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1.
Neuropharmacology ; 255: 110019, 2024 Sep 01.
Article de Anglais | MEDLINE | ID: mdl-38810926

RÉSUMÉ

The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol consumption in two drinking paradigms: limited access "Drinking in the Dark" and intermittent access. Quinine was added to the drinking bottles in the DID experiment to test aversion-resistant, "compulsive" drinking. Nicotine and sucrose drinking were also assessed so comparisons could be made with other rewarding substances. Cholinergic MOR deletion did not influence consumption or preference for ethanol (EtOH) in either drinking task. Differences were observed in aversion-resistance in males with Cre + mice tolerating lower concentrations of quinine than Cre-. In contrast to EtOH, preference for nicotine was reduced following cholinergic MOR deletion while sucrose consumption and preference was increased in Cre+ (vs. Cre-) females. Locomotor activity was also greater in females following the deletion. These results suggest that cholinergic MORs participate in preference for rewarding substances. Further, while they are not required for consumption of alcohol alone, cholinergic MORs may influence the tendency to drink despite negative consequences.


Sujet(s)
Consommation d'alcool , Souris knockout , Quinine , Récepteur mu , Récompense , Animaux , Récepteur mu/génétique , Récepteur mu/métabolisme , Mâle , Femelle , Souris , Quinine/pharmacologie , Quinine/administration et posologie , Consommation d'alcool/génétique , Consommation d'alcool/psychologie , Nicotine/pharmacologie , Éthanol/pharmacologie , Éthanol/administration et posologie , Neurones cholinergiques/effets des médicaments et des substances chimiques , Neurones cholinergiques/physiologie , Neurones cholinergiques/métabolisme , Autoadministration , Saccharose/administration et posologie , Apprentissage par évitement/effets des médicaments et des substances chimiques , Apprentissage par évitement/physiologie , Interneurones/effets des médicaments et des substances chimiques , Interneurones/physiologie , Interneurones/métabolisme
2.
Dis Model Mech ; 17(5)2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38616770

RÉSUMÉ

Dystonia is thought to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted an established cerebellar dystonia mouse model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe) and striatal neurons were activated in the model. Next, we examined whether administration of a dopamine D1 receptor agonist and dopamine D2 receptor antagonist or selective ablation of striatal parvalbumin (PV, encoded by Pvalb)-expressing interneurons could modulate the involuntary movements of the mice. The cerebellar dystonia mice had a higher number of cells positive for c-fos (encoded by Fos) in the EPN, SNr and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons, than those in control mice. Furthermore, systemic administration of combined D1 receptor agonist and D2 receptor antagonist and selective ablation of striatal PV interneurons relieved the involuntary movements of the mice. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.


Sujet(s)
Corps strié , Modèles animaux de maladie humaine , Dystonie , Interneurones , Parvalbumines , Protéines proto-oncogènes c-fos , Récepteur D2 de la dopamine , Animaux , Interneurones/métabolisme , Interneurones/effets des médicaments et des substances chimiques , Parvalbumines/métabolisme , Protéines proto-oncogènes c-fos/métabolisme , Dystonie/anatomopathologie , Dystonie/métabolisme , Dystonie/physiopathologie , Corps strié/anatomopathologie , Corps strié/métabolisme , Récepteur D2 de la dopamine/métabolisme , Récepteur dopamine D1/métabolisme , Cervelet/anatomopathologie , Cervelet/métabolisme , Ouabaïne/pharmacologie , Souris de lignée C57BL , Souris , Mâle
3.
J Nutr Sci Vitaminol (Tokyo) ; 70(2): 164-173, 2024.
Article de Anglais | MEDLINE | ID: mdl-38684387

RÉSUMÉ

Bitterness and astringency are the aversive tastes in mammals. In humans, aversion to bitterness and astringency may be reduced depending on the eating experience. However, the cellular and molecular mechanisms underlying plasticity in preference to bitter and astringent tastants remain unknown. This study aimed to investigate the preference plasticity to bitter and astringent tea polyphenols, including catechins and tannic acids, in the model animal Caenorhabditis elegans. C. elegans showed avoidance behavior against epigallocatechin gallate (EGCG), tannic acid, and theaflavin. However, they displayed diminishing avoidance against EGCG depending on their EGCG-feeding regime at larval stages. Additionally, the behavioral plasticity in avoiding EGCG required the transcription factor DAF-16/FOXO. Isoform-specific deletion mutant analysis and cell-specific rescue analysis revealed that the function of daf-16 isoform b in AIY interneurons is necessary for experience-dependent behavioral plasticity to EGCG.


