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Putting forward a model for the role of the cerebellum in cocaine-induced pavlovian memory

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Official websites use. Share sensitive information only on official, secure websites. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Long-lasting molecular and structural changes in brain regions functionally and anatomically linked to the cerebellum, such as the prefrontal cortex, amygdala, hippocampus, basal ganglia, and ventral tegmental area, are characteristic of SUD. Direct and indirect reciprocal connectivity between the cerebellum and these brain regions can explain cerebellar roles in Pavlovian and reinforcement learning, fear memory, and executive functions. It is increasingly clear that the cerebellum modulates brain functions altered in SUD and other neuropsychiatric disorders that exhibit comorbidity with SUD. In the present manuscript, we review and discuss this evidence and present new research exploring the role of the cerebellum in cocaine-induced conditioned memory using chemogenetic tools designer receptor exclusively activated by designer drug, DREADDs. Our preliminary data showed that inactivation of a region that includes the interposed and lateral deep cerebellar nuclei reduces the facilitating effect of a posterior vermis lesion on cocaine-induced preference conditioning. These findings support our previous research and suggest that posterior vermis damage may increase drug impact on the addiction circuitry by regulating activity in the DCN. However, they raise further questions that will also be discussed. Substance Use Disorder SUD is a devastating mental disorder associated with brain circuit alterations that lead to emotional, motivational, and cognitive dysfunction. SUD involves long-lasting molecular and structural plasticity in brain regions anatomically and functionally related to the cerebellum, including the prefrontal cortex, amygdala, hippocampus, basal ganglia, including the nucleus accumbens NAc , and ventral tegmental area VTA Sacchetti et al. Although the canonical view linked the cerebellum to motor control, growing evidence points to a broader modulatory function of this region McAfee et al. It is now evident that the cerebellum modulates brain functions impaired in SUD and other neuropsychiatric disorders that exhibit comorbidity with SUD such as cognitive flexibility, executive control, and reinforcement learning Miquel et al. Indeed, several findings link cerebellar dysfunction to neuropsychiatric conditions such as autism Becker and Stoodley, ; Wang et al. Nevertheless, it has taken long for the cerebellum to emerge as a relevant region for SUD Miquel et al. As recently recognized, reciprocal connectivity between the cerebellum and the rest of the brain is crucial to understanding cerebellar function Galliano and De Zeeuw, ; McAfee et al. In particular, the cerebellum modulates activity in limbic regions Sacchetti et al. Moreover, results from different laboratories revealed the existence of reciprocal loops between the medial prefrontal cortex mPFC and the cerebellum Chen et al. Transneuronal viral labeling Watabe-Uchida et al. This area includes prelimbic PL and infralimbic IL cortices. Altogether, evidence indicates that the cerebellum not only can regulate mPFC activity through direct control over dopaminergic and non-dopaminergic neurons in the VTA Watabe-Uchida et al. Recently, we have also shown that a neurotoxic lesion in the posterior vermis dramatically facilitates learning of cocaine-induced conditioned preference and increases neuronal activity in the mPFC, NAc, and all striatal subdivisions except the ventrolateral striatum, pointing at the VTA as a plausible hotspot for a modulatory action of the cerebellum on the establishment of drug preference Gil-Miravet et al. In the present work, we review and discuss evidence of the cerebellar contribution to the establishment and maintenance of drug-induced conditioned memory and present new research using chemogenetic tools designer receptor exclusively activated by designer drug, DREADDs. Our goal with this new exploratory study was to obtain further evidence to propose a working model capable of explaining why posterior vermis impairment facilitates drug effects on memory and increases VTA, mPFC, and basal ganglia activity Gil-Miravet et al. In people with SUD, cue-action-reward associations appear to be particularly strong, with these conditioned memories becoming powerful motivational triggers for drug seeking even after protracted abstinence Everitt and Robbins, ; Hyman et al. Studies of cue reactivity in SUD patients have assessed the capacity of drug-associated cues to induce conditioned emotional responses and craving. These studies have shown that the presentation of drug-related cues elicits drug craving and increases cerebellar activity for a review, see Moulton et al. This evidence, however, does not allow us to postulate a causal relationship between cerebellar activity and craving. Although several studies found a positive correlation between self-reports of craving and cerebellar activity Grant et al. Also, similar cerebellar activity patterns have been found after exposure to cocaine cues and other arousing stimuli like anger-related scripts Kilts et al. Furthermore, activity in the cerebellum increases when fear- Utz et al. These findings suggest a general role of the cerebellum in processing and storing reward-predicting cues and other behaviorally relevant events more than in the generation of conscious feelings such as drug