Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Gangal, Himanshu; Xie, Xueyi; Cheng, Yidong; Lu, Jiayi; Zhuang, Xiaowen; Essoh, Amanda; Huang, Yufei; Smith, Liane; Smith, Rachel J.; Wang, Jun

doi:10.1101/2022.10.27.514125

Cited by 5 publications

(10 citation statements)

References 71 publications

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“…We hypothesize that it is triggered by GABA release from D1-MSNs during reward-acquiring actions, with supporting evidence from our observation that D1-MSN optogenetic activation can induce a pauserebound in CIN firing [39]. The subsequent ACh increase may have dual origins: pauserebound firing of CINs [25,39] and thalamic CIN activation [27,30]. The following ACh dip might arise from another CIN firing pause, often seen in post-thalamic activation [27,65].…”

Section: Discussionsupporting

confidence: 79%

“…3D) for pause disruption. We then used a reversal learning paradigm [37, 39] to uncover behavioral impacts. In this setup, animals initially associate a left lever with sucrose and a right lever with food pellets.…”

Section: Resultsmentioning

confidence: 99%

“…6), and our previous study showed a similar effect. When CINs were inhibited, rats pressed more levers only in the first 10-20 minutes of the first 40-minute extinction session [39]. These results imply that CINs predominantly modulate extinction rather than being required for it.…”

Section: Discussionmentioning

confidence: 99%

“…Operant conditioning was conducted on rats as previously described [37, 39]. Blinding was applied to behavioral experiments.…”

Section: Methodsmentioning

confidence: 99%

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Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Huang,

Chen,

et al. 2023

Preprint

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Striatal cholinergic interneurons (CINs) regulate behavioral flexibility, but their exact contribution to this process remains elusive. In this study, we report that extinction learning enhances acetylcholine (ACh) release. Mimicking this enhancement by optogenetically inducing CIN burst firing promotes extinction learning. CINs receive excitatory thalamic inputs, and we observed that extinction training augmented thalamic activity. Optogenetically stimulating these thalamic inputs caused CIN burst firing and enhanced ACh release, strengthening extinction learning. Notably, CIN burst firing is usually followed by a pause in firing. We found that disrupting this pause through continuous optogenetic stimulation reversibly impaired the updating of goal-directed behaviors. Furthermore, excessive alcohol consumption reduced thalamus-induced burst-pause firing in CINs and impaired the reversal of goal-directed learning. In summary, thalamic-driven CIN burst firing promotes extinction learning, while the pause is pivotal for reversing goal-directed behavior, a process impacted by excessive alcohol. These findings shed light on how CIN’s dynamic responses affect behavioral flexibility.HighlightsH1.Burstfiring of CINs promotes extinction learningH2. Thalamic-CINexcitationenhances extinction learningH3.Pauseof CIN is critical for the reversal of goal-directed learningH4. Chronic alcohol consumption reduces theburst-pauseofCINsand impairs the reversal of goal-directed learning.

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Operant conditioning was conducted on rats as previously described [37, 39]. Blinding was applied to behavioral experiments.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Huang,

Chen,

et al. 2023

Preprint

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“…Numerous studies have suggested that CINs play a crucial role in regulating the activity of MSNs and dopamine transmission in the NAcSh, which is a key brain region involved in alcohol consumption (Kolpakova et al., 2022). Conversely, alcohol and other addictive substances have been shown to interact with cholinergic neurons in different brain regions, including NAc, to cause impairment in behaviors, such as learning and cognition (Bariselli et al., 2023; Gangal et al., 2023; Ma et al., 2022; Smiley et al., 2021; Yorgason et al., 2022). However, the direct causal relationship between CINs and alcohol consumption remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study

Sharma,

Chischolm,

Parikh

et al. 2024

Alcohol, Clinical and Experimental Research

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BackgroundBinge drinking, characterized by heavy episodic alcohol consumption, poses significant health hazards and increases the likelihood of developing an alcohol use disorder (AUD). Given the growing prevalence of this behavior and its negative consequences, there is a need to explore novel therapeutic targets. Accumulating evidence suggests that cholinergic interneurons (CIN) within the shell region of the nucleus accumbens (NAcSh) play a critical role in reward and addiction. However, their specific involvement in binge alcohol administration remains unclear. We hypothesized that CIN in the NAcSh regulates binge alcohol consumption.MethodsTo test this hypothesis, we used male ChAT‐cre mice expressing Cre‐recombinase in cholinergic neurons. We performed chemogenetic manipulation using Designer Receptor Exclusively Activated by Designer Drugs (DREADD) to examine the activity, and genetic ablation of CIN in the NAcSh to examine the amount of alcohol consumed in mice exposed to binge alcohol consumption using the 4‐Days Drinking‐in‐Dark (DID) paradigm. The impact of CIN manipulations in the NAcSh on sucrose self‐administration was used to control for taste and caloric effects. Additionally, in a separate group of mice, c‐Fos immunofluorescence was employed to verify chemogenetic activation or inhibition. Histological and immunohistochemical techniques were used to verify microinfusion sites, DREADD expression in CINs, and genetic ablation.ResultsWe found that, while chemogenetic activation of CIN in the NAcSh caused a significant increase in alcohol consumption, chemogenetic inhibition or genetic ablation of CIN significantly reduced the amount of alcohol consumed without affecting sucrose self‐administration. The chemogenetic inhibition caused a significant reduction, whereas activation caused a significant increase, in the number of c‐Fos‐labeled CIN in the NAcSh.ConclusionsOur findings highlight the crucial involvement of CIN in the NAcSh in modulating binge alcohol consumption, suggesting that targeting these neurons could serve to modify alcohol‐related behaviors.

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Chronic Ethanol Exposure Produces Persistent Impairment in Cognitive Flexibility and Decision Signals in the Striatum

Cheng,

Magnard,

Langdon

et al. 2024

Preprint

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Lack of cognitive flexibility is a hallmark of substance use disorders and has been associated with drug-induced synaptic plasticity in the dorsomedial striatum (DMS). Yet the possible impact of altered plasticity on real-time striatal neural dynamics during decision-making is unclear. Here, we identified persistent impairments induced by chronic ethanol (EtOH) exposure on cognitive flexibility and striatal decision signals. We showed that after a substantial withdrawal period of EtOH vapor exposure, rats exhibited reduced adaptability and exploratory behavior during a dynamic decision-making task. Reinforcement learning models showed that repeated EtOH exposure enhanced learning from rewards over omissions, leading to increased relative value updates on the selected action. Notably, neural signals in the DMS related to the decision outcome were enhanced, while those related to choice and choice-outcome conjunction were reduced, in EtOH-treated rats compared to the controls. These findings highlight the profound impact of chronic EtOH exposure on adaptive decision-making, pinpointing specific changes in striatal representations of actions and outcomes as underlying mechanisms for cognitive deficits.

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Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Cited by 5 publications

References 71 publications

Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Dynamic Responses of Striatal Cholinergic Interneurons Control the Extinction and Updating of Goal-Directed Learning

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study

Chronic Ethanol Exposure Produces Persistent Impairment in Cognitive Flexibility and Decision Signals in the Striatum

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