Sujet(s)
Protéines de Caenorhabditis elegans , Caenorhabditis elegans , Catéchine , Facteurs de transcription Forkhead , Interneurones , Animaux , Catéchine/analogues et dérivés , Catéchine/pharmacologie , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Protéines de Caenorhabditis elegans/métabolisme , Protéines de Caenorhabditis elegans/génétique , Facteurs de transcription Forkhead/métabolisme , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Apprentissage par évitement/effets des médicaments et des substances chimiques , Biflavonoïdes/pharmacologie , Goût/effets des médicaments et des substances chimiques , Thé/composition chimique , Comportement animal/effets des médicaments et des substances chimiques , Larve/effets des médicaments et des substances chimiques
4.
Nature ; 628(8009): 818-825, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-38658687

RÉSUMÉ

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.


Sujet(s)
Trouble autistique , Syndrome du QT long , Oligonucléotides antisens , Syndactylie , Animaux , Femelle , Humains , Mâle , Souris , Épissage alternatif/effets des médicaments et des substances chimiques , Épissage alternatif/génétique , Trouble autistique/traitement médicamenteux , Trouble autistique/génétique , Calcium/métabolisme , Canaux calciques de type L/métabolisme , Canaux calciques de type L/génétique , Mouvement cellulaire/effets des médicaments et des substances chimiques , Dendrites/métabolisme , Exons/génétique , Syndrome du QT long/traitement médicamenteux , Syndrome du QT long/génétique , Neurones/métabolisme , Neurones/effets des médicaments et des substances chimiques , Oligonucléotides antisens/pharmacologie , Oligonucléotides antisens/usage thérapeutique , Organoïdes/effets des médicaments et des substances chimiques , Organoïdes/métabolisme , Prosencéphale/métabolisme , Prosencéphale/cytologie , Syndactylie/traitement médicamenteux , Syndactylie/génétique , Interneurones/cytologie , Interneurones/effets des médicaments et des substances chimiques
5.
ACS Chem Neurosci ; 15(9): 1738-1754, 2024 05 01.
Article de Anglais | MEDLINE | ID: mdl-38613458

RÉSUMÉ

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3ß2ß3 or α6/α3ß4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.


Sujet(s)
Transporteurs de la dopamine , Dopamine , Ibogaïne , Ibogaïne/analogues et dérivés , Nicotine , Récepteurs nicotiniques , Animaux , Dopamine/métabolisme , Mâle , Récepteurs nicotiniques/métabolisme , Récepteurs nicotiniques/effets des médicaments et des substances chimiques , Nicotine/pharmacologie , Ibogaïne/pharmacologie , Souris , Transporteurs de la dopamine/métabolisme , Transporteurs de la dopamine/effets des médicaments et des substances chimiques , Noyau accumbens/effets des médicaments et des substances chimiques , Noyau accumbens/métabolisme , Souris de lignée C57BL , Antagonistes nicotiniques/pharmacologie , Ovocytes/effets des médicaments et des substances chimiques , Agonistes nicotiniques/pharmacologie , Transmission synaptique/effets des médicaments et des substances chimiques , Transmission synaptique/physiologie , Autoadministration , Xenopus laevis , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Relation dose-effet des médicaments , Activité motrice/effets des médicaments et des substances chimiques
6.
J Neurosci ; 44(17)2024 Apr 24.
Article de Anglais | MEDLINE | ID: mdl-38438258

RÉSUMÉ

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.


Sujet(s)
Acétylcholine , Cholécystokinine , Souris de lignée C57BL , Rythme thêta , Rythme thêta/effets des médicaments et des substances chimiques , Rythme thêta/physiologie , Animaux , Mâle , Souris , Femelle , Acétylcholine/pharmacologie , Acétylcholine/métabolisme , Cholécystokinine/pharmacologie , Cholécystokinine/métabolisme , Interneurones/physiologie , Interneurones/effets des médicaments et des substances chimiques , Somatostatine/métabolisme , Somatostatine/pharmacologie , Amygdale (système limbique)/physiologie , Amygdale (système limbique)/effets des médicaments et des substances chimiques , Groupe nucléaire basolatéral/physiologie , Groupe nucléaire basolatéral/effets des médicaments et des substances chimiques , Réseau nerveux/physiologie , Réseau nerveux/effets des médicaments et des substances chimiques , Récepteur muscarinique de type M3/physiologie , Récepteur muscarinique de type M3/métabolisme , Parvalbumines/métabolisme
7.
PLoS One ; 18(5): e0286031, 2023.
Article de Anglais | MEDLINE | ID: mdl-37216370