craving Moreno-Rius and Miquel, It is important to mention, nevertheless, that cerebellar activity highly correlates with addiction severity Shen et al. Given that cue-reactivity studies were all conducted under withdrawal conditions, increased activity in the cerebellum might result from an apparent mismatch between exteroceptive drug-predicting cues and context and the absence of expected interoceptive signals drug effects triggered by the cue presentation. In this case, cerebellar activity could be associated with a prediction error for the internal representation that anticipated sensory and rewarding consequences of drug effects in a given context. Accordingly, blood oxygen level dependent imaging in the dorsal caudate, mPFC and the cerebellum were greater when SUD patients were in the presence of a mismatch between mentally represented drug effects and drug taking contexts De Pirro et al. Activity of the fronto-striatal-cerebellar network was larger when drug taking was mentally represented in a non-associated context for drug consumption, outside-home for heroin and the home context for cocaine De Pirro et al. Moreover, recent animal research has shown that violations of reward expectations activate climbing fibers Heffley and Hull, and specific subpopulations of granule cells Wagner et al. It has also been described that an expected drug treatment evokes a larger cerebellar response to drug administration methylphenidate than an unexpected treatment Volkow et al. However, challenging the mismatch hypothesis, it has been shown that receiving placebo after expecting a drug does not activate the cerebellum Volkow et al. These findings indicate that expectations can enhance drug effects on the cerebellum, but expectancy as a process underlying placebo response does not recruit cerebellar mechanisms. The capacity of addictive drugs to induce Pavlovian conditioning in preclinical studies has been very well documented Bardo and Bevins, ; Cunningham et al. The most widely used animal model of Pavlovian conditioning in drug addiction has been conditioned place preference CPP , in which distinctive contextual cues are paired with the drug. The conditioned response is expressed as the preference for the drug-associated context. Distinct processes contribute to the formation of drug-induced conditioned preferences including Pavlovian learning, motivation, and reward McKendrick and Graziane, Our rodent studies on cocaine-induced CPP consistently evidenced increased neural activity cFos in granule cells of the vermis Carbo-Gas et al. We also found a robust enhanced expression of perineuronal nets PNNs around Golgi interneurons in the same cerebellar region Carbo-Gas et al. PNNs are extracellular matrix structures expressed by the cell-body and proximal neurites of some neuronal subpopulations that generate restrictive conditions for synaptic remodeling Grimpe and Silver, ; Fawcett et al. Increased cerebellar activity and PNN expression in the cerebellar cortex were exclusive features of animals that expressed CPP and were not observed when cocaine was randomly paired with cues or in saline-treated animals Carbo-Gas et al. These results preclude the possibility that cerebellar changes merely result from unconditioned stimulating properties of cocaine or movements performed during the test. In fact, motor activity during the preference test was not different between saline and cocaine-treated groups Carbo-Gas et al. In addition, the effect of cocaine-induced conditioning on cerebellar activity was not replicated when mice were confined and presented with cocaine-related cues without the possibility of expressing the conditioned response Carbo-Gas et al. Given that granule cell activity has been demonstrated to encode reward, the expectation of reward, reward omission, and conditioned responses Wagner et al. Distinct granule cells subsets are tuned to combinations of actions and rewards enabling specific subpopulations of Purkinje cells to learn what particular action in a specific context is expected to be rewarded Wagner et al. Nevertheless, it is not clear the extent to which the cerebellar cortex would represent the drug-cue association. Our recent results challenge that the initial encoding of drug-cue associative memory involves the vermis. Decreasing glutamatergic transmission from parallel fibers to Purkinje synapsis using a6Cre-Cacna1a KO mice Galliano et al. Furthermore, enzymatic digestion of PNNs around Golgi interneurons in the posterior vermis impaired short-term memory of cocaine-induced CPP but did not affect its acquisition Guarque-Chabrera et al. Overall, our results suggest that the drug-induced memory engram could be initially encoded elsewhere and conveyed to the vermis for stabilization. Previous studies on the role of the cerebellum in Pavlovian conditioning indicate that acquisition and short-term expression of the conditioned motor response rely on specific regions in the cerebellar cortex Galliano et al. Electrical Steinmetz et al. In addition, acquisition Supple and Leaton, , consolidation Sacchetti et al. Considering that parallel fibers granule cell axons make contacts with dendrites of molecular interneurons Dizon and Khodakhah, , increased granule cell activity in conditioned animals might enhance the inhibitory effect of molecular interneurons onto Purkinje cells in turn facilitating cerebellar outflow by reducing Purkinje inhibitory control over DCN neurons. Medial prefrontal cortex dysfunction is a key part of the physiopathology of SUD McFarland and Kalivas, ; Goldstein and Volkow, and other neuropsychiatric disorders