Compulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex

Timme, Nicholas M.; Ma, Baofeng; Linsenbardt, David N.; Cornwell, Ethan; Galbari, Taylor; Lapish, Christopher C.

doi:10.1038/s41467-022-31731-4

Cited by 21 publications

(17 citation statements)

References 63 publications

(85 reference statements)

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“…At the level of individual nodes, REL exhibited decreased centrality of several widely distributed regions implicated in multiple brain systems, many of which correlated with shorter abstinence duration after detoxification. In line with our predictions, we found decreased nodal strength centrality in prefrontal brain regions, including the left dorsomedial prefrontal cortex (dmPFC, BA 9) and ventrolateral prefrontal cortex (vlPFC, BA 44), two critical neural substrates involved in a variety of higher‐order executive functions, including inhibitory control, self‐regulation and goal‐directed behavioural control 51,52 . Blunted vlPFC activation 53 as well as decreased dmPFC connectivity across different cognitive tasks 13,54 have been linked to relapse in previous work, substantiating the link between decreased regulatory control and relapse in AD.…”

Section: Discussionsupporting

confidence: 89%

“…In line with our predictions, we found decreased nodal strength centrality in prefrontal brain regions, including the left dorsomedial prefrontal cortex (dmPFC, BA 9) and ventrolateral prefrontal cortex (vlPFC, BA 44), two critical neural substrates involved in a variety of higher-order executive functions, including inhibitory control, self-regulation and goal-directed behavioural control. 51,52 Blunted vlPFC activation 53 as well as decreased dmPFC connectivity across different cognitive tasks 13,54 have been linked to relapse in previous work, substantiating the link between decreased regulatory control T A B L E 3 Edges exhibiting significantly altered functional connectivity in relapsing patients with AD compared with controls (REL < CON) and in relapsing patients with AD compared with abstaining patients with AD (REL > ABS) as identified by NBS. and relapse in AD.…”

Section: Discussionsupporting

confidence: 59%

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Aberrant functional brain network organization is associated with relapse during 1‐year follow‐up in alcohol‐dependent patients

Böhmer,

Reinhardt,

Garbusow

et al. 2023

Addiction Biology

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Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long‐lasting abstinence. In the present study, we analysed resting‐state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified patients with AD (n = 93) who were followed up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL, n = 59), future abstainers (ABS, n = 28) and age‐ and gender‐matched controls (CON, n = 83). Our results suggest increased whole‐brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared with CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared with CON, encompassing regions associated with higher‐order executive functions, sensory and reward processing. Among patients with AD, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow‐up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 59%

Aberrant functional brain network organization is associated with relapse during 1‐year follow‐up in alcohol‐dependent patients

Böhmer,

Reinhardt,

Garbusow

et al. 2023

Addiction Biology

View full text Add to dashboard Cite

show abstract

“…The relationship between aversion-resistant drinking and so-called compulsive drinking has been a source of discussion in the AUD research field, with some authors challenging the view that aversion-resistant drinking can be equated with compulsive drinking in pre-clinical animal models in particular [3]. Prior work (including ours [18, 19]) has equated compulsive drinking with aversion-resistant drinking. Aversion-resistant drinking can be directly assessed behaviorally by investigating the degree to which an animal will continue to consume alcohol despite negative consequences such as quinine or footshock.…”

Section: Discussionmentioning

confidence: 99%

Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice

Timme,

Ardinger,

Weir

et al. 2023

Preprint

Self Cite

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A key facet of alcohol use disorder is continuing to drink alcohol despite negative consequences (so called “aversion-resistant drinking”). In this study, we sought to assess the degree to which head-fixed mice exhibit aversion-resistant drinking and to leverage behavioral analysis techniques available in head-fixture to relate non-consummatory behaviors to aversion-resistant drinking. We assessed aversion-resistant drinking in head-fixed female and male C57BL/6J mice. We adulterated 20% (v/v) alcohol with varying concentrations of the bitter tastant quinine to measure the degree to which animals would continue to drink despite this aversive stimulus. We recorded high-resolution video of the mice during head-fixed drinking, tracked body parts with machine vision tools, and analyzed body movements in relation to consumption. Female and male head-fixed mice exhibited heterogenous levels of aversion-resistant drinking. Additionally, non-consummatory behaviors, such as paw movement and snout movement, were related to the intensity of aversion-resistant drinking. These studies demonstrate that head-fixed mice exhibit aversion-resistant drinking and that non-consummatory behaviors can be used to assess perceived aversiveness in this paradigm. Furthermore, these studies lay the groundwork for future experiments that will utilize advanced electrophysiological techniques to record from large populations of neurons during aversion-resistant drinking to understand the neurocomputational processes that drive this clinically relevant behavior.

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“…Some of these include where alcohol cue- [ 107 , 108 ] and negative affect-induced [ 109 ] AIC activation predict real-world drinking [ 110 ], AIC activation to alcohol images predicts later transition to heavy drinking [ 111 ], and therapies that reduce drinking also decrease AIC activity and/or connectivity (e.g., [ 112 , 113 ]). Importantly for the current work, rodent studies have shown that specific AIC-related circuits (including AIC projections to NAcb) and dmPFC are important for the expression of compulsion-like drinking (with little role in alcohol-only intake) [ 53 , 114 , 115 , 116 ]. Quinine-resistance is also associated with dysregulation in dmPFC glutamate systems [ 38 , 53 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats

et al. 2022

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With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 hr free-choice paradigm). Further, after 4–5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.

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Compulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex

Cited by 21 publications

References 63 publications

Aberrant functional brain network organization is associated with relapse during 1‐year follow‐up in alcohol‐dependent patients

Aberrant functional brain network organization is associated with relapse during 1‐year follow‐up in alcohol‐dependent patients

Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice

Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats

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