RÉSUMÉ

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and its concentrations in the brain could be associated with EtOH-induced impairment of motor coordination. GABA is synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. Mice deficient in GAD65 (GAD65-KO) can grow up to adulthood, and show that GABA concentration in their adult brains was 50-75% that of wild-type C57BL/6 mice (WT). Although a previous study showed that there was no difference in recovery from the motor-incoordination effect of acute intraperitoneally administered injections of 2.0 g/kg EtOH between WT and GAD65-KO, the sensitivity of GAD65-KO to acute EtOH-induced ataxia has not been fully understood. Here, we sought to determine whether motor coordination and spontaneous firing of cerebellar Purkinje cells (PCs) in GAD65-KO are more sensitive to the effect of EtOH than in WT. Motor performance in WT and GAD65-KO was examined by rotarod and open-field tests following acute administration of EtOH at lower-doses, 0.8, 1.2 and 1.6 g/kg. In a rotarod test, there was no significant difference between WT and GAD65-KO in terms of baseline motor coordination. However, only the KO mice showed a significant decrease in rotarod performance of 1.2 g/kg EtOH. In the open-field test, GAD65-KO showed a significant increase in locomotor activity after 1.2 and 1.6 g/kg EtOH injections, but not WT. In in vitro studies of cerebellar slices, the firing rate of PCs was increased by 50 mM EtOH in GAD65-KO compared with WT, whereas no difference was observed in the effect of EtOH at more than 100 mM between the genotypes. Taken together, GAD65-KO are more susceptible to the effect of acute EtOH exposure on motor coordination and PC firing than WT. This different sensitivity could be attributed to the basal low GABA concentration in the brain of GAD65-KO.


Sujet(s)
Éthanol , Glutamate decarboxylase , Interneurones , Animaux , Souris , Éthanol/pharmacologie , Acide gamma-amino-butyrique , Glutamate decarboxylase/génétique , Interneurones/effets des médicaments et des substances chimiques , Souris de lignée C57BL
8.
Int J Mol Sci ; 24(7)2023 Apr 05.
Article de Anglais | MEDLINE | ID: mdl-37047741

RÉSUMÉ

We traced the changes in GABAergic parvalbumin (PV)-expressing interneurons of the hippocampus and reticulo-thalamic nucleus (RT) as possible underlying mechanisms of the different local cortical and hippocampal electroencephalographic (EEG) microstructures during the non-rapid-eye movement (NREM) sleep compared with anesthesia-induced unconsciousness by two anesthetics with different main mechanisms of action (ketamine/diazepam versus propofol). After 3 h of recording their sleep, the rats were divided into two experimental groups: one half received ketamine/diazepam anesthesia and the other half received propofol anesthesia. We simultaneously recorded the EEG of the motor cortex and hippocampus during sleep and during 1 h of surgical anesthesia. We performed immunohistochemistry and analyzed the PV and postsynaptic density protein 95 (PSD-95) expression. PV suppression in the hippocampus and at RT underlies the global theta amplitude attenuation and hippocampal gamma augmentation that is a unique feature of ketamine-induced versus propofol-induced unconsciousness and NREM sleep. While PV suppression resulted in an increase in hippocampal PSD-95 expression, there was no imbalance between inhibition and excitation during ketamine/diazepam anesthesia compared with propofol anesthesia in RT. This increased excitation could be a consequence of a lower GABA interneuronal activity and an additional mechanism underlying the unique local EEG microstructure in the hippocampus during ketamine/diazepam anesthesia.