that have shown comorbidity with SUD Hester and Garavan, ; Winstanley et al. Many of these disorders also involve alterations in the cerebellum Moulton et al. Recently, we intended to approach the study of cerebellar responses when cocaine-induced conditioning is acquired under mPFC impairment Gil-Miravet et al. Deactivation of the IL but not PL cortex encourages the acquisition of preference for cocaine-related cues Guarque-Chabrera et al. More importantly, only IL deactivation during drug learning affected neural activity and PNN expression in the posterior cerebellar vermis. IL deactivation increases activity specifically in vGluT2 synapses, but it does not affect vGluT1-related activity. These cerebellar hallmarks would result from the interaction between IL impairment and cocaine-induced learning, given that neither of these changes were found when the drug was randomly associated with the contextual cues. A decade ago, we proposed that prefrontal dysfunction would encourage cerebellar hyper-responsiveness if exposure to addictive drugs was repeated Miquel et al. Our recent findings support this working hypothesis and suggest that taking drugs when there is a ventral prefrontal dysfunction can cause a functional reorganization of the prefrontal-cerebellar network and boost drug impact on behavior. Studies over the last decade have established the existence of bidirectional anatomical and functional loops between the mPFC and cerebellum Watson et al. A dopaminergic VTA-cerebellar projection releases detectable dopamine DA levels in the posterior lobules of the vermis VII—X , the right and left hemispheres and the fastigial, interposed, and dentate nuclei Glaser et al. In turn, the cerebellar cortex regulates DA activity by several independent pathways. In addition, the cerebellum connects to the VTA through the reticulotegmental and pedunculopontine nuclei Forster and Blaha, as well as through the mediodorsal, ventrolateral, and ventromedial thalamus Rogers et al. At a functional level, it has been evidenced that the cerebellum modulates cerebral cortical functions Chen et al. Therefore, cerebellar cortex disruption in the posterior vermis potentiates neural activity and mechanisms for synaptic stabilization in the addiction circuitry that might facilitate drug-induced learning. Together, our previous findings indicate that only the IL cortex is functionally related to the cerebellum whereas the cerebellum exerts a modulatory action on the addiction circuitry including both subdivisions of the mPFC Gil-Miravet et al. The cerebellum-IL loop regulates drug effects on behavior in an inhibitory compensatory manner given that impairment of each region is sufficient to enhance neural activity and mechanisms for synaptic stabilization PNNs in the other region, potentiating drug-related learning. In the following sections, we present the results of a preliminary study in which we tested the causal link between cerebellar cortex impairment and increased cocaine impact on CPP learning in rats. More specifically, this study used chemogenetic tools to inhibit the activity of a region in the DCN that includes the Int and Lat nuclei Low et al. A Experimental timeline. Different stages of the experimental procedure from stereotaxic surgeries to behavioral protocol. B Schematic depiction of intracranial infusions and cannula placements. Cerebellar tissue was obtained the last conditioning day in which the Veh and CNO animals received a saline injection. Data are shown as single scores and mean. Top left label on each plot reports the common treatment of both groups. G Schematic representation of the open field box. H CNO treatment did not have any effect on motor activity. Deep cerebellar nuclei DCN effect of sham and quinolinic acid infusions. A Schematic depiction of intracranial infusions and cannula placements. B Representative confocal images of Sham and QA injections. C Schematic diagram depicting the largest light purple and smallest dark purple diffusion areas in the apical region of LVIII in the vermis. The diffusion areas were established overlaying each cerebellar image over the correspondent rat brain digital atlas image Paxinos and Watson, White arrows display examples of a Purkinje cell axon terminal. In two earlier studies, we showed that an excitotoxic lesion with QA in the apical region of LVIII dramatically facilitated the acquisition of cocaine-induced conditioned preference Gil-Miravet et al. Then, the facilitation of drug conditioning did not affect the magnitude but the fraction of subjects that expressed the conditioned response. The present results showed a similar effect. Our previous findings showed that a neurotoxic lesion with QA in the apical region of LVIII of the vermis facilitates learning of cocaine-induced conditioned preferences and increases neuronal activity in the Lat nucleus, mPFC, NAc, and all striatal subdivisions, except the ventrolateral striatum Gil-Miravet et al. These findings suggested an inhibitory modulation of the posterior vermis on the activity of the addiction circuitry through the Int and Lateral DCN. This inhibitory control may be compromised under cerebellar vermis dysfunction and potentiates drug effects on behavior Schmahmann and Sherman, ; Miquel et al. With the present exploratory study, we aimed to further support this working model using a chemogenetic inhibition of the aDCN. In line with this model, our preliminary findings suggest that DCN inhibition reduces the facilitating effect of a vermis lesion on learning cocaine-induced conditioned preferences. Inhibition of the Int and Lat DCN left