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

Abstract

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.

The Cerebellum on Cocaine

“…Overall, our recent findings reveal that the cerebellum may modulate cocaine-induced learning, but also neural activity and synaptic stabilization mechanisms in the IL (Gil-Miravet et al, 2019b). Impairment of the posterior vermis increased activity and perineuronal expression in the IL, but only in those rats that expressed the conditioned response of preference for drug associated cues.…”

“…Optogenetic stimulation of DCN-VTA glutamatergic projections activated VTA neurons and was sufficient to induce a strong CPP. In agreement, the apical lesion of lobule 8 increased neural activity in the dentate nucleus, likely by reducing the tonic inhibition exerts by Purkinje onto DCN neurons (Gil-Miravet et al, 2019b). We were also interested in the role of the functional loops between the cerebellum and medial prefrontal cortex as well.…”

“…Unexpectedly, the apical lesion dramatically raises the probability of learning/expressing the cocaine-cue Pavlovian association (Gil-Miravet et al, 2019a,b). More important, the cerebellar lesion increased neuronal activity in the mPFC, NAC, and all striatal subdivisions except the ventrolateral striatum, backing the idea of the VTA as a plausible hotspot for a modulatory action of the cerebellum on drug-related memory effects (Carta et al, 2019;Gil-Miravet et al, 2019b). Indeed, using both retrograde and anterograde tracing, we demonstrated that neurons from the apical region of lobule 8 in the vermis reach both the interposed and lateral nuclei (DCN) in the deep cerebellum running laterally to the middle line.…”

“…It is worth noting that the cerebellum connects bidirectionally to functional loops involved in drug addiction. In particular, the cerebellum modulates cortical influences on striatal activity (Chen et al, 2014;Watson et al, 2014) and exerts an indirect (Forster and Blaha, 2003;Rogers et al, 2011) but also a direct control over VTA dopaminergic neurons (Watabe-Uchida et al, 2012;Carta et al, 2019;Gil-Miravet et al, 2019b; Figure 2). Nevertheless, evidence is still partial and related mainly to drug-induced reward memory, but recent results may provide with a wider perspective of cerebellar roles in drug addiction.…”

An Immunohistochemical Analysis on The Human Cerebellar Dopaminergic System

“…From each lobules of cerebellar cortex, were obtained 3 fragments of 25-55 mm 3 , which included the entire cerebellar cortex and part of the underlying white matter; from each dentate nucleus were taken fragments that include its total extension surface considering the transverse axis of the nucleus. The fragments were xed by immersion for 3h at 4°C in Zamboni's uid [38]. We chose a xative solution composed by 10% formaldehyde and a satured concentration of picric acid, because in our previous experimental procedures the same xative solution had shown to be optimal and useful for postmortem nervous tissue xation, and for immunohistochemical visualization of different neuroactive molecules The fragments after the xation procedure, were washed and dehydrated in series of ethanol and incorporated in a semi-synthetic para n. The para n blocks were serially cut into 5μm sections, respectively oriented orthogonally to the long axis of the cerebellar cortex and to the major axis of the dentate nucleus.…”