Sujet(s)
Interneurones , Kétamine , Propofol , Animaux , Rats , Diazépam/pharmacologie , Hippocampe/métabolisme , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Kétamine/pharmacologie , Parvalbumines/métabolisme , Propofol/pharmacologie , Perte de conscience/induit chimiquement
9.
Neuropharmacology ; 232: 109527, 2023 07 01.
Article de Anglais | MEDLINE | ID: mdl-37011784

RÉSUMÉ

Parvalbumin-expressing dorsal striatal fast-spiking interneurons, comprising ∼1% of the total dorsal striatal neuronal population, are necessary for the expression of compulsive-like ethanol consumption mice. Fast-spiking interneurons are driven to fire by glutamatergic inputs derived primarily from the cortex. However, these neurons also receive substantial GABAergic input from two sources: the globus pallidus and the reticular nucleus of the thalamus. How ethanol modulates inhibitory input onto fast-spiking neurons is unclear and, more broadly, alcohol effects on GABAergic synaptic transmission onto GABAergic interneurons are understudied. Examining this, we found that acute bath application of ethanol (50 mM) potentiated GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto fast-spiking interneurons in mouse of both sexes. This ethanol-induced potentiation required postsynaptic calcium and was not accompanied by a sustained change in presynaptic GABA release probability. Examining whether this ethanol effect persisted following chronic intermittent ethanol exposure, we found attenuated acute-ethanol potentiation of GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto striatal fast-spiking interneurons. These data underscore the impact of ethanol on GABAergic signaling in the dorsal striatum and support the notion that ethanol may disinhibit the dorsolateral striatum.


Sujet(s)
Corps strié , Éthanol , Neurones GABAergiques , Interneurones , Animaux , Femelle , Mâle , Souris , Corps strié/cytologie , Corps strié/effets des médicaments et des substances chimiques , Éthanol/administration et posologie , Éthanol/pharmacologie , Neurones GABAergiques/effets des médicaments et des substances chimiques , Neurones GABAergiques/métabolisme , Globus pallidus/cytologie , Globus pallidus/effets des médicaments et des substances chimiques , Interneurones/effets des médicaments et des substances chimiques , Transmission synaptique/effets des médicaments et des substances chimiques , Noyaux du thalamus/cytologie , Noyaux du thalamus/effets des médicaments et des substances chimiques , Noyaux du thalamus/métabolisme , Synapses/effets des médicaments et des substances chimiques , Synapses/métabolisme , Calcium/métabolisme
10.
Neuropharmacology ; 206: 108926, 2022 03 15.
Article de Anglais | MEDLINE | ID: mdl-34921828

RÉSUMÉ

Perseveration is a characteristic of patients with obsessive-compulsive disorder (OCD). Clinically, neuronal activity in the lateral orbitofrontal cortex (OFC) is increased in OCD patients. Successful treatment with selective serotonin reuptake inhibitors (SSRIs) reduces activity in the lateral OFC of OCD patients, but the precise mechanisms underlying this effect are unclear. Previously, we reported that repeated injection of the dopamine D2 receptor agonist quinpirole (QNP) resulted in OCD-like deficits, including perseveration in a reversal learning task. QNP-treated mice showed hyperactivity in lateral OFC pyramidal neurons. The present study demonstrated that 4-week administration of an SSRI increased the rate of correct choice in a reversal learning task. Using the electrophysiological approach, we revealed that an SSRI decreased the activity of lateral OFC pyramidal neurons in QNP-treated mice by potentiating inhibitory inputs. The 4-week administration of an SSRI inhibited the potentiation of neuronal activity induced by a 5-HT2C receptor agonist. Additionally, both 4-week administration of SSRI and acute application of 5-HT2C receptor antagonist prevented the QNP-induced potentiation of inhibitory inputs to fast-spiking interneurons in the lateral OFC. Administration of a 5-HT2C receptor antagonist to mice for 4 days increased the rate of correct choice in a reversal learning task. Collectively, these results indicate that chronic SSRI ameliorated perseverative behavior in QNP-treated mice by modulating inhibitory inputs in the lateral OFC. Short-term 5-HT2C receptor blockade also ameliorated QNP-induced behavioral and neurological abnormalities by, at least in part, a common mechanism with chronic SSRI.


