Identifying functionally relevant candidate genes for inflexible ethanol intake in mice and humans using a guilt‐by‐association approach

Carvalho, Luana Martins de; Fonseca, Pablo Augusto de Souza; Paiva, Isadora Marques; Damasceno, Samara; Pedersen, Agatha Sondertoft Braga; Silva, Daniel Almeida da Silva e; Wiers, Corinde E.; Volkow, Nora D.; Godard, Ana Lúcia Brunialti

doi:10.1002/brb3.1879

Cited by 10 publications

(8 citation statements)

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“…In this context, our research group identified relations of the Lrrk2 gene, until then associated with Parkinson’s and inflammatory bowel diseases, in preference behavior and loss of control by alcohol in mice, Zebrafish, and humans ( 31 , 32 , 36 , 108 – 110 ). This gene is involved in neural processes, such as the reuptake of synaptic components and synaptic plasticity, and in several signaling pathways by performing GTPase and kinase functions, which influence processes such as cell proliferation and differentiation, apoptosis, inflammation, and immune response ( 50 , 111 – 116 ).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the inflammatory process is observed in the striatum, changing its function and stimulating the drug compulsive use, even in the presence of negative consequences (16). Changes in the striatum are associated with compulsion as this brain region plays a central role in goal-directed behaviors and it is part of the Mesolimbic Dopaminergic System, popularly known as the reward system (28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

et al. 2023

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IntroductionMechanisms that dictate the preference for ethanol and its addiction are not only restricted to the central nervous system (CNS). An increasing body of evidence has suggested that abusive ethanol consumption directly affects the immune system, which in turn interacts with the CNS, triggering neuronal responses and changes, resulting in dependence on the drug. It is known that neuroinflammation and greater immune system reactivity are observed in behavioral disorders and that these can regulate gene transcription. However, there is little information about these findings of the transcriptional profile of reward system genes in high consumption and alcohol preference. In this regard, there is a belief that, in the striatum, an integrating region of the brain reward system, the interaction of the immune response and the transcriptional profile of the Lrrk2 gene that is associated with loss of control and addiction to ethanol may influence the alcohol consumption and preference. Given this information, this study aimed to assess whether problematic alcohol consumption affects the transcriptional profile of the Lrrk2 gene, neuroinflammation, and behavior and whether these changes are interconnected.MethodsAn animal model developed by our research group has been used in which male C57BL/6 mice and knockouts for the Il6 and Nfat genes were subjected to a protocol of high fat and sugar diet intake and free choice of ethanol in the following stages: Stage 1 (T1)—Dietary treatment, for 8 weeks, in which the animals receive high-calorie diet, High Sugar and Butter (HSB group), or standard diet, American Institute of Nutrition 93-Growth (AIN93G group); and Stage 2 (T2)—Ethanol consumption, in which the animals are submitted, for 4 weeks, to alcohol within the free choice paradigm, being each of them divided into 10 groups, four groups continued with the same diet and in the other six the HSB diet is substituted by the AIN93G diet. Five groups had access to only water, while the five others had a free choice between water and a 10% ethanol solution. The weight of the animals was evaluated weekly and the consumption of water and ethanol daily. At the end of the 12-week experiment, anxiety-like behavior was evaluated by the light/dark box test; compulsive-like behavior by Marble burying, transcriptional regulation of genes Lrrk2, Tlr4, Nfat, Drd1, Drd2, Il6, Il1β, Il10, and iNOS by RT-qPCR; and inflammatory markers by flow cytometry. Animals that the diet was replaced had an ethanol high preference and consumption.Results and discussionWe observed that high consumption and preference for ethanol resulted in (1) elevation of inflammatory cells in the brain, (2) upregulation of genes associated with cytokines (Il6 and Il1β) and pro-inflammatory signals (iNOS and Nfat), downregulation of anti-inflammatory cytokine (Il10), dopamine receptor (Drd2), and the Lrrk2 gene in the striatum, and (3) behavioral changes such as decreased anxiety-like behavior, and increased compulsive-like behavior. Our findings suggest that interactions between the immune system, behavior, and transcriptional profile of the Lrrk2 gene influence the ethanol preferential and abusive consumption.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

et al. 2023

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“…The QTL enrichment analysis was performed using GALLO as described by Fonseca et al (2020a). A guilt-by-association approach was performed to identify potential functional candidate genes (Fonseca et al, 2020b;Martins de Carvalho et al, 2020;Sweett et al, 2020;Lam et al, 2021). Briefly, a trained list containing genes associated with stillbirth and pregnancy persistence was obtained from GUILDify (Guney et al, 2014), using the following list of keywords: stillbirth, pregnancy, and pregnancy loss.…”

Section: Functional Candidate Genes Searchmentioning

confidence: 99%

Genome-wide association study using haplotype libraries and repeated-measures model to identify candidate genomic regions for stillbirth in Holstein cattle

Fonseca

Schenkel

Cánovas

2022

Journal of Dairy Science

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Reduced fertility is one of the main causes of economic losses on dairy farms, resulting in economic losses estimated at $938 per stillbirth case in Holstein herds. The identification of genomic regions associated with stillbirth could help to develop better management and breeding strategies aimed to reduce the frequency of undesirable gestation outcomes. Here, 10,570 cows and 50,541 birth records were used to perform a haplotypebased GWAS. A total of 41 significantly associated pseudo-SNPs (haplotypes within haplotype blocks converted to a binary classification) were identified after Bonferroni adjustment for multiple tests. A total of 117 positional candidate genes were annotated within or close (in a 200-kb interval) to significant pseudo-SNPs (haplotype blocks). The guilt-by-association functional prioritization identified 31 potential functional candidate genes for reproductive performance out of the 117 positional candidate genes annotated. These genes play crucial roles in biological processes associated with pregnancy persistence, fetus development, immune response, among others. These results helped us to better understand the genetic basis of stillbirth in dairy cattle and may be useful for the prediction of stillbirth in Holstein cattle, helping to reduce the related economic losses caused by this phenotype.

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“…Mutations in the human LRRK2 gene are associated with Parkinson’s disease [ 8 , 9 ], which is characterized by prominent impairment in dopamine signaling and basal ganglia function. Recent work has linked changes in striatal expression of the Lrrk2 gene with alcohol drinking in humans and rodents [ 10 , 11 ]. A positive correlation between striatal levels of Lrrk2 mRNA and alcohol drinking was reported in mice, especially an association with inflexible alcohol drinking that persists despite adverse outcomes or punishment [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking

da Silva,

Matsui,

Murray

et al. 2023

Neuropsychopharmacol.

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The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson’s-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

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Identifying functionally relevant candidate genes for inflexible ethanol intake in mice and humans using a guilt‐by‐association approach

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 37 publications

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

Genome-wide association study using haplotype libraries and repeated-measures model to identify candidate genomic regions for stillbirth in Holstein cattle

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking

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