intact the ability to acquire conditioned preferences for drug-related stimuli and did not cause any motor impairment or anxiogenic effects. Nevertheless, we did find an increase in lateral rearing after conditioning. This result points to motor sensitization following four cocaine administrations despite having conducted the motor test in a different chamber from that used for conditioning. Our QA lesion permanently damages the most external region of the granule cell layer, Purkinje neurons, and molecular layer interneurons in the same region, reducing the inhibitory control of a subpopulation of Purkinje neurons onto DCN neurons. Consequently, lacking Purkinje inhibition, the activity in the cerebellar output neurons and the other regions in the striatum-cortico-limbic circuitry may increase and encourage drug-induced learning Gil-Miravet et al. Interestingly, our rats still learned to prefer the cocaine-associated configuration despite Int and Lat inhibition, which suggests that the formation of the drug-cue memory trace does not require these cerebellar nuclei. Accordingly, acquisition and expression of eyeblink and fear conditioning do not rely on the DCN but in specific regions of the cerebellar cortex Supple and Leaton, ; Galliano et al. Even so, the DCN may fuel drug memory acquisition when there is posterior vermis dysfunction, hypothetically, through the modulation of activity in the VTA. Altogether, these results confirm the modulatory role of the cerebellum on cocaine-induced conditioned memory and support the causal link between vermis dysfunction and the facilitation of drug effects. Dysregulation of the cerebellar vermis has been also proposed as a potential etiological factor for ADHD and other disorders of the impulsive spectrum Mulder et al. Therefore, the present findings may open new avenues to consider the cerebellum as a therapeutic target for stimulation in SUD and other comorbid mental disorders such as ADHD. Rats were housed individually in the animal facilities Jaume I University, Spain under standard conditions h light cycle from a. Before beginning with behavioral procedures, rats were handled for 3 weeks and habituated to experimental protocols. Cocaine hydrochloride Alcaliber S. Saline solution was used as a control vehicle. After the infusion completion, the injector remained in place for 3 min for a better absorption of the substance. Then, the guide cannula and injector were removed, and the wound was sutured Figures 1A, B. After the infusion was completed, the injector remained in place for 5 min to avoid liquid aspiration. Then, the guide cannula and injector were removed. Then, a dummy cannula gauge external diameter, Rats were left undisturbed for 4 days for recovery. For behavioral experiments with intracranial infusions, rats were gently handled while restrained, and CNO or saline were infused bilaterally into the Int 5 min before each training session 0. Rats were not anesthetized during the microinjections because this procedure does not involve pain or discomfort for the animals. Behavioral trials began 5 min after the infusion. Two days before the training, animals were habituated to the apparatus in a min session without texturized floor stainless-steel floor with perforated small holes or big holes Leroy Merlin SL. All the test sessions were videotaped and scored by a blind observer. The first 5 min were not considered to allow the animal to explore the location of the odors. On alternate days, the other configuration was associated with IP saline injections CS-. For each pairing session, rats were confined in one of the lateral chambers of the apparatus for 25 min. Therefore, four cocaine- and four saline-paired sessions were conducted on alternate days Figure 1E. The preference test was identical to the preconditioning test and was carried out 24 h after the last conditioning session and 48 h after the last cocaine administration Figure 1E. The location of the cues in the corridor was counterbalanced between animals. We performed this test during habituation before training and the last saline-paired day after training but without CNO; without Int inactivation. These parameters were recorded in three blocks of 5 min. Only the intermedium 5 min block is represented in figures to avoid confounding effects such as initial exploration and boredom at the end of the period. All animals were perfused transcardially 60 min following the last preference test on each behavioral protocol using saline 0. Immunolabeling was performed on free-floating sections. We used cFos immunofluorescent staining as a neural activity marker. Laser intensity, gain, and offset remained stable across animals. When two groups were compared, we used an unpaired t -test. Then we assessed whether that probability of change as a group was different or not from chance 0. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. MM and RP: conceptualization. IM-E and MM: methodology. IM-E: investigation. MM: funding acquisition. All authors full access to all data, take responsibility for all the information in the present manuscript, made a notable contribution to the manuscript, were involved in critically revising the present version, and approved the present version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Front Syst Neurosci. Find articles by Ignasi Melchor-Eixea. Find articles by Julian Guarque-Chabrera. Find articles by Aitor Sanchez-Hernandez. Find articles by Marta Miquel. Received Jan 30; Accepted May 25; Collection date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

How can I buy cocaine online in Bellinzona