Sujet(s)
Comportement animal/effets des médicaments et des substances chimiques , Trouble obsessionnel compulsif/traitement médicamenteux , Cortex préfrontal/effets des médicaments et des substances chimiques , Récepteur de la sérotonine de type 5-HT2C/effets des médicaments et des substances chimiques , Inbiteurs sélectifs de la recapture de la sérotonine/pharmacologie , Animaux , Modèles animaux de maladie humaine , Interneurones/effets des médicaments et des substances chimiques , Souris , Cellules pyramidales/effets des médicaments et des substances chimiques , Apprentissage inversé/effets des médicaments et des substances chimiques , Agonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Antagonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques
11.
Biochim Biophys Acta Mol Cell Res ; 1869(1): 119146, 2022 01.
Article de Anglais | MEDLINE | ID: mdl-34599984

RÉSUMÉ

Gaba-ergic neurons are a diverse cell class with extensive influence over cortical processing, but their role in experience-dependent plasticity is not completely understood. Here we addressed the role of cortical somatostatin- (SOM-INs) and vasoactive intestinal polypeptide- (VIP-INs) containing interneurons in a Pavlovian conditioning where stimulation of the vibrissae is used as a conditioned stimulus and tail shock as unconditioned one. This procedure induces a plastic change observed as an enlargement of the cortical functional representation of vibrissae activated during conditioning. Using layer-targeted, cell-selective DREADD transductions, we examined the involvement of SOM-INs and VIP-INs activity in learning-related plastic changes. Under optical recordings, we injected DREADD-expressing vectors into layer IV (L4) barrels or layer II/III (L2/3) areas corresponding to the activated vibrissae. The activity of the interneurons was modulated during all conditioning sessions, and functional 2-deoxyglucose (2DG) maps were obtained 24 h after the last session. In mice with L4 but not L2/3 SOM-INs suppressed during conditioning, the plastic change of whisker representation was absent. The behavioral effect of conditioning was disturbed. Both L4 SOM-INs excitation and L2/3 VIP-INs inhibition during conditioning did not affect the plasticity or the conditioned response. We found the activity of L4 SOM-INs is indispensable in the formation of learning-induced plastic change. We propose that L4 SOM-INs may provide disinhibition by blocking L4 parvalbumin interneurons, allowing a flow of information into upper cortical layers during learning.


Sujet(s)
Interneurones/physiologie , Apprentissage , Inhibition nerveuse , Plasticité neuronale , Cortex somatosensoriel/physiologie , Animaux , Neurones GABAergiques/effets des médicaments et des substances chimiques , Neurones GABAergiques/métabolisme , Neurones GABAergiques/physiologie , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Modulateurs du transport transmembranaire/pharmacologie , Souris , Cortex somatosensoriel/cytologie , Somatostatine/génétique , Somatostatine/métabolisme , Vibrisses/innervation , Vibrisses/physiologie
12.
Cell Rep ; 37(13): 110165, 2021 12 28.
Article de Anglais | MEDLINE | ID: mdl-34965425

RÉSUMÉ

Ongoing neural activity has been observed across several brain regions and is thought to reflect the internal state of the brain. Yet, it is important to understand how ongoing neural activity interacts with sensory experience and shapes sensory representations. Here, we show that the projection neurons of the fruit fly antennal lobe exhibit spatiotemporally organized ongoing activity. After repeated exposure to odors, we observe a gradual and cumulative decrease in the amplitude and number of calcium events occurring in the absence of odor stimulation, as well as a reorganization of correlations between olfactory glomeruli. Accompanying these plastic changes, we find that repeated odor experience decreases trial-to-trial variability and enhances the specificity of odor representations. Our results reveal an odor-experience-dependent modulation of ongoing and sensory-evoked activity at peripheral levels of the fruit fly olfactory system.


Sujet(s)
Antennes des arthropodes/physiologie , Drosophila melanogaster/physiologie , Interneurones/physiologie , Plasticité neuronale , Odorisants/analyse , Bulbe olfactif/physiologie , Odorat , Animaux , Antennes des arthropodes/effets des médicaments et des substances chimiques , Calcium/métabolisme , Drosophila melanogaster/effets des médicaments et des substances chimiques , Femelle , Interneurones/effets des médicaments et des substances chimiques , Bulbe olfactif/effets des médicaments et des substances chimiques , Voies olfactives
13.
Cell Rep ; 37(5): 109950, 2021 11 02.
Article de Anglais | MEDLINE | ID: mdl-34731619

RÉSUMÉ

Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.


