Dataset Information

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain.

ABSTRACT: Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking initiation in rats, persist into early abstinence in both species, and are associated with a robust decrease in extracellular space tortuosity explained by a microglial reaction. Mathematical modeling of the diffusivity changes unveils an increased spatial reach of extrasynaptically released transmitters like dopamine that may contribute to alcohol's progressively enhanced addictive potency.

SUBMITTER: De Santis S

PROVIDER: S-EPMC7314532 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain.

De Santis Silvia S Cosa-Linan Alejandro A Garcia-Hernandez Raquel R Dmytrenko Lesia L Vargova Lydia L Vorisek Ivan I Stopponi Serena S Bach Patrick P Kirsch Peter P Kiefer Falk F Ciccocioppo Roberto R Sykova Eva E Moratal David D Sommer Wolfgang H WH Canals Santiago S

Science advances 20200624 26

Already moderate alcohol consumption has detrimental long-term effects on brain function. However, how alcohol produces its potent addictive effects despite being a weak reinforcer is a poorly understood conundrum that likely hampers the development of successful interventions to limit heavy drinking. In this translational study, we demonstrate widespread increased mean diffusivity in the brain gray matter of chronically drinking humans and rats. These alterations appear soon after drinking init ...[more]

PMID: 32637601

Similar Datasets

Project description:Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane.

Project description:BackgroundAlcohol withdrawal is a key component of severe alcohol use disorder. Animal models of alcohol withdrawal tend to focus on traditional anxiety/stress tests. While these have been essential to advancing our understanding of the biology of alcohol withdrawal, abrupt cessation of drinking following heavy alcohol consumption can also trigger withdrawal-related affective states that impact responses to a variety of life events and stressors. To this end, we show that behaviors in a variety of tasks that differ in task demand and intensity are altered during withdrawal in male and female mice after voluntary alcohol access.MethodsMale and female miceunderwent six weeks of intermittent two-bottle choice alcohol exposure followed by behavioral tests. The tests included-Home cage: low-stress baseline environment to measure spontaneous natural behaviors; Open field: anxiety-inducing bright novel environment; Looming disc: arena with a protective hut where mice are exposed to a series of discs that mimic an overhead advancing predator, and Robogator-simulated predator task: forced foraging behavioral choice in the presence of an advancing robot predator that "attacks" when mice are near a food pellet in a large open arena.ResultsA history of alcohol exposure impacted behaviors in these tasks in a sex-dependent manner. In the home cage, alcohol induced reductions in digging and heightened stress coping through an increase in grooming time. In males, increased rearing yielded greater vigilance/exploration in a familiar environment. The open-field test revealed an anxiety phenotype in both male and female mice exposed to alcohol. Male mice showed no behavioral alterations to the looming disc task, while females exposed to alcohol showed greater escape responses than water controls, indicative of active stress-response behaviors. In males, the Robogator task revealed a hesitant/avoidant phenotype in alcohol-exposed mice under greater task demands.ConclusionsFew drugs show robust evidence of efficacy in clinical trials for alcohol withdrawal. Understanding how withdrawal alters a variety of behaviors in both males and females that are linked to stress coping can increase our understanding of alcohol misuse and aid in developing better medications for treating individuals with AUD.

Dataset Information

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain.

Publications

Chronic alcohol consumption alters extracellular space geometry and transmitter diffusion in the brain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets