presynaptic GPCR function represents a mechanism by which alcohol could disinhibit DLS neurons and thus bias toward use of DLS-dependent behaviors. Metabotropic glutamate receptor 2 (mGlu₂) is a G_i/o-coupled GPCR that robustly modulates glutamate transmission in the DLS, inducing long-term depression (LTD) at both cortical and thalamic synapses. Loss of mGlu₂ function has recently been associated with increased ethanol seeking and consumption, but the ability of alcohol to produce adaptations in mGlu₂ function in the DLS has not been investigated. We exposed male C57Bl/6J mice to a 2-week chronic intermittent ethanol (CIE) paradigm followed by a brief withdrawal period, then used whole-cell patch clamp recordings of glutamatergic transmission in the striatum to assess CIE effects on mGlu₂-mediated synaptic plasticity. We report that CIE differentially disrupts mGlu₂-mediated long-term depression in the DLS vs. dorsomedial striatum (DMS). Interestingly, CIE-induced impairment of mGlu₂-LTD in the dorsolateral striatum is only observed when alcohol exposure occurs during adolescence. Incubation of striatal slices from CIE-exposed adolescent mice with a positive allosteric modulator of mGlu₂ fully rescues mGlu₂-LTD. In contrast to the 2-week CIE paradigm, acute exposure of striatal slices to ethanol concentrations that mimic ethanol levels during CIE exposure fails to disrupt mGlu₂-LTD. We did not observe a reduction of mGlu₂ mRNA or protein levels following CIE exposure, suggesting that alcohol effects on mGlu₂ occur at the functional level. Our findings contribute to growing evidence that adolescents are uniquely vulnerable to certain alcohol-induced neuroadaptations, and identify enhancement of mGlu₂ activity as a strategy to reverse the effects of adolescent alcohol exposure on DLS physiology.

Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank's alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

OBJECTIVE:

Alcohol use disorder (AUD) is a complex, dynamic condition that waxes and wanes with unhealthy drinking episodes and varies in drinking patterns and effects on brain structure and function with age. Its excessive use renders chronically heavy drinkers vulnerable to direct alcohol toxicity and a variety of comorbidities attributable to nonalcohol drug misuse, viral infections, and accelerated or premature aging. AUD affects widespread brain systems, commonly, frontolimbic, frontostriatal, and frontocerebellar networks.

METHOD AND RESULTS:

Multimodal assessment using selective neuropsychological testing and whole-brain neuroimaging provides evidence for AUD-related specific brain structure-function relations established with double dissociations. Longitudinal study using noninvasive imaging provides evidence for brain structural and functional improvement with sustained sobriety and further decline with relapse. Functional imaging suggests the possibility that some alcoholics in recovery can compensate for impairment by invoking brain systems typically not used for a target task but that can enable normal-level performance.

CONCLUSIONS:

Evidence for AUD-aging interactions, indicative of accelerated aging, together with increasing alcohol consumption in middle-age and older adults, put aging drinkers at special risk for developing cognitive decline and possibly dementia. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: Alcohol use disorder (AUD) is a complex, dynamic condition that waxes and wanes with unhealthy drinking episodes and varies in drinking patterns and effects on brain structure and function with age. Its excessive use renders chronically heavy drinkers vulnerable to direct alcohol toxicity and a variety of comorbidities attributable to nonalcohol drug misuse, viral infections, and accelerated or premature aging. AUD affects widespread brain systems, commonly, frontolimbic, frontostriatal, and frontocerebellar networks. Method and Results: Multimodal assessment using selective neuropsychological testing and whole-brain neuroimaging provides evidence for AUD-related specific brain structure-function relations established with double dissociations. Longitudinal study using noninvasive imaging provides evidence for brain structural and functional improvement with sustained sobriety and further decline with relapse. Functional imaging suggests the possibility that some alcoholics in recovery can compensate for impairment by invoking brain systems typically not used for a target task but that can enable normal-level performance. Conclusions: Evidence for AUD-aging interactions, indicative of accelerated aging, together with increasing alcohol consumption in middle-age and older adults, put aging drinkers at special risk for developing cognitive decline and possibly dementia. (PsycINFO Database Record (c) 2019 APA, all rights reserved)

 