Sujet(s)
Neuroleptiques/pharmacologie , Comportement animal/effets des médicaments et des substances chimiques , Cognition/effets des médicaments et des substances chimiques , Dysfonctionnement cognitif/traitement médicamenteux , Agonistes des acides aminés excitateurs/pharmacologie , Glycine/analogues et dérivés , Interneurones/effets des médicaments et des substances chimiques , Cortex préfrontal/effets des médicaments et des substances chimiques , Récepteurs métabotropes au glutamate/agonistes , Résorcinol/pharmacologie , Schizophrénie/traitement médicamenteux , Psychologie des schizophrènes , Somatostatine/métabolisme , Animaux , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/psychologie , Modèles animaux de maladie humaine , Femelle , Neurones GABAergiques/effets des médicaments et des substances chimiques , Neurones GABAergiques/métabolisme , Glycine/pharmacologie , Interneurones/métabolisme , Mâle , Mémoire à court terme/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Souris transgéniques , Inhibition nerveuse/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Cortex préfrontal/physiopathologie , Rat Sprague-Dawley , Récepteurs métabotropes au glutamate/métabolisme , Schizophrénie/métabolisme , Schizophrénie/physiopathologie , Somatostatine/génétique
14.
Pflugers Arch ; 473(12): 1911-1924, 2021 12.
Article de Anglais | MEDLINE | ID: mdl-34724104

RÉSUMÉ

The nucleus accumbens (NAc) receives cortical projections principally from the insular cortex (IC) and medial prefrontal cortex (mPFC). Among NAc neurons, cholinergic interneurons (ChNs) regulate the activities of medium spiny neurons (MSNs), which make up ~ 95% of NAc neurons, by modulating their firing and synaptic properties. However, little is known about the synaptic mechanisms, including their cell-type-dependent corticoaccumbal projection properties and cholinergic effects on the NAc core. Here, we performed whole-cell patch-clamp recordings from NAc MSNs and ChNs in acute brain slice preparations obtained from rats that received an AAV5-hSyn-ChR2(H134R)-mCherry injection into the IC or mPFC. Light stimulation of IC or mPFC axons induced comparable phase-locked excitatory postsynaptic currents (EPSCs) in MSNs. On the other hand, ChNs showed consistent EPSCs evoked by light stimulation of mPFC axons, whereas light stimulation of IC axons evoked much smaller EPSCs, which often showed failure in ChNs. Light-evoked EPSCs were abolished by tetrodotoxin and were recovered by 4-aminopyridine, suggesting that corticoaccumbal projections monosynaptically induce EPSCs in MSNs and ChNs. Carbachol effectively suppressed the amplitude of EPSCs in MSNs and ChNs evoked by light stimulation of IC or mPFC axons and in ChNs evoked by stimulating mPFC axons. The carbachol-induced suppression was recovered by atropine or pirenzepine, while preapplication of gallamine, J104129, PD102807, or AF-DX384 did not block the carbachol-induced EPSC suppression. These results suggest that NAc MSNs and ChNs are differentially regulated by excitatory projections from the IC and mPFC and that these corticoaccumbal excitatory inputs are modulated by M1 receptor activation.


Sujet(s)
Neurones cholinergiques/métabolisme , Noyau accumbens/métabolisme , Cortex préfrontal/métabolisme , Acétylcholine/pharmacologie , Animaux , Animal génétiquement modifié/métabolisme , Carbachol/pharmacologie , Agents cholinergiques/métabolisme , Neurones cholinergiques/effets des médicaments et des substances chimiques , Potentiels post-synaptiques excitateurs/effets des médicaments et des substances chimiques , Potentiels post-synaptiques excitateurs/physiologie , Femelle , Acide glutamique/métabolisme , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Mâle , Noyau accumbens/effets des médicaments et des substances chimiques , Techniques de patch-clamp/méthodes , Cortex préfrontal/effets des médicaments et des substances chimiques , Rats , Transmission synaptique/effets des médicaments et des substances chimiques , Transmission synaptique/physiologie
15.
J Integr Neurosci ; 20(3): 613-622, 2021 Sep 30.
Article de Anglais | MEDLINE | ID: mdl-34645094

