Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues

Laque, Amanda; Ness, Genna L De; Wagner, Grant E.; Nedelescu, Hermina; Carroll, Ayla; Watry, Debbie D.; Kerr, Tony M.; Koya, Eisuke; Hope, Bruce T.; Weiss, Friedbert; Elmer, Gregory I.; Suto, Nobuyoshi

doi:10.1038/s41467-019-11799-1

Cited by 28 publications

(13 citation statements)

References 78 publications

(142 reference statements)

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“…This suggests that the IL cortex can also function as a driver of heroin seeking, consistent with other reports 5 – 7 . Nonetheless, our findings in this heroin model are consistent with observations that IL neuronal ensembles exert inhibitory control over alcohol seeking 41 , 42 . As specific IL outputs were not identified in the latter studies, these apparent discrepancies may relate to different IL outputs being engaged under different conditions.…”

Section: Discussionsupporting

confidence: 91%

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model

et al. 2021

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Activity in numerous brain regions drives heroin seeking, but no circuits that limit heroin seeking have been identified. Furthermore, the neural circuits controlling opioid choice are unknown. In this study, we examined the role of the infralimbic cortex (IL) to nucleus accumbens shell (NAshell) pathway during heroin choice and relapse. This model yielded subpopulations of heroin versus food preferring rats during choice, and choice was unrelated to subsequent relapse rates to heroin versus food cues, suggesting that choice and relapse are distinct behavioral constructs. Supporting this, inactivation of the IL with muscimol produced differential effects on opioid choice versus relapse. A pathway-specific chemogenetic approach revealed, however, that the IL-NAshell pathway acts as a common limiter of opioid choice and relapse. Furthermore, dendritic spines in IL-NAshell neurons encode distinct aspects of heroin versus food reinforcement. Thus, opioid choice and relapse share a common addiction-limiting circuit in the IL-NAshell pathway.

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Section: Discussionsupporting

confidence: 91%

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model

et al. 2021

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“…The present results also mirror findings showing distinct roles of neuronal ensembles in mediating diverse behaviors. We and others found that different neuronal ensembles in the vmPFC mediate self‐administration versus extinction of food and cocaine seeking 23,26,27 . In a separate study, we found that neuronal ensembles in dorsomedial striatum are critical for methamphetamine seeking but not food seeking 19 .…”

Section: Discussionsupporting

confidence: 51%

“…Until relatively recently, the tools required to test the role of neuronal ensembles in drug‐seeking have not been available. Recent reports indicate that neuronal ensembles are critical for conditioned responses and relapse to several drugs, including cocaine, heroin, alcohol, nicotine, and methamphetamine 18–26 . In a previous studies, we found that neuronal ensembles within ventral mPFC are critical for both cocaine and food seeking 24,27 .…”

Section: Introductionmentioning

confidence: 46%

Fos‐expressing neuronal ensemble in rat ventromedial prefrontal cortex encodes cocaine seeking but not food seeking in rats

et al. 2020

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Neuronal ensembles in ventromedial prefrontal cortex (vmPFC) play a role in both cocaine and palatable food seeking. However, it is unknown whether similar or different vmPFC neuronal ensembles mediate food and cocaine seeking. Here, we used the Daun02 inactivation procedure to assess whether the neuronal ensembles mediating food and cocaine seeking can be functionally distinguished. We trained male and female Fos‐LacZ rats to self‐administer palatable food pellets and cocaine on alternating days for 18 days. We then exposed the rats to a brief nonreinforced food‐ or cocaine‐seeking test to induce Fos and β‐gal in neuronal ensembles associated with food or cocaine seeking, respectively and infused Daun02 into vmPFC to ablate the β‐gal‐expressing ensembles. Two days later, we tested the rats for food or cocaine seeking under extinction conditions. Although inactivation of the food‐seeking ensemble did not influence food or cocaine seeking, inactivation of the cocaine‐seeking ensemble reduced cocaine seeking but not food seeking. Results indicate that the neuronal ensemble activated by cocaine seeking in vmPFC is functionally separate from the ensemble activated by food seeking.

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“…Our findings here suggest that simply reducing activity in the OFC shallow layers is not sufficient to reduce sucrose seeking and highlight how Fos levels are not necessarily influenced by changes in behavioral output on test day. Mounting evidence from our group and others demonstrate that distinct, sparse sets of activated neurons or “neuronal ensembles” in the prefrontal cortex mediate cue‐evoked reward seeking for food and drug rewards (Laque et al., 2019; Suto et al., 2016; Warren et al., 2016, 2019; Whitaker et al., 2017). These findings raise the possibility that while long exposure to EE may reduce activity in the OFC more generally, it may not necessarily do so in neuronal ensembles which subserves conditioned approach responses.…”

Section: Discussionmentioning

confidence: 97%

Acute, but not longer‐term, exposure to environmental enrichment attenuates Pavlovian cue‐evoked conditioned approach and Fos expression in the prefrontal cortex in mice

Margetts-Smith

Macnaghten

Brebner

et al. 2021

Eur J of Neuroscience

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Exposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose‐associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker “Fos.” Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non‐contingent or “forced” exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward‐seeking across species.

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Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues

Cited by 28 publications

References 78 publications

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model

A common limiter circuit for opioid choice and relapse identified in a rodent addiction model

Fos‐expressing neuronal ensemble in rat ventromedial prefrontal cortex encodes cocaine seeking but not food seeking in rats

Acute, but not longer‐term, exposure to environmental enrichment attenuates Pavlovian cue‐evoked conditioned approach and Fos expression in the prefrontal cortex in mice

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