The emergence of state-level approval of cannabis for both medical and recreational use is likely to increase the already prevalent co-use of alcohol and cannabis (Yurasek et al., 2017) and raise many important health and social concerns (National Academies of Sciences, 2017). Cannabis research has lagged behind that of alcohol research, but important studies are emerging on the interactions between alcohol and cannabinoids. In this Virtual Issue, Cannabis and Alcohol: From Basic Science to Public Policy, we present 9 leading-edge research publications spanning preclinical and epidemiological studies, as well as a critical review of the potential therapeutic use of cannabidiol (CBD) in the treatment of alcohol use disorder (AUD) (Turna et al., 2019), which recently appeared in Alcoholism: Clinical and Experimental Research. The Virtual Issue addresses the potential risks and benefits of alcohol and cannabis co-use, which may depend on the particular subgroup of individuals, and whether these drugs are used simultaneously (i.e., drug effects overlap) (Pakula et al., 2009) or concurrently (i.e., drug effects do not overlap in time) (Subbaraman et al., 2019). Simultaneous drug use may be perceived as a means to complement or enhance the effects of each substance (Patrick et al., 2018), despite some individuals reporting negative effects (Lee et al., 2017). The positive perception of complementary drug effects is concerning given the greater health risks associated with simultaneous use (Volkow et al., 2014; Yurasek et al., 2017). Another pattern of use has also developed that substitutes cannabis for alcohol use, particularly in individuals who are making efforts to reduce alcohol intake (Subbaraman, 2016). As summarized in the sections below, this Virtual Issue provides a current assessment of cannabis–alcohol interactions and shows patterns of drug use and risk profiles that may impact the prevalence of co-use and dependence.

The emergence of state‐level approval of cannabis for both medical and recreational use is likely to increase the already prevalent co‐use of alcohol and cannabis (Yurasek et al., 2017) and raise many important health and social concerns (National Academies of Sciences, 2017). Cannabis research has lagged behind that of alcohol research, but important studies are emerging on the interactions between alcohol and cannabinoids. In this Virtual Issue, Cannabis and Alcohol: From Basic Science to Public Policy, we present 9 leading‐edge research publications spanning preclinical and epidemiological studies, as well as a critical review of the potential therapeutic use of cannabidiol (CBD) in the treatment of alcohol use disorder (AUD) (Turna et al., 2019), which recently appeared in Alcoholism: Clinical and Experimental Research.

The Virtual Issue addresses the potential risks and benefits of alcohol and cannabis co‐use, which may depend on the particular subgroup of individuals, and whether these drugs are used simultaneously (i.e., drug effects overlap) (Pakula et al., 2009) or concurrently (i.e., drug effects do not overlap in time) (Subbaraman et al., 2019). Simultaneous drug use may be perceived as a means to complement or enhance the effects of each substance (Patrick et al., 2018), despite some individuals reporting negative effects (Lee et al., 2017). The positive perception of complementary drug effects is concerning given the greater health risks associated with simultaneous use (Volkow et al., 2014; Yurasek et al., 2017). Another pattern of use has also developed that substitutes cannabis for alcohol use, particularly in individuals who are making efforts to reduce alcohol intake (Subbaraman, 2016). As summarized in the sections below, this Virtual Issue provides a current assessment of cannabis–alcohol interactions and shows patterns of drug use and risk profiles that may impact the prevalence of co‐use and dependence.

Background

Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes‐related neuropathies, neuropathy associated with alcohol use disorders (AUD ) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy.

Methods

In seeking a central substrate for AUD ‐related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self‐report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2‐point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD ‐related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ ‐glutamyltransferase), were evaluated.

Results

The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD ‐related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors.

Conclusions

This study supports CNS involvement in objective signs of neuropathy in AUD.

BACKGROUND:

Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes-related neuropathies, neuropathy associated with alcohol use disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy.

METHODS:

In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ-glutamyltransferase), were evaluated.

RESULTS:

The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors.

CONCLUSIONS:

This study supports CNS involvement in objective signs of neuropathy in AUD.

Rationale

Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors.

Objectives

The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking.

Methods

Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS− associated with the absence of EtOH (extinction training), and a neutral stimulus (CS⁰) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS−, or CS⁰ to assess the effect of the conditioned cues on EtOH-seeking behavior.

Results

 

Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS− in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS− in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking.

Conclusion

Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS− may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment.

 

RATIONALE:

Evidence indicates that drug-paired stimuli can evoke drug-craving leading to drug-seeking and repeated relapse periods can influence drug-seeking behaviors.

OBJECTIVES:

The present study examined (1) the effect of an interaction between repeated deprivation cycles and excitatory conditioning stimuli (CS+) on ethanol (EtOH)-seeking; (2) the effects of EtOH-paired cue-exposure in a non-drug-paired environment on subsequent conditioning in a drug-paired environment; and (3) the temporal effects of conditioned cues on subsequent EtOH-seeking.

METHODS:

Adult female alcohol-preferring (P) rats were exposed to three conditioned odor cues; CS+ associated with EtOH self-administration, CS- associated with the absence of EtOH (extinction training), and a neutral stimulus (CS⁰) presented in a neutral non-drug-paired environment. The rats underwent four deprivation cycles or were non-deprived, following extinction they were maintained in a home cage for an EtOH-free period, and then exposed to no cue, CS+, CS-, or CS⁰ to assess the effect of the conditioned cues on EtOH-seeking behavior.

RESULTS:

Repeated deprivations enhanced and prolonged the duration of CS+ effects on EtOH-seeking. Presentation of the CS- in a non-drug-paired environment blocked the ability of a CS+ to enhance EtOH-seeking in a drug-paired environment. Presentation of the CS+ or CS- in a non-drug-paired environment 2 or 4 h earlier significantly altered EtOH-seeking.

