Histone Acetylation in the Nucleus Accumbens Shell Modulates Ethanol-Induced Locomotor Activity in DBA/2J Mice

A growing body of literature suggests that epigenetic mechanisms, including histone acetylation, may play key roles in drug abuse and the development of addiction. Experiments in the present study were designed to investigate the role of histone acetylation in ethanol-induced locomotor sensitization

IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice

Proinflammatory cytokines have been implicated in alcohol-induced neurodegeneration, but the role of the neuroimmune system in alcohol related behaviors has only recently come to the forefront. Herein, the effects of binge-like drinking on IL-1β mRNA and immunoreactivity within the amygdala were measured following the “drinking in the dark” (DID) paradigm, a model of binge-like ethanol drinking in C57BL/6J mice. Moreover, the role of IL-1 receptor signaling in the amygdala on ethanol consumption was assessed. Results indicated that a history of binge-like ethanol drinking promoted a significant increase of IL-1β mRNA expression within the amygdala, and immunohistochemistry analyses revealed that the basolateral amygdala (BLA), but not central amygdala (CeA), exhibited significantly increased IL-1β immunoreactivity. Fluoro-Jade® C labeling indicated that multiple cycles of the DID paradigm were not sufficient to elicit neuronal death. Bilateral infusions of IL-1 receptor antagonist (IL-1Ra) reduced ethanol consumption when infused into the BLA but not the CeA. These observations were specific to ethanol drinking as the IL-1Ra did not alter either sucrose drinking or open-field locomotor activity. The current findings highlight a specific role for IL-1 receptor signaling in modulating binge-like ethanol consumption and indicate that proinflammatory cytokines can be induced prior to dependence or any evidence of neuronal cell death. These findings provide a framework in which to understand how neuroimmune adaptations may alter ethanol consumption and therein contributing to alcohol abuse

Assessment of the Effects of 6 Standard Rodent Diets on Binge-Like and Voluntary Ethanol Consumption in Male C57BL/6J Mice

In recent years much attention has been given to the lack of reproducibility in biomedical research, particularly in pre-clinical animal studies. This is a problem that also plagues the alcohol research field, particularly in consistent consumption in animal models of alcohol use disorders. One often overlooked factor that could affect reproducibility is the maintenance diet used in pre-clinical studies

Repeated Cycles of Binge-Like Ethanol Drinking in Male C57BL/6J Mice Augments Subsequent Voluntary Ethanol Intake But Not Other Dependence-Like Phenotypes

Recently, procedures have been developed to model specific facets of human alcohol abuse disorders, including those that model excessive binge-like drinking (i.e., “drinking in the dark”, or DID procedures) and excessive dependence-like drinking (i.e., intermittent ethanol vapor exposure). Similar neuropeptide systems modulate excessive ethanol drinking stemming from both procedures, raising the possibility that both paradigms are actually modeling the same phenotypes and triggering the same central neuroplasticity. Therefore, the goal of the present project was to study the effects of a history of binge-like ethanol drinking, using DID procedures, on phenotypes that have previously been described with procedures to model dependence-like drinking

Central Neuropeptide Y Modulates Binge-Like Ethanol Drinking in C57BL/6J Mice via Y1 and Y2 Receptors

Frequent binge drinking has been linked to heart disease, high blood pressure, type 2 diabetes, and the development of ethanol dependence. Thus, identifying pharmaceutical targets to treat binge drinking is of paramount importance. Here we employed a mouse model of binge-like ethanol drinking to study the role of neuropeptide Y (NPY). To this end, the present set of studies utilized pharmacological manipulation of NPY signaling, immunoreactivity (IR) mapping of NPY and NPY receptors, and electrophysiological recordings from slice preparations of the amygdala. The results indicated that central infusion of NPY, a NPY Y1 receptor (Y1R) agonist, and a Y2R antagonist significantly blunted binge-like ethanol drinking in C57BL/6J mice (that achieved blood ethanol levels >80 mg/dl in control conditions). Binge-like ethanol drinking reduced NPY and Y1R IR in the central nucleus of the amygdala (CeA), and 24 h of ethanol abstinence after a history of binge-like drinking promoted increases of Y1R and Y2R IR. Electrophysiological recordings of slice preparations from the CeA showed that binge-like ethanol drinking augmented the ability of NPY to inhibit GABAergic transmission. Thus, binge-like ethanol drinking in C57BL/6J mice promoted alterations of NPY signaling in the CeA, and administration of exogenous NPY compounds protected against binge-like drinking. The current data suggest that Y1R agonists and Y2R antagonists may be useful for curbing and/or preventing binge drinking, protecting vulnerable individuals from progressing to the point of ethanol dependence

