Alcohol and the brain: from genes to circuits

Abstract

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits. Together, these mechanisms produce long-lasting cellular adaptations in the brain that in turn can drive the development and maintenance of alcohol use disorder (AUD). We provide an update on alcohol research, focusing on multiple levels of alcohol-induced adaptations, from intracellular changes to changes in neural circuits. A better understanding of how alcohol affects these diverse and interlinked mechanisms may lead to the identification of novel therapeutic targets and to the development of much-needed novel and efficacious treatment options.

Keywords: alcohol; central nervous system; epigenetics; intracellular signaling; neural circuits.

Figure 1.. Molecular pathways in alcohol use disorder.

Alcohol binds to a number of transmembrane receptors including glutamate, GABA and dopamine receptors, as well as receptors of different neuropeptides and neurotrophic factors. These in turn affect the activity of several second messenger cascades and intracellular signaling pathways. These pathways mediate long-lasting cellular adaptations affecting, among others, translation and synaptic plasticity, which contribute to neuronal adaptations underlying AUD. In the nucleus of neurons, alcohol has complex effects on the epigenetic regulation of gene expression. These complex and highly interlinked pathways activate specific gene expression programs, which underlie neuronal maladaptations and contribute to the development of alcohol use disorder. Abbreviations: ACSS2: acetyl-CoA synthetase 2, ADNP: activity dependent neuroprotector homeobox, ALK: anaplastic lymphoma kinase, BDNF: brain-derived neurotrophic factor, cAMP: cyclic adenosine monophosphate, CBP: CREB(cAMP response element-binding protein)-binding protein, CRMP2: collapsing response mediator protein family 2, SRC: sarcoma, D1R: dopamine receptor D1, DNTM1: DNA methyltransferase 1, ERK1/2: extracellular signal-regulated kinase 1/2, FGF2: fibroblast growth factor 2, FGFR1: FGF receptor 1, FMRP: fragile X mental retardation protein, GABA_AR: gamma aminobutyric acid receptor A, GDNF: glial cell line-derived neurotrophic factor, GFRa1: GDNF family receptor alpha 1, GluN2B: glutamate N-methyl-D-aspartate receptor subunit 2B, GSK3b: glycogen synthase kinase 3b, IKKb: inhibitor of nuclear factor kappa-B kinase subunit beta, KDM6B: lysine demethylase 6B, LMO4: LIM domain only 4, mTORC1/2: mammalian target of rapamycin complex 1/2, PDE: phosphodiesterase, NFkB: nuclear factor kappa-B, PKA: protein kinase A, PKCe: protein kinase C epsilon, PI3K: phosphoinositide-3-kinase, Prosapip1: Prosap2(prolin-rich synapse-associated protein 2) interacting protein 1, Ret: Rearranged during transfection, Su(H): suppressor of hairless, TNF: tumor necrosis factor, TrkB: tropomyosin receptor kinase B. Figure was created with BioRender.com.

Figure 2.. Neuronal circuits affected by alcohol.

Acute and chronic use of alcohol affects the activity of multiple neuronal circuits, depicted here schematically in the context of a rodent brain. For example, alcohol activates the mesocorticolimbic brain reward circuit, which encompasses dopaminergic projections from the VTA in the midbrain to several forebrain structures including the striatum and cortex. These circuits underlie the rewarding effects of alcohol. Anxiolytic effects of ethanol have been linked to the amygdala. In addition, CRF neurons projecting from the central amygdala to the BNST were shown to contribute to the escalation of alcohol intake. Prefrontal cortical circuits have been implicated in impaired executive control that underlies excessive drinking, as well as weakened cognitive function in AUD. For example, projections from the mPFC to the dorsal striatum have been linked to habitual alcohol drinking and continued use despite negative consequences. Further, neurons projecting from the mPFC to the dPAG play a critical role in compulsive drinking. Strikingly, mice that display inhibitory activity in this circuit during the first alcohol exposure are more likely to develop compulsive drinking behavior. Abbreviations: BLA: basolateral amygdala; BNST: bed nucleus of the stria terminalis; CeA: central amygdala; CRF: corticotropin releasing factor; DLS: dorsolateral striatum; DMS: dorsomedial striatum; HPC: hippocampus; LA: lateral amygdala; mPFC: medial prefrontal cortex; NAc: nucleus accumbensm; dPAG: dorsal periaqueductal gray; OFC: orbitofrontal cortex; VTA: ventral tegmental area. Figure was created with BioRender.com.