CONCLUSION:

Results indicated an interaction between repeated deprivation cycles and CS+ resulted in a potentiation of CS+ evoked EtOH-seeking. In addition, a CS- may have therapeutic potential by providing prophylactic protection against relapse behavior in the presence of cues in the drug-using environment.

The unconventional N-methyl-D-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

The unconventional N-methyl-D-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

Recent advances in robust and reliable methods of MRI-derived cerebellar lobule parcellation volumetry present the opportunity to assess effects of Alcohol Use Disorder (AUD) on selective cerebellar lobules and relations with indices of nutrition and motor functions. In pursuit of this opportunity, we analyzed high-resolution MRI data acquired in 24 individuals with AUD and 20 age- and sex-matched controls with a 32-channel head coil using three different atlases: the online automated analysis pipeline volBrain Ceres, SUIT, and the Johns Hopkins atlas. Participants had also completed gait and balance examination and hematological analysis of nutritional and liver status, enabling testing of functional meaningfulness of each cerebellar parcellation scheme. Compared with controls, each quantification approach yielded similar patterns of group differences in regional volumes: All three approaches identified AUD-related deficits in total tissue and total gray matter, but only Ceres identified a total white matter volume deficit. Convergent volume differences occurred in lobules I-V, Crus I, VIIIB, and IX. Coefficients of variation (CVs) were <20% for 46 of 56 regions measured and in general were graded: Ceres<SUIT<Hopkins. The most robust correlations were identified between poorer stability in balancing on one leg and smaller lobule VI and Crus I volumes from the Ceres atlas. Lower values of two essential vitamins—thiamine (vitamin B1) and serum folate (vitamin B9)—along with lower red blood cell count, which are dependent on adequate levels of B vitamins, correlated with smaller gray matter volumes of lobule VI and Crus I. Higher γ-glutamyl transferase (GGT) levels, possibly reflecting compromised liver function, correlated with smaller volumes of lobules VI and X. These initial results based on high resolution data produced with clinically practical imaging procedures hold promise for expanding our knowledge about the relevance of focal cerebellar morphology in AUD and other neuropsychiatric conditions.

Recent advances in robust and reliable methods of MRI-derived cerebellar lobule parcellation volumetry present the opportunity to assess effects of Alcohol Use Disorder (AUD) on selective cerebellar lobules and relations with indices of nutrition and motor functions. In pursuit of this opportunity, we analyzed high-resolution MRI data acquired in 24 individuals with AUD and 20 age- and sex-matched controls with a 32-channel head coil using three different atlases: the online automated analysis pipeline volBrain Ceres, SUIT, and the Johns Hopkins atlas. Participants had also completed gait and balance examination and hematological analysis of nutritional and liver status, enabling testing of functional meaningfulness of each cerebellar parcellation scheme. Compared with controls, each quantification approach yielded similar patterns of group differences in regional volumes: All three approaches identified AUD-related deficits in total tissue and total gray matter, but only Ceres identified a total white matter volume deficit. Convergent volume differences occurred in lobules I-V, Crus I, VIIIB, and IX. Coefficients of variation (CVs) were <20% for 46 of 56 regions measured and in general were graded: Ceres<SUIT<Hopkins. The most robust correlations were identified between poorer stability in balancing on one leg and smaller lobule VI and Crus I volumes from the Ceres atlas. Lower values of two essential vitamins-thiamine (vitamin B1) and serum folate (vitamin B9)-along with lower red blood cell count, which are dependent on adequate levels of B vitamins, correlated with smaller gray matter volumes of lobule VI and Crus I. Higher γ-glutamyl transferase (GGT) levels, possibly reflecting compromised liver function, correlated with smaller volumes of lobules VI and X. These initial results based on high resolution data produced with clinically practical imaging procedures hold promise for expanding our knowledge about the relevance of focal cerebellar morphology in AUD and other neuropsychiatric conditions.

Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.

Alcohol use disorder (AUD) is a complex psychiatric disorder with strong genetic and environmental risk factors. We studied the molecular perturbations underlying risky drinking behavior by measuring transcriptome changes across the neurocircuitry of addiction in a genetic mouse model of binge drinking. Sixteen generations of selective breeding for high blood alcohol levels after a binge drinking session produced global changes in brain gene expression in alcohol-naïve High Drinking in the Dark (HDID-1) mice. Using gene expression profiles to generate circuit-level hypotheses, we developed a systems approach that integrated regulation of gene coexpression networks across multiple brain regions, neuron-specific transcriptional signatures, and knowledgebase analytics. Whole-cell, voltage-clamp recordings from nucleus accumbens shell neurons projecting to the ventral tegmental area showed differential ethanol-induced plasticity in HDID-1 and control mice and provided support for one of the hypotheses. There were similarities in gene networks between HDID-1 mouse brains and postmortem brains of human alcoholics, suggesting that some gene expression patterns associated with high alcohol consumption are conserved across species. This study demonstrated the value of gene networks for data integration across biological modalities and species to study mechanisms of disease.