Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers

Anna S. Warden; Sarah A. Wolfe; Sophia Khom; Florence P. Varodayan; Reesha R. Patel; Michael Q. Steinman; Michal Bajo; Sarah E. Montgomery; Roman Vlkolinsky; Tali Nadav; Ilham Polis; Amanda J. Roberts; R. Dayne Mayfield; R. Adron Harris; Marisa Roberto

doi:10.1016/j.biopsych.2020.05.011

Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers

Anna S. Warden
, Sarah A. Wolfe
, Sophia Khom
, Florence P. Varodayan
, Reesha R. Patel
, Michael Q. Steinman
, Michal Bajo
, Sarah E. Montgomery
, Roman Vlkolinsky
, Tali Nadav
, Ilham Polis
, Amanda J. Roberts
, R. Dayne Mayfield
, R. Adron Harris
, Marisa Roberto (Corresponding author)

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

BACKGROUND: Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake.

METHODS: We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies.

RESULTS: PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABA(A) and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function.

CONCLUSIONS: Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.

Original language	English
Pages (from-to)	910-921
Number of pages	12
Journal	Biological Psychiatry
Volume	88
Issue number	12
DOIs	https://doi.org/10.1016/j.biopsych.2020.05.011
Publication status	Published - 15 Dec 2020

Funding

This work was supported by the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (Grants No. U01 AA020926 [to RDM], U01 AA013498 [to MR], P60 AA006420 [to MR], R01 AA015566 [to MR], AA017477 [to MR], R01 AA027700 [to MR], R01 AA021491 [to MR], T32 AA007456 [to MR], P01 AA020683 [to RAH], R01 AA012404 [to RAH], F31 AA025499 [to ASW], and K99 AA025408 [to FPV]).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

301406 Neuropharmacology
301402 Neurobiology

Keywords

CHRONIC ETHANOL EXPOSURE
SEX-DIFFERENCES
CENTRAL AMYGDALA
CONSUMPTION
TRANSMISSION
ASSOCIATION
ABSTINENCE
EXPRESSION
WITHDRAWAL
MECHANISM
Transcriptome
Electrophysiology
Alcohol
PLX5622
Microglia
Ethanol dependence

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10.1016/j.biopsych.2020.05.011

Cite this

Warden, A. S., Wolfe, S. A., Khom, S., Varodayan, F. P., Patel, R. R., Steinman, M. Q., Bajo, M., Montgomery, S. E., Vlkolinsky, R., Nadav, T., Polis, I., Roberts, A. J., Mayfield, R. D., Harris, R. A., & Roberto, M. (2020). Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers. Biological Psychiatry, 88(12), 910-921. https://doi.org/10.1016/j.biopsych.2020.05.011

@article{4a0555c1843347bdae9d409805c761d2,

title = "Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers",

abstract = "BACKGROUND: Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake. METHODS: We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies. RESULTS: PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABA(A) and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. CONCLUSIONS: Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.",

keywords = "CHRONIC ETHANOL EXPOSURE, SEX-DIFFERENCES, CENTRAL AMYGDALA, CONSUMPTION, TRANSMISSION, ASSOCIATION, ABSTINENCE, EXPRESSION, WITHDRAWAL, MECHANISM, Transcriptome, Electrophysiology, Alcohol, PLX5622, Microglia, Ethanol dependence",

author = "Warden, \{Anna S.\} and Wolfe, \{Sarah A.\} and Sophia Khom and Varodayan, \{Florence P.\} and Patel, \{Reesha R.\} and Steinman, \{Michael Q.\} and Michal Bajo and Montgomery, \{Sarah E.\} and Roman Vlkolinsky and Tali Nadav and Ilham Polis and Roberts, \{Amanda J.\} and Mayfield, \{R. Dayne\} and Harris, \{R. Adron\} and Marisa Roberto",

note = "Publisher Copyright: {\textcopyright} 2020 Society of Biological Psychiatry",

year = "2020",

month = dec,

day = "15",

doi = "10.1016/j.biopsych.2020.05.011",

language = "English",

volume = "88",

pages = "910--921",

journal = "Biological Psychiatry",

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number = "12",

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Warden, AS, Wolfe, SA, Khom, S, Varodayan, FP, Patel, RR, Steinman, MQ, Bajo, M, Montgomery, SE, Vlkolinsky, R, Nadav, T, Polis, I, Roberts, AJ, Mayfield, RD, Harris, RA & Roberto, M 2020, 'Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers', Biological Psychiatry, vol. 88, no. 12, pp. 910-921. https://doi.org/10.1016/j.biopsych.2020.05.011

TY - JOUR

T1 - Microglia Control Escalation of Drinking in Alcohol-Dependent Mice

T2 - Genomic and Synaptic Drivers

AU - Warden, Anna S.

AU - Wolfe, Sarah A.

AU - Khom, Sophia

AU - Varodayan, Florence P.

AU - Patel, Reesha R.

AU - Steinman, Michael Q.

AU - Bajo, Michal

AU - Montgomery, Sarah E.

AU - Vlkolinsky, Roman

AU - Nadav, Tali

AU - Polis, Ilham

AU - Roberts, Amanda J.

AU - Mayfield, R. Dayne

AU - Harris, R. Adron

AU - Roberto, Marisa

PY - 2020/12/15

Y1 - 2020/12/15

N2 - BACKGROUND: Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake. METHODS: We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies. RESULTS: PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABA(A) and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. CONCLUSIONS: Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.

AB - BACKGROUND: Microglia, the primary immune cells of the brain, are implicated in alcohol use disorder. However, it is not known if microglial activation contributes to the transition from alcohol use to alcohol use disorder or is a consequence of alcohol intake. METHODS: We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex and CeA from the same animals used for behavioral studies. RESULTS: PLX5622 prevented escalations in voluntary alcohol intake and decreased anxiety-like behavior associated with alcohol dependence. PLX5622 also reversed expression changes in inflammatory-related genes and glutamatergic and GABAergic (gamma-aminobutyric acidergic) genes in the medial prefrontal cortex and CeA. At the cellular level in these animals, microglia depletion reduced inhibitory GABA(A) and excitatory glutamate receptor-mediated synaptic transmission in the CeA, supporting the hypothesis that microglia regulate dependence-induced changes in neuronal function. CONCLUSIONS: Our multifaceted approach is the first to link microglia to the molecular, cellular, and behavioral changes associated with the development of alcohol dependence, suggesting that microglia may also be critical for the development and progression of alcohol use disorder.

KW - CHRONIC ETHANOL EXPOSURE

KW - SEX-DIFFERENCES

KW - CENTRAL AMYGDALA

KW - CONSUMPTION

KW - TRANSMISSION

KW - ASSOCIATION

KW - ABSTINENCE

KW - EXPRESSION

KW - WITHDRAWAL

KW - MECHANISM

KW - Transcriptome

KW - Electrophysiology

KW - Alcohol

KW - PLX5622

KW - Microglia

KW - Ethanol dependence

UR - https://www.scopus.com/pages/publications/85088368411

U2 - 10.1016/j.biopsych.2020.05.011

DO - 10.1016/j.biopsych.2020.05.011

M3 - Article

SN - 0006-3223

VL - 88

SP - 910

EP - 921

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 12

ER -

Microglia Control Escalation of Drinking in Alcohol-Dependent Mice: Genomic and Synaptic Drivers

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

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