Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry

Miquel, Marta; Vázquez-Sanromán, Dolores; Carbó-Gas, Maria; Gil‐Miravet, Isis; Sanchis‐Segura, Carles; Carulli, Daniela; Manzo, Jorge; Coria-Ávila, Genaro A.

doi:10.1016/j.neubiorev.2015.11.005

Cited by 94 publications

(76 citation statements)

References 156 publications

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“…Addiction literature has not paid much attention to the cerebellum until recently (Miquel et al, 2009(Miquel et al, , 2016Moulton et al, 2014).The cerebellum is a hindbrain structure that contains more neurons than the rest of the brain (Herculano-Houzel, 2009). This structure presents some organizational similarities with the cerebral cortex (Herrup, 2000).…”

Section: Introductionmentioning

confidence: 99%

The cerebellum in drug craving

Moreno-Rius

Miquel

2017

Drug and Alcohol Dependence

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Craving has been considered one of the core features of addiction. It can be defined as the urge or conscious desire to use a drug elicited by the drug itself, drug-associated cues or stressors. Craving plays a major role in relapse, even after prolonged periods of abstinence, as well as in the maintenance of drug seeking in non-abstinent addicts. The circuitry of craving includes medial parts of the prefrontal cortex, ventral striatal zones, ventral tegmental area, ventral pallidum, and limbic regions. Interestingly, the cerebellum shows reciprocal loops with many of these areas. The cerebellum has been linked traditionally to motor functions but increasing evidence indicates that this part of the brain is also involved in functions related to cognition, prediction, learning, and memory. Moreover, the functional neuroimaging studies that have addressed the study of craving in humans repeatedly demonstrate cerebellar activation when craving is elicited by the presentation of drug-related cues. However, the role of cerebellar activity in these craving episodes remains unknown. Therefore, the main goal of this review is to provide a brief update on craving studies and the traditional neural basis of this phenomenon, and then discuss and propose a hypothesis for the function of the cerebellum in craving episodes.

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Section: Introductionmentioning

confidence: 99%

The cerebellum in drug craving

Moreno-Rius

Miquel

2017

Drug and Alcohol Dependence

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“…Deficits in this fundamental cognitive ability are proposed to underlie the maladaptive behaviors which characterize a wide range of neuropsychiatric disorders including autism (Hughes et al, 1994, Hill, 2004), schizophrenia (Pantelis et al, 1999, Floresco et al, 2009, Leeson et al, 2009), and drug addiction (Woicik et al, 2011, McCracken and Grace, 2013, Moreno-Lopez et al, 2015, Verdejo-Garcia et al, 2015, Miquel et al, 2016). Although cognitive flexibility is often discussed as a unitary construct, it can be subdivided into at least two dissociable cognitive processes.…”

Section: Introductionmentioning

confidence: 99%

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice

et al. 2017

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Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0%–100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher- and lower-order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108, 390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with ≥ 95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher-order cognitive flexibility, lower-order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher- and lower-order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.

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confidence: 99%

“…Sin embargo, muy pocos estudios se han centrado en áreas cerebrales más allá de los circuitos corticoestriatal-límbicos. A pesar de la creciente evidencia que confirma la participación del cerebelo en las alteraciones inducidas por drogas, esta estructura ha sido tradicionalmente descartada en el campo de la adicción Miquel et al, 2016).…”

Section: Implicación De Cerebelo En Las Memorias Inducidas Por La Cocunclassified

“…However, very few studies have focused on brain areas beyond the corticostriatal-limbic circuitry. Despite the growing evidence confirming the involvement of the cerebellum in drug-induced alterations, this structure has been traditionally disregarded in the addiction field Miquel et al, 2016).The general aim of the present research is to address wether the cerebellum is part of the neuronal systems that sustains the plasticity mechanisms underlying drug-induced conditioned memories. We have focused our research in an attempt to clarify if the cerebellum is involved in the acquisition and storage of drug memories.…”

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Involvement of the cerebellum in cocaine-induced memory

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PREFACEBecause of its role in drug-seeking, consumption and addictive behavior, there is a growing interest in identifying the neural circuits and molecular mechanisms underlying the formation, maintenance and retrieval of drug-induced memories. However, very few studies have focused on brain areas beyond the corticostriatal-limbic circuitry. Despite the growing evidence confirming the involvement of the cerebellum in drug-induced alterations, this structure has been traditionally disregarded in the addiction field Miquel et al, 2016).The general aim of the present research is to address wether the cerebellum is part of the neuronal systems that sustains the plasticity mechanisms underlying drug-induced conditioned memories. We have focused our research in an attempt to clarify if the cerebellum is involved in the acquisition and storage of drug memories. Although previous scattered reports described the involvement of the cerebellum in drug-related memories, this is the first attempt to address a detailed functional analysis about the issue.The present doctoral thesis contains three different chapters. The first two include two investigations that have been already published (Carbo-gas et al., 2014ab), and the third is one currently under revision. In the first chapter, Involving the cerebellum in cocaineinduced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine, we explored the pattern of neuronal activation as revealed by cFos immunoreactivity of mice trained to develop conditioned preference for an olfactory stimulus paired with cocaine. In the second one, entitled Cerebellar hallmarks of conditioned preference for cocaine, we used the same behavioral task of the first study in order to further extend the description of cFos expression patterns in cerebellar circuitry, including now the major inputs and one of the output nuclei of the cerebellum. 9In the last chapter, Cerebellar perineuronal nets in cocaine-induced Pavlovian memory:site does matter, we accomplished a broad analysis of perineuronal nets (PNNs) expression of cerebellar vermis. First, we analysed an outbred mouse strain trained to acquire preference for olfactory stimuli associated with cocaine. Second, α6Cre-Cacna1a mice were used to test if a reduction in the glutamate release of parallel fibres to Purkinje dendrites would alter the acquisition of cocainepreference conditioning and the expression of PNNs in the cerebellum.After the presentation of the chapters, there is a section where summarised findings, strengths and pitfalls as well as future directions are provided. References can be also found at the end of the present document.Finally, we conclude this thesis with an appendix. This document is formed by research not finished yet, but that may be of great relevance to understand the role of the cerebellum in addictive disorders. In that appendix, we explored the effect of a focal lesion in the dorsal cerebellar cortex (Lobule VIII) on the acquisition of food selfadministration. This researc...

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Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry

Cited by 94 publications

References 156 publications

The cerebellum in drug craving

The cerebellum in drug craving

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice

Involvement of the cerebellum in cocaine-induced memory

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