Corticotropin Releasing Factor Signaling in the Central Amygdala is Recruited during Binge-Like Ethanol Consumption in C57BL/6J Mice

A well-established body of work indicates a crucial role for corticotropin releasing factor (CRF) in neurobiological responses associated with excessive dependence-like ethanol drinking in ethanol vapor exposed rodents. Recent evidence demonstrates a role for CRF in the modulation of binge-like ethanol consumption by non-dependent mice, a behavior which can precede ethanol dependence. The CRF circuitry that is engaged by binge-like ethanol exposure, however, is unknown. Using converging approaches, we provide evidence that, similar to ethanol vapor-induced increases in ethanol intake, CRF signaling in the central nucleus of the amygdala (CeA) is engaged during binge-like ethanol consumption by C57BL/6J mice. Specifically, we found that binge-like consumption of an ethanol solution (20% ethanol v/v) was attenuated by pretreatment with the CRF1R antagonists antalarmin, (4-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino-1-butanol (LWH-63), and NBI-27914 at doses (30 mg/kg, i.p.) that did not alter non-binge-like ethanol consumption. Binge-like ethanol consumption resulted in significant increases of CRF immunoreactivity in the CeA immediately following ethanol drinking and 18-24 h following ethanol removal and also blocked the ability of CRF to enhance GABAergic transmission in the CeA 18-24 h following ethanol removal. Pretreatment with bilateral injections of antalarmin (1 μg/ 0.5 μl per side) into the CeA, but not the adjacent basolateral amygdala (BLA), significantly attenuated binge-like ethanol consumption. These findings suggest that CRF signaling in the CeA is recruited during excessive ethanol intake, prior to the development of dependence. We hypothesize that plastic changes in CRF signaling develop with repeated binge-like drinking episodes, contributing to the transition to dependence

A novel, likely pathogenic variant in UBTF‐related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype

Abstract Background A de novo, pathogenic, missense variant in UBTF, c.628G>A p.Glu210Lys, has been described as the cause of an emerging neurodegenerative disorder, Childhood‐Onset Neurodegeneration with Brain Atrophy (CONDBA). The p.Glu210Lys alteration yields a positively charged stretch of three lysine residues. Functional studies confirmed this change results in a stronger interaction with negatively charged DNA and gain‐of‐function activity when compared to the wild‐type sequence. The CONDBA phenotype reported in association with p.Glu210Lys consists of normal early‐neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early‐to‐middle childhood. Methods and Results The current proband presented at 9 months of age with baseline developmental delay and more extensive neuroradiological findings, including pontine hypoplasia, thalamic volume loss and signal abnormality, and hypomyelination. Like the recurrent CONDBA p.Glu210Lys variant, this novel variant, c.608A>G p.(Gln203Arg) lies within the highly conserved second HMG‐box homology domain and involves the replacement of the wild‐type residue with a positively charged residue, arginine. Computational structural modeling demonstrates that this amino acid substitution potentiates the interaction between UBTF and DNA, likely resulting in a gain‐of‐function effect for the UBTF protein, UBF. Conclusion Here we present a new divergent phenotype associated with a novel, likely pathogenic, missense variant at a different position in the UBTF gene, c.608A>G p.(Gln203Arg)