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Cannabinoids modulate associative cerebellar learning via alterations in behavioral state.

ABSTRACT: Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.

SUBMITTER: Albergaria C

PROVIDER: S-EPMC7575324 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Impaired associative learning in schizophrenia: behavioral and computational studies.

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A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

Project description:BackgroundImpaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered.ObjectiveTo systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex.MethodsOriginal neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model.ResultsIsolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies.ConclusionsThe similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

| S-EPMC9313805 | biostudies-literature

Cerebellar associative sensory learning defects in five mouse autism models.

Project description:Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2(R308/Y), Cntnap2-/-, L7-Tsc1 (L7/Pcp2(Cre)::Tsc1(flox/+)), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2-/-, patDp(15q11-13)/+, and L7/Pcp2(Cre)::Tsc1(flox/+), which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2(Cre)::Tsc1(flox/+) as well as Shank3+/ΔC and Mecp2(R308/Y), which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2(R308/Y) also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models.

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Project description:Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions.

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Pheromones modulate reward responsiveness and non-associative learning in honey bees.

Project description:Pheromones are chemical messengers that trigger stereotyped behaviors and/or physiological processes in individuals of the same species. Recent reports suggest that pheromones can modulate behaviors not directly related to the pheromonal message itself and contribute, in this way, to behavioral plasticity. We tested this hypothesis by studying the effect of pheromones on sucrose responsiveness and habituation in honey bees. We exposed workers to three pheromone components: geraniol, which in nature is used in an appetitive context, and isopentyl acetate (IPA) and 2-heptanone (2H), which signal aversive situations. Pheromones associated with an aversive context induced a significant decrease of sucrose responsiveness as 40% and 60% of bees exposed to IPA and 2H, respectively, did not respond to any sucrose concentration. In bees that responded to sucrose, geraniol enhanced sucrose responsiveness while 2H, but not IPA, had the opposite effect. Geraniol and IPA had no effect on habituation while 2H induced faster habituation than controls. Overall, our results demonstrate that pheromones modulate reward responsiveness and to a lower degree habituation. Through their effect on sucrose responsiveness they could also affect appetitive associative learning. Thus, besides conveying stereotyped messages, pheromones may contribute to individual and colony-level plasticity by modulating motivational state and learning performances.

| S-EPMC5574997 | biostudies-literature

Parvalbumin Interneurons Modulate Striatal Output and Enhance Performance during Associative Learning.

Project description:The prevailing view is that striatal parvalbumin (PV)-positive interneurons primarily function to downregulate medium spiny projection neuron (MSN) activity via monosynaptic inhibitory signaling. Here, by combining in vivo neural recordings and optogenetics, we unexpectedly find that both suppressing and over-activating PV cells attenuates spontaneous MSN activity. To account for this, we find that, in addition to monosynaptic coupling, PV-MSN interactions are mediated by a competing disynaptic inhibitory circuit involving a variety of neuropeptide Y-expressing interneurons. Next we use optogenetic and chemogenetic approaches to show that dorsolateral striatal PV interneurons influence the initial expression of reward-conditioned responses but that their contribution to performance declines with experience. Consistent with this, we observe with large-scale recordings in behaving animals that the relative contribution of PV cells on MSN activity diminishes with training. Together, this work provides a possible mechanism by which PV interneurons modulate striatal output and selectively enhance performance early in learning.

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Differential expression: associative and nonassociative learning

Project description:Hippocamus and amygdala expression was examined in naïve, conditioned stimulus exposed, and fear conditioned mice 30 minutes after behavioral manipulation Keywords: comparison of 3 groups x 2 brain regions

2006-03-20 | GSE3963 | GEO

Cerebellar-dependent associative learning is impaired in very preterm born children and young adults.

Project description:Preterm birth incorporates an increased risk for cerebellar developmental disorders likely contributing to motor and cognitive abnormalities. Experimental evidence of cerebellar dysfunction in preterm subjects, however, is sparse. In this study, classical eyeblink conditioning was used as a marker of cerebellar dysfunction. Standard delay conditioning was investigated in 20 adults and 32 preschool children born very preterm. Focal lesions were excluded based on structural magnetic resonance imaging. For comparison, an equal number of matched term born healthy peers were tested. Subgroups of children (12 preterm, 12 controls) were retested. Preterm subjects acquired significantly less conditioned responses (CR) compared to controls with slower learning rates. A likely explanation for these findings is that preterm birth impedes function of the cerebellum even in the absence of focal cerebellar lesions. The present findings are consistent with the assumption that prematurity results in long-term detrimental effects on the integrity of the cerebellum. It cannot be excluded, however, that extra-cerebellar pathology contributed to the present findings.

| S-EPMC5740078 | biostudies-literature

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Project description:Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

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Cerebellar-dependent associative learning is preserved in Duchenne muscular dystrophy: a study using delay eyeblink conditioning.

Project description:ObjectiveBesides progressive muscle weakness cognitive deficits have been reported in patients with Duchenne muscular dystrophy (DMD). Cerebellar dysfunction has been proposed to explain cognitive deficits at least in part. In animal models of DMD disturbed Purkinje cell function has been shown following loss of dystrophin. Furthermore there is increasing evidence that the lateral cerebellum contributes to cognitive processing. In the present study cerebellar-dependent delay eyeblink conditioning, a form of associative learning, was used to assess cerebellar function in DMD children.MethodsDelay eyeblink conditioning was examined in eight genetically defined male patients with DMD and in ten age-matched control subjects. Acquisition, timing and extinction of conditioned eyeblink responses (CR) were assessed during a single conditioning session.ResultsBoth groups showed a significant increase of CRs during the course of learning (block effect p < 0.001). CR acquisition was not impaired in DMD patients (mean total CR incidence 37.4 ± 17.6%) as compared to control subjects (36.2 ± 17.3%; group effect p = 0.89; group by block effect p = 0.38; ANOVA with repeated measures). In addition, CR timing and extinction was not different from controls.ConclusionsDelay eyeblink conditioning was preserved in the present DMD patients. Because eyeblink conditioning depends on the integrity of the intermediate cerebellum, this older part of the cerebellum may be relatively preserved in DMD. The present findings agree with animal model data showing that the newer, lateral cerebellum is primarily affected in DMD.

| S-EPMC4431835 | biostudies-literature

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