Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

Ma, Tengfei; Huang, Ziming; Xie, Xueyi; Cheng, Yidong; Zhuang, Xiaowen; Childs, Matthew J; Gangal, Himanshu; Smith, Liane; Smith, Rachel J.; Zhou, Yubin; Wang, Jun

doi:10.1172/jci154969

Cited by 30 publications

(40 citation statements)

References 81 publications

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“…Reinforcement of drug and alcohol use has also been associated with reduced cognitive flexibility, which contributes to compulsive drug and alcohol use (Barker et al, 2017;Izquierdo and Jentsch, 2012;Jentsch et al, 2002;Luscher et al, 2020;Ma et al, 2021;McCracken and Grace, 2013;West et al, 2021). However, the neurocircuitry involved in this reinforcement-induced inflexibility has not been identified.…”

Section: Introductionmentioning

confidence: 99%

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Gangal

Xie

Cheng

et al. 2022

Preprint

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The mechanisms underlying the reduction in cognitive flexibility associated with reinforcement of addictive substance use are unknown. This reinforcement is mediated by substance-induced synaptic plasticity in direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by cholinergic interneurons (CINs), which receive extensive local inhibition from the striatum. Here, we report that cocaine or alcohol administration caused a long-lasting potentiation of local inhibitory dMSN-->CIN transmission in the dorsomedial striatum (DMS), a brain region critical for goal-directed behavior and cognitive flexibility. This dMSN-->CIN potentiation reduced CIN firing activity. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. Importantly, rabies-mediated tracing and physiological studies revealed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN-->CIN circuit mediates a reinforcement-induced reduction in cognitive flexibility.

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Section: Introductionmentioning

confidence: 99%

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Gangal

Xie

Cheng

et al. 2022

Preprint

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“…Nonetheless, only few investigations on mechanisms by which this receptor regulates alcohol drinking have been accomplished thus far. In this study, we investigated for the first-time the alcohol drinking behavior of mice lacking functional GABA B R with the 2-bottle choice (2BC) paradigm, and then we analyzed the expression and function of extrasynaptic δ-GABA A Rs that are functionally related to GABA B Rs in brain areas relevant to alcohol drinking and dependence ( Jia et al, 2008 ; Enoch et al, 2012 ; Diaz et al, 2014 ; Ma et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors

Floris

Asuni

Talani

et al. 2022

Front. Behav. Neurosci.

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Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB(1), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and δ-containing GABAA receptor (δ-GABAAR), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR δ subunit in the hippocampus of the GABAB(1) KO alcohol-naïve mice that was associated with increased ɣ2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABAAR occurring in the GABAB(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB(1) KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB(1) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB(1) KO mice. In addition, we documented that GABAB(1) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.

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“…Virus infusion was conducted as described previously ( Cheng et al., 2021 ; Lu et al, 2021b ; Ma et al, 2021 ). Animals were anesthetized with 3–4% isoflurane at 1.0 L/min and immobilized in a stereotaxic surgery frame with ear bars (David Kopf Instruments); lubricant ophthalmic ointment was applied to prevent eye drying.…”

Section: Star Methodsmentioning

confidence: 99%

“…Brain slice preparation: Slices were prepared as previously described (Lu et al, 2019;Ma et al, 2018;Ma et al, 2021). Mice were anesthetized with isoflurane and subsequently decapitated.…”

Section: Electrophysiological Recordings Of Brain Slicesmentioning

confidence: 99%

“…Mice were anesthetized with isoflurane and subsequently decapitated. Electrophysiological recordings: Recordings were performed as previously described (Cheng et al, 2018;Huang et al, 2017;Lu et al, 2019;Ma et al, 2018;Ma et al, 2021). The brain slice was positioned in a recording chamber attached to the fixed stage of an upright microscope (Olympus) and perfused with oxygenated external solution at 32°C, with a flow rate of 2 mL/min.…”

Section: Electrophysiological Recordings Of Brain Slicesmentioning

confidence: 99%

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Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

Wang

Xie

Zhuang

et al. 2022

Preprint

Self Cite

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Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of mu-opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse.

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Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

Cited by 30 publications

References 81 publications

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors

Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect

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