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1.
Nat Commun ; 13(1): 3211, 2022 06 09.
Article in English | MEDLINE | ID: mdl-35680891

ABSTRACT

Chronic Levodopa therapy, the gold-standard treatment for Parkinson's Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment.


Subject(s)
Dyskinesia, Drug-Induced , Parkinson Disease , Animals , Antiparkinson Agents/adverse effects , Cerebellum/metabolism , Dyskinesia, Drug-Induced/complications , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/prevention & control , Humans , Levodopa/adverse effects , Mice , Parkinson Disease/drug therapy
2.
Elife ; 112022 06 14.
Article in English | MEDLINE | ID: mdl-35699413

ABSTRACT

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (Gnal+/-) mice carry a heterozygous knockout mutation of the Gnal gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, Gnal+/- mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.


Subject(s)
Dystonia , Dystonic Disorders , Animals , Cerebellum , Disease Models, Animal , Dystonia/genetics , Dystonic Disorders/genetics , Mice , Neural Pathways , Thalamus
3.
Nat Commun ; 11(1): 5207, 2020 10 15.
Article in English | MEDLINE | ID: mdl-33060630

ABSTRACT

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.


Subject(s)
Central Nervous System/physiology , Fear/physiology , Memory/physiology , Neural Pathways/physiology , Periaqueductal Gray/physiology , Amygdala/physiology , Animals , Central Nervous System/pathology , Cerebellum/diagnostic imaging , Cerebellum/physiology , Conditioning, Classical/physiology , Conditioning, Operant/physiology , Learning , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Optogenetics
4.
Neuropharmacology ; 137: 268-274, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29778010

ABSTRACT

The endocannabinoid (eCB) system is involved in the modulation of the reward system and participates in the reinforcing effects of different drugs of abuse, including alcohol. The most abundant receptor of the eCB system in the central nervous system is the CB1 receptor (CB1R), which is predominantly expressed in areas involved in drug addiction, such as the nucleus accumbens, the ventral tegmental area, the substantia nigra and the raphe nucleus. CB1R is expressed in early stages during development, and reaches maximum levels during early adolescence. In addition, cannabinoid receptor 2 has been found expressed also in the central nervous system at postsynaptic level. In order to analyze the participation of the eCB system on ethanol (EtOH) preference, mice were exposed to cannabinoid agonist WIN 55,212-2 (WIN) for 5 consecutive days during early adolescence. Anxiety tests were performed the day after WIN treatment withdrawal, and EtOH preference was measured throughout adolescence. Mice exposed to WIN during early adolescence exhibited a significant increase in EtOH intake and preference after treatment. Moreover, WIN exposure during early adolescence induced an anxiogenic effect. Morphometric analysis revealed higher dendritic ramifications and fewer dendritic spines in neurons of the substantia nigra pars compacta in WIN-treated mice. On the other hand, immunohistochemical analysis revealed an increase in the number of tryptophan hydroxylase-expressing neurons in the dorsal raphe nucleus but no differences were found in the ventral tegmental area or substantia nigra pars compacta for tyrosine hydroxylase-expressing neurons. These results demonstrate that exposure to WIN in early adolescence can affect neural development and induce alcohol preference and anxiety-like behavior during late adolescence.


Subject(s)
Alcohol Drinking , Anxiety/etiology , Benzoxazines/adverse effects , Cannabinoid Receptor Agonists/adverse effects , Morpholines/adverse effects , Naphthalenes/adverse effects , Alcohol Drinking/metabolism , Alcohol Drinking/pathology , Animals , Anxiety/metabolism , Anxiety/pathology , Central Nervous System Depressants/administration & dosage , Dorsal Raphe Nucleus/drug effects , Dorsal Raphe Nucleus/growth & development , Dorsal Raphe Nucleus/metabolism , Dorsal Raphe Nucleus/pathology , Ethanol/administration & dosage , Male , Mice , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Pars Compacta/drug effects , Pars Compacta/growth & development , Pars Compacta/metabolism , Pars Compacta/pathology , Random Allocation , Receptors, Cannabinoid/metabolism , Serotonin/metabolism , Sexual Maturation , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/growth & development , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/pathology
5.
Ann Anat ; 198: 41-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25488259

ABSTRACT

Olfactory epithelium has the capability to continuously regenerate olfactory receptor neurons throughout life. Adult neurogenesis results from proliferation and differentiation of neural stem cells, and consequently, olfactory neuroepithelium offers an excellent opportunity to study neural regeneration and the factors involved in the maintenance and regeneration of all their cell types. We analyzed the expression of BDNF in the olfactory system under normal physiological conditions as well as during a massive regeneration induced by chemical destruction of the olfactory epithelium in Xenopus laevis larvae. We described the expression and presence of BDNF in the olfactory epithelium and bulb. In normal physiological conditions, sustentacular (glial) cells and a few scattered basal (stem) cells express BDNF in the olfactory epithelium as well as the granular cells in the olfactory bulb. Moreover, during massive regeneration, we demonstrated a drastic increase in basal cells expressing BDNF as well as an increase in BDNF in the olfactory bulb and nerve. Together these results suggest an important role of BDNF in the maintenance and regeneration of the olfactory system.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Olfactory Bulb/pathology , Olfactory Bulb/physiopathology , Olfactory Mucosa/pathology , Olfactory Mucosa/physiopathology , Animals , Nerve Regeneration/physiology , Neurogenesis/physiology , Xenopus laevis
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