Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

Chen, H.; Lasek, Amy W.

doi:10.1101/504571

Cited by 9 publications

(16 citation statements)

References 40 publications

(50 reference statements)

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“…for norepinephrine [104] and orexin [25, 105] which can be important regulators of alcohol drinking. It is also interesting that human CLAD studies implicate insula circuitry in both women and men [48, 49], agreeing with insula importance for CLAD in rodents [50,52,53,59], and we [59] and others [106] also find insula importance for promoting AOnly, consistent with the importance of the insula-related salience network in motivated behavior more generally [54,107–110]. Nonetheless, there are a wide range of brain regions and signaling pathways that contribute to alcohol intake.…”

Section: Discussionmentioning

confidence: 82%

Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats

Sergio

Darevsky

Soares

et al. 2022

Preprint

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Problem alcohol drinking is a substantial social and economic burden. Studies show that the misuse of alcohol is increasing in women, and that women can face higher consequences from alcohol exposure, but females have historically been understudied. Thus, there is considerable interest in understanding potential sex-different and -similar cognitive/emotional strategies, and underlying mechanisms, for alcohol responding, which would inform more effective, personalized treatments. Here, we used large cohorts of adult Wistar rats (28 females, 30 males) to provide robust assessment of potential sex differences in responding for alcohol-only and under compulsion-like drinking with moderate or higher challenge (since intake despite negative consequences can be a major obstacle to human treatment). Females had similar total licking but higher intake for all drinking conditions. However, females had significantly longer bouts under alcohol-only and moderate challenge, but not higher challenge. Further, under higher challenge, females retained several aspects of responding not seen in males, including more efficient lick volume and earlier onset of longer bouts. In addition, females overall licked slightly faster, but licking speed averaged within-bout showed no sex differences, and female intake level under alcohol-only and moderate challenge was unlinked from licking speed (unlike males, where slower licking predicted lower intake). We interpret these differences as greater persistence-like responding but not vigor per se in females, and with different strategies under lower versus higher challenge. Finally, drinking levels did not differ across the estrous cycle, although ovariectomy reduced alcohol-only and moderate-challenge intake. Together, while many aspects were sex-similar, suggesting some common drinking mechanisms, there was clear evidence for (perhaps more nuanced) sex-different alcohol strategies, which might make an outsized contribution to excessive drinking since women can have more drinking problems. Thus, our studies provide important context for future work examining sex differences in pathological drinking mechanisms.

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Section: Discussionmentioning

confidence: 82%

Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats

Sergio

Darevsky

Soares

et al. 2022

Preprint

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“…We found that aINS-NAcb core in rat is critical for compulsion-like responding for alcohol, using quinine or footshock as the aversive consequence [33] (see also aINS-NAcb for compulsion-like responding for sugar [80]), and that aINS-Locus Coeruleus area is also critical for rat CLAD [34], while neither pathway is necessary to regulate AOD. Further, modulating putative aINS GABA signaling significantly decreases CLAD but not AOD in rat [34] and mouse [35]. In concurrence, aINS circuit activity in heavy drinking humans is related both to the level of punishment-resistant responding for alcohol and subjective compulsivity for alcohol [38].…”

Section: Discussionmentioning

confidence: 99%

“…The aINS, a key regulator of the Salience Network, mediates rapid identification and responding to important situations [28–32], and human aINS is linked to many aspects of alcohol drinking [28] (see Discussion). Importantly, we have previously shown that specific aINS projections, aINS-Nucleus Accumbens Core (NAcb) [33] and aINS-Locus Coeruleus area [34], are essential for promoting CLAD in male rodents, with little impact on alcohol-only drinking (AOD), suggesting particular aINS importance for CLAD (see also [35,36]). In interesting concurrence, compulsion-like responding for alcohol in human AUD involves activation of a similar aINS-striatal circuits [37,38], and risk- and aversion-related responding more generally relates to aINS activity (reviewed in [28]).…”

Section: Introductionmentioning

confidence: 99%

“…Together, these validate the use of the technically simple quinine-resistance for studying CLAD, and quinine-resistance is also easier to test in a graded manner to assess responding under different levels of challenge. In addition, when seeking to predict what aINS activity patterns might contribute to driving alcohol intake, we note that CLAD shows greater aINS cFos in mice than AOD [35], suggesting importance of higher aINS firing for CLAD (see also [36]). Further, aINS has been widely related to initiation of responding, consistent with Salience Network (above), and also linked to sustaining salience-driven behavior, with maintained aINS activity reflecting the main task goal and/or overall reward value of a situation [44–47].…”

Section: Introductionmentioning

confidence: 99%

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Anterior insular cortex firing links initial and sustained encoding during aversion-resistant alcohol consumption

Starski

Morningstar

Katner

et al. 2022

Preprint

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Compulsive-like alcohol drinking (CLAD), where intake persists despite adverse consequences, is often a core facet of alcohol use disorder. Recent work sheds light on underlying mechanisms, but much remains unknown about CLAD etiology. Previously, we showed that projections from anterior insula (aINS), a central mediator of emotion, motivation, and interoception, promote CLAD in rodents, and heavy human drinkers exhibit similar insula-circuit recruitment under compulsion-like conditions. However, global aINS inhibition also reduces alcohol-only drinking (AOD), and one major obstacle is the lack of information on aINS firing patterns that could promote different aspects of intake. Here, we recorded single-unit activity in right aINS from 15 rats during AOD or CLAD (10mg/L or 60mg/L quinine in alcohol). Neurons with a sustained-increase or sustained-decrease phenotype (SIP, SDP) showed no firing differences across drinking conditions. In contrast, aINS neurons with a phenotype of strong firing increase at initiation of responding (IRP) showed significantly greater activity across the rest of licking during CLAD versus AOD, concurring with our previous behavioral findings suggesting quick evaluation and response strategy adjustment under CLAD. There were also no condition-related differences in firing-phenotype abundance. Further, total responding only correlated with abundance of SDP cells, but SDP firing returned to baseline during pauses in licking, while IRP and SIP sustained responding through pauses in licking. Thus, only aINS cells with a particular strong firing at licking onset showd greater sustained responding under compulsion-like conditions, while other cells likely promoted drinking more generally, providing critical new information about how aINS activity could promote alcohol consumption under different drinking conditions.

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“…The insular cortex is a brain region that plays a critical role in the integration of internal and external states (Gehrlach et al, 2020). Human imaging studies have implicated the insula as a region altered in AUD (Claus et al, 2011;Ihssen et al, 2011;Grodin et al, 2017), with findings supported by multiple rodent studies (Seif et al, 2013;Jaramillo et al, 2018a;Centanni et al, 2019;Chen and Lasek, 2020).…”

Section: Introductionmentioning

confidence: 99%

Insula dynorphin and kappa opioid receptor systems regulate alcohol drinking in a sex-specific manner in mice

Pina

Pati

Neira

et al. 2021

Preprint

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Alcohol use disorder is complex and multi-faceted, involving the engagement of multiple signaling systems across numerous brain regions to drive pathological behavior. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit elements on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR systems in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact their sucrose intake. In male mice, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA only. Alcohol consumption as not affected by insula KOR knockout. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest that there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR circuit elements.

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Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

Cited by 9 publications

References 40 publications

Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats

Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats

Anterior insular cortex firing links initial and sustained encoding during aversion-resistant alcohol consumption

Insula dynorphin and kappa opioid receptor systems regulate alcohol drinking in a sex-specific manner in mice

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