Corticostriatal Activity Driving Compulsive Reward Seeking

Harada, Masaya; Pascoli, Vincent; Hiver, Agnès; Flakowski, Jérôme; Lüscher, Christian

doi:10.1016/j.biopsych.2021.08.018

Cited by 25 publications

(20 citation statements)

References 172 publications

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“…It is notably suggested that the transition to compulsion is controlled, in part, by cortico-striatal projections [3,18,22]. This hypothesis is supported by studies demonstrating hypoactivity of the mPFC [67,72] and hyperactivity of OFC projections to the dorsal striatum [76][77][78], leading to an imbalance between these two structures [79] in mice with compulsive-like behaviors. Taken with the present findings, the emergence of the hypodopaminergic state of the nigrostriatal pathway and the imbalance between mPFC and OFC may act in synergy to drive compulsive drug use.…”

Section: Discussionmentioning

confidence: 92%

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

et al. 2022

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The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes, dopamine (DA), is suspected to play an important role in this pathology, but its exact role remains to be determined. Here, we found that rats expressing compulsive-like alcohol use, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that chemogenetic-induced selective hypodopaminergia of this pathway resulted in compulsive-like alcohol self-administration in otherwise resilient rats, accompanied by the emergence of alcohol withdrawal-like motivational impairments (i.e., impaired motivation for a natural reinforcer). Finally, the use of the monoamine stabilizer OSU6162, previously reported to correct hypodopaminergic states, transiently decreased compulsive-like alcohol self-administration in vulnerable rats. These results suggest a potential critical role of tonic nigrostriatal hypodopaminergic states in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

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Section: Discussionmentioning

confidence: 92%

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

et al. 2022

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“…It is well established that many behavioral functions are specifically regulated by distinct subregions of the PFC. For example, conditioned fear response or trauma (as evidenced in PTSD) is encoded in the ILA 36 , while cue or context-associated reward memory is encoded in PL 37,38 , and compulsive behavior (often associated with drug addiction) is associated with ORBm 39 . Thus, revealing the differential neuron subtype distribution in the different PFC subregions may help link the PFC subregion-specific functions to the various differentially distributed neuron subtypes.…”

Section: Resultsmentioning

confidence: 99%

Understanding prefrontal cortex functions by decoding its molecular, cellular and circuit organization

Bhattacherjee

Zhang

Watson

et al. 2022

Preprint

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The prefrontal cortex (PFC) is functionally one of the most complex regions of mammalian brain. Unlike other cortical areas that process single sensory modalities (like vision, touch, smell etc.), the PFC integrates information across brain regions to regulate diverse functions ranging from cognition, emotion, executive action to even pain sensitivity. However, it is unclear how such diverse functions are organized at the cellular and circuit levels within the anatomical modules of the PFC. Here we employed spatially resolved single cell profiling to decode PFC's organizational heterogeneity. The results revealed that PFC has very distinct cell type composition relative to all neighboring cortical areas. Interestingly, PFC adopts specialized transcriptional features, distinct from all neighbors, with differentially express genes regulating neuronal excitability. Additionally, projections of PFC neuron subclusters to major subcortical targets are determined in a target-intrinsic fashion. These cellular and molecular features further segregated within subregions of PFC, alluding to the subregion-specific specialization of several PFC functions. Finally, to exemplify the utility of these unique cellular, molecular and projection properties, we identified distinct cell types and circuits in PFC engaging in pathogenesis of chronic pain. Collectively, we not only present a comprehensive organizational map of the PFC, critical for supporting its diverse functions, but also reveal the cluster and circuit identity of a pathway underlying chronic pain pathogenesis, which paves ways for mechanistic understanding and potential interventions.

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“…2 ). Moreover, the adjacent orbitofrontal cortex, which is involved in compulsive behaviors ( 58 ), was not affected by viral infusions targeting the AIC ( SI Appendix , Fig. 3 ).…”

Section: Discussionmentioning

confidence: 99%

Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in adolescent rats

Jadhav

Bernheim

Aeschlimann

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Clinical evidence suggests that adolescents engage in dangerous activities despite understanding the risks involved, questioning the theory of decreased top-down control of the immature prefrontal cortex promoting adolescent disinhibited behaviors. In the present study, we report that adolescent rats show a much higher degree of inflexible behavior when making decisions under conflict compared to adults. Unexpectedly, we identified a lower excitability of layer 5 pyramidal neurons in the anterior insular cortex (AIC) of adolescent rats and smaller synaptic glutamatergic inputs to these cells but no difference in layer 5 prefrontal cortex pyramidal neurons. Chemogenetic activation of AIC neurons reduced persistent reward-seeking despite punishment, suggesting that the delayed maturation of the insula may promote inflexible reward-related behaviors in adolescent rats.

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Corticostriatal Activity Driving Compulsive Reward Seeking

Cited by 25 publications

References 172 publications

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

Understanding prefrontal cortex functions by decoding its molecular, cellular and circuit organization

Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in adolescent rats

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