The role of the cerebellum in drug‐cue associative memory: functional interactions with the medial prefrontal cortex

Gil‐Miravet, Isis; Guarque-Chabrera, Julian; Carbó-Gas, Maria; Olucha‐Bordonau, Francisco E.; Miquel, Marta

doi:10.1111/ejn.14187

Cited by 22 publications

(53 citation statements)

References 72 publications

(160 reference statements)

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“…Recent findings from our laboratory indicate that the cerebellum can control learning-related activity (Gil-Miravet et al, 2018) and plasticity in the infralimbic cortex (unpublished results). Neurotoxic lesion of the posterior cerebellar cortex performed before conditioning increased cFos expression and mechanisms for synaptic stabilization in the infralimbic cortex.…”

Section: Cerebellar Underpinnings Of Compulsivitymentioning

confidence: 62%

A Working Hypothesis for the Role of the Cerebellum in Impulsivity and Compulsivity

Miquel

Nicola

Gil‐Miravet

et al. 2019

Front. Behav. Neurosci.

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Growing evidence associates cerebellar abnormalities with several neuropsychiatric disorders in which compulsive symptomatology and impulsivity are part of the disease pattern. Symptomatology of autism, addiction, obsessive-compulsive (OCD), and attention deficit/hyperactivity (ADHD) disorders transcends the sphere of motor dysfunction and essentially entails integrative processes under control of prefrontal-thalamic-cerebellar loops. Patients with brain lesions affecting the cortico-striatum thalamic circuitry and the cerebellum indeed exhibit compulsive symptoms. Specifically, lesions of the posterior cerebellar vermis cause affective dysregulation and deficits in executive function. These deficits may be due to impairment of one of the main functions of the cerebellum, implementation of forward internal models of the environment. Actions that are independent of internal models may not be guided by predictive relationships or a mental representation of the goal. In this review article, we explain how this deficit might affect executive functions. Additionally, regionalized cerebellar lesions have been demonstrated to impair other brain functions such as the emergence of habits and behavioral inhibition, which are also altered in compulsive disorders. Similar to the infralimbic cortex, clinical studies and research in animal models suggest that the cerebellum is not required for learning goal-directed behaviors, but it is critical for habit formation. Despite this accumulating data, the role of the cerebellum in compulsive symptomatology and impulsivity is still a matter of discussion. Overall, findings point to a modulatory function of the cerebellum in terminating or initiating actions through regulation of the prefrontal cortices. Specifically, the cerebellum may be crucial for restraining ongoing actions when environmental conditions change by adjusting prefrontal activity in response to the new external and internal stimuli, thereby promoting flexible behavioral control. We elaborate on this explanatory framework and propose a working hypothesis for the involvement of the cerebellum in compulsive and impulsive endophenotypes.

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Section: Cerebellar Underpinnings Of Compulsivitymentioning

confidence: 62%

A Working Hypothesis for the Role of the Cerebellum in Impulsivity and Compulsivity

Miquel

Nicola

Gil‐Miravet

et al. 2019

Front. Behav. Neurosci.

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“…Infusions were released through a removable stainless-steel injector (length, Figure 4A). More detailed information can be found in Gil-Miravet et al 37…”

Section: Brain Infusions and Stereotactic Surgerymentioning

confidence: 99%

“…37 Moreover, simultaneous IL-cerebellar deactivation prevented the effect of either of the separate manipulations. 37 These results were in agreement with findings reporting that the IL cortex is required for the suppression of cocaine-seeking response and expression of extinction memory. 38,39 Overall, our findings suggested that both the cerebellum and IL cortex might act together in regulating the establishment of drug-cue Pavlovian associations.…”

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confidence: 97%

From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues

et al. 2019

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It is now increasingly clear that the cerebellum may modulate brain functions altered in drug addiction. We previously demonstrated that cocaine-induced conditioned preference increased activity at the dorsal posterior cerebellar vermis. Unexpectedly, a neurotoxic lesion at this region increased the probability of cocaine-induced conditioned preference acquisition. The present research aimed at providing an explanatory model for such as facilitative effect of the cerebellar lesion. First, we addressed a tracing study in which we found a direct projection from the lateral (dentate) nucleus to the VTA that also receives Purkinje axons from lobule VIII in the vermis. This pathway might control the activity and plasticity of the cortico-striatal circuitry. Then, we evaluated cFos expression in different regions of the medial prefrontal cortex and striatum after a lesion in lobule VIII before conditioning. Additionally, perineuronal net (PNN) expression was assessed to explore whether the cerebellar lesion might affect synaptic stabilization mechanisms in the medial prefrontal cortex (mPFC). Damage in this region of the vermis induced general disinhibition of the mPFC and striatal subdivisions that receive dopaminergic projections, mainly from the ventral tegmental area (VTA). Moreover, cerebellar impairment induced an upregulation of PNN expression in the mPFC. The major finding of this research was to provide an explanatory model for the function of the posterior cerebellar vermis on drug-related memory. In this model, damage of the posterior vermis would release striatum-cortical networks from the inhibitory tonic control exerted by the cerebellar cortex over VTA, thereby promoting drug effects.

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“…Cerebellar-mediated dopamine pathways have previously been shown to exhibit plasticity and compensatory changes in the neural circuitry of rodent models of autism, providing a foundation for the cerebellum to develop unique connections between cerebral hemispheres [67]. Some hypothesize that the corpus callosum enables hemispheric specializations, allowing one hemisphere to reconfigure circuits and adapt to certain environmental changes while the other hemisphere preserves existing functions [77].…”

Section: Discussionmentioning

confidence: 99%

Cerebellar Modulation of Mesolimbic Dopamine Transmission is Functionally Asymmetrical

Holloway¹,

Paige²,

Comstock³

et al. 2019

Preprint

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Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed-potential amperometry with carbon-fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections. (PPT), which projects to and stimulates dopamine cell bodies in the VTA [46,47]. For this reason, the present study stimulated the DN located contralateral to the NAc recording site (left DN stimulation with right NAc recording and vice versa). Lastly, in Experiment 3, we examined the potential cross-hemispheric influence of cerebellar DN on this dopaminergic pathway. During contralateral DN stimulation-evoked dopamine recordings, separate groups of mice received an infusion of either lidocaine or phosphate-buffered saline (PBS; vehicle control) into the ipsilateral DN to determine if communication between each cerebellar DN can influence the contralateral, active pathway being stimulated. (See Figure 1 for a depiction of the experimental configurations.) These experiments are the first to systematically examine the contribution of the cerebellum on lateralized stimulation-evoked phasic dopamine release in the NAc. An improved understanding of cerebello-cortico circuitry may help identify targets for pharmacological interventions in neuropathologies related to dopamine dysfunction.

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The role of the cerebellum in drug‐cue associative memory: functional interactions with the medial prefrontal cortex

Cited by 22 publications

References 72 publications

A Working Hypothesis for the Role of the Cerebellum in Impulsivity and Compulsivity

A Working Hypothesis for the Role of the Cerebellum in Impulsivity and Compulsivity

From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues

Cerebellar Modulation of Mesolimbic Dopamine Transmission is Functionally Asymmetrical

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