Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol

Jaramillo, Anel A.; Voorhies, Kalynn Van; Randall, Patrick A.; Besheer, Joyce

doi:10.1016/j.bbr.2018.04.007

Cited by 60 publications

(39 citation statements)

References 50 publications

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“…The insula is an important neural substrate for reward and addiction (Droutman et al., ; Naqvi et al., ) and is critical for mediating cue‐induced craving that can drive drug use (Droutman et al., ; Naqvi et al., ). This is supported by rodent models of alcohol addiction, which have shown that disrupting excitatory insular‐striatal circuitry decreases alcohol self‐administration and increases sensitivity to alcohol (Jaramillo et al., ,). Decrements in FA in the vicinity of the insula in our young adult AUD sample may lead to impaired ability to detect changes in internal states such as alcohol intoxication (Berk et al., ; Migliorini et al., ).…”

Section: Discussionmentioning

confidence: 87%

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder

Chumin

Grecco

Džemidžić

et al. 2019

Alcoholism Clin & Exp Res

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Background: Magnetic resonance imaging (MRI) studies have shown differences in volume and structure in the brains of individuals with alcohol use disorder (AUD). Most research has focused on neuropathological effects of alcohol that appear after years of chronic alcohol misuse. However, few studies have investigated white matter (WM) microstructure and diffusion MRI-based (DWI) connectivity during early stages of AUD. Therefore, the goal of this work was to investigate WM integrity and structural connectivity in emerging adulthood AUD subjects using both conventional DWI metrics and a novel connectomics approach.Methods: Twenty-two AUD and 18 controls (CON) underwent anatomic and diffusion MRI. Outcome measures were scalar diffusion metrics and structural network connectomes. Tract-Based Spatial Statistics was used to investigate group differences in diffusion measures. Structural connectomes were used as input into a community structure procedure to obtain a coclassification index matrix (an indicator of community association strength) for each subject. Differences in coclassification and structural connectivity (indexed by streamline density) were assessed via the Network Based Statistics Toolbox.Results: AUD had higher fractional anisotropy (FA) values throughout the major WM tracts, but also had lower FA values in WM tracts in the cerebellum and right insula (p TFCE < 0.05). Mean diffusivity was generally lower in the AUD group (p TFCE < 0.05). AUD had lower coclassification of nodes between ventral attention and default mode networks and higher coclassification between nodes of visual, default mode, and somatomotor networks. Additionally, AUD had higher fiber density between an adjacent pair of nodes within the default mode network.Conclusions: Our results indicate that emerging adulthood AUD subjects may have differential patterns of FA and distinct differences in structural connectomes compared with CON. These data suggest that such alterations in microstructure and structural connectivity may uniquely characterize early stages of AUD and/or a predisposition for development of AUD.

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Section: Discussionmentioning

confidence: 87%

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder

Chumin

Grecco

Džemidžić

et al. 2019

Alcoholism Clin & Exp Res

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“…However, despite its close location, AI seems to perform qualitatively different functions: AI inhibition increases drinking and self-administration, whereas OFC inhibition decreases reinstatement, but not drinking or self-administration. It is also worth noting that specific circuits within these regions may differentially contribute to seeking and use of alcohol and other reinforcers as, for example, inactivation of AI projections to nucleus accumbens actually decreased alcohol self-administration (Jaramillo et al, 2018a;Jaramillo et al, 2018b;Seif et al, 2013). In general, addressing both regional and circuit-selective differences in contributions to behavior is a key strategy going forward.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue‐induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats

Hernandez

Binette

Rahman

et al. 2020

Alcoholism Clin & Exp Res

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Background The orbitofrontal cortex (OFC) encodes internal representations of outcomes and subjective value to facilitate flexible reward seeking. OFC activation is associated with drug seeking in both human subjects and animal models. OFC plays a role in alcohol use, but studies in animal models have produced conflicting results with some showing decreased seeking after OFC inactivation but others showing increased seeking or no changes. In part, this may be due to the different measures of alcohol seeking used (e.g., homecage drinking vs. operant seeking). Methods We characterized the impact of transient inactivation of OFC (primarily lateral and, to a lesser extent, ventral subregions) using inhibitory hM4Di designer receptors exclusively activated by designer drugs (DREADDs). OFC neurons were transiently inhibited during 10% and 20% alcohol (ethanol, EtOH) and sucrose homecage consumption, fixed ratio (FR1) operant self‐administration, and cue‐induced reinstatement of either 10% EtOH or sucrose in male and female rats. Results OFC inactivation did not affect sucrose or EtOH consumption in the homecage, nor did it influence seeking or consumption under FR1 operant conditions. In contrast, OFC inactivation suppressed cued‐induced reinstatement for both EtOH and sucrose in both male and female rats. Conclusions Our results are aligned with previous work indicating a selective suppressive effect of OFC inactivation on reinstatement for alcohol and other drugs of abuse. They extend these findings to demonstrate no effect on homecage consumption or FR1 seeking as well as showing an impact of sucrose reinstatement. These data indicate that OFC plays a uniquely important role when reward seeking is driven by associations between external stimuli and internal representations of reward value, both for natural and drug rewards. They further implicate the OFC as a key structure driving relapse‐associated seeking and potentially contributing to alcohol use disorder and other diseases of compulsive reward seeking.

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“…Similarly, chemogenetic silencing of insula projections to the nucleus accumbens decreased alcohol self-administration and potentiated the subjective, or interoceptive, effects of alcohol in rats (10)(11)(12). Analogous behavioral studies in humans showed that heavy drinkers attempted to earn more alcohol drinks than light drinkers under threat of shock and exhibited greater connectivity between the insula and nucleus accumbens, a brain region involved in motivation and reward, when viewing shock-predictive alcohol cues (3).…”

Section: Introductionmentioning

confidence: 98%

Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

Chen

Lasek

2018

Preprint

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One of the most pernicious characteristics of alcohol use disorder is the compulsion to drink despite negative consequences. The insular cortex (insula) controls decision-making under conditions of risk or conflict and regulates maladaptive behaviors in the context of addiction.Cortical activity is tightly controlled by fast-spiking inhibitory interneurons that are often enclosed by specialized extracellular matrix structures known as perineuronal nets, which regulate neuronal excitability and plasticity. Using a mouse model of compulsive drinking in which alcohol was adulterated with the bitter tastant quinine, we demonstrate that disrupting perineuronal nets in the insula rendered mice more sensitive to quinine-adulterated alcohol.Activation of the insula, as measured by c-fos expression, occurred during aversion-resistant drinking and was further enhanced by elimination of perineuronal nets. These results provide fundamental insight into neuroanatomical and cellular mechanisms that control compulsive drinking.

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Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol

Cited by 60 publications

References 50 publications

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder

Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue‐induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats

Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

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