RÉSUMÉ

As a gamma-aminobutyric acid type A receptor agonist sevoflurane is a common general anesthetic used in anesthesia and affects the neural development in offspring. We hypothesized that sevoflurane could regulate interneurons via the neuregulin-1-epidermal growth factor receptor-4 (NRG1-ErbB4) pathway in the entorhinal cortex (ECT) of the middle pregnancy. Six female rats in middle pregnancy (14.5 days of pregnancy) were randomly and equally divided into sevoflurane (SeV) and control groups. The rats in the SeV group were exposed to 4% sevoflurane for 3 hours. The expression levels of NRG1 and ErbB4, parvalbumin (PV) and glutamic acid decarboxylase (GAD67), and N-methyl-D-aspartate receptor subunit 2A (NR2A) and subunit 2B (NR2B) in offspring were examined through immunohistochemistry. The pyramidal neurons in the ECT were examined via Golgi staining. The levels of NRG1 and ErbB4 were significantly decreased (P < 0.01) and the levels of PV and GAD67 (interneurons) were found to be decreased in the SeV group (P < 0.01). The level of NR2B was found to be increased while the level of NR2A being decreased in the SeV group (P < 0.01). The development of pyramidal neurons was abnormal in the SeV group (P < 0.05). Conclusively, prenatal sevoflurane exposure could lead to the disturbance of the interneurons by activating the NRG1-ErbB4 pathway and subsequently result in abnormal development of pyramidal neurons in middle pregnancy. Prenatal sevoflurane exposure in middle pregnancy could be potentially harmful to the neural development of rat offspring. This study may reveal a novel pathway in the influence mechanism of sevoflurane on rat offspring.


Sujet(s)
Cortex entorhinal/effets des médicaments et des substances chimiques , Agonistes du récepteur GABA-A/pharmacologie , Interneurones/effets des médicaments et des substances chimiques , Neuréguline-1/effets des médicaments et des substances chimiques , Effets différés de l'exposition prénatale à des facteurs de risque/induit chimiquement , Cellules pyramidales/effets des médicaments et des substances chimiques , Récepteur ErbB-4/effets des médicaments et des substances chimiques , Sévoflurane/pharmacologie , Animaux , Modèles animaux de maladie humaine , Femelle , Agonistes du récepteur GABA-A/administration et posologie , Grossesse , Rats , Sévoflurane/administration et posologie
16.
Nat Commun ; 12(1): 6112, 2021 10 20.
Article de Anglais | MEDLINE | ID: mdl-34671051

RÉSUMÉ

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.


Sujet(s)
Interneurones/physiologie , Accident vasculaire cérébral/thérapie , Peptide vasoactif intestinal/métabolisme , Animaux , Clozapine/analogues et dérivés , Clozapine/usage thérapeutique , Humains , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Souris , Inhibition nerveuse/effets des médicaments et des substances chimiques , Récepteur muscarinique de type M3/génétique , Récepteur muscarinique de type M3/métabolisme , Récupération fonctionnelle , Cortex somatosensoriel/cytologie , Cortex somatosensoriel/effets des médicaments et des substances chimiques , Cortex somatosensoriel/physiologie , Accident vasculaire cérébral/métabolisme , Accident vasculaire cérébral/physiopathologie
17.
Sci Rep ; 11(1): 19102, 2021 09 27.
Article de Anglais | MEDLINE | ID: mdl-34580351

RÉSUMÉ

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood-brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.


Sujet(s)
Anticonvulsivants/pharmacologie , Épilepsie temporale/étiologie , Pilocarpine/toxicité , Animaux , Anticonvulsivants/usage thérapeutique , Marqueurs biologiques/analyse , Jeux de données comme sujet , Modèles animaux de maladie humaine , Découverte de médicament , Épilepsie temporale/diagnostic , Épilepsie temporale/traitement médicamenteux , Épilepsie temporale/anatomopathologie , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Hippocampe/cytologie , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/anatomopathologie , Humains , Interneurones/effets des médicaments et des substances chimiques , Interneurones/métabolisme , Mâle , Souris , Pilocarpine/administration et posologie , Cellules pyramidales/effets des médicaments et des substances chimiques , Cellules pyramidales/métabolisme , RNA-Seq , Analyse sur cellule unique , Lobe temporal/effets des médicaments et des substances chimiques , Lobe temporal/anatomopathologie
18.
Neurobiol Dis ; 159: 105514, 2021 11.
Article de Anglais | MEDLINE | ID: mdl-34555537

RÉSUMÉ

Synchronized and properly balanced electrical activity of neurons is the basis for the brain's ability to process information, to learn, and to remember. In Alzheimer's disease (AD), which causes cognitive decline in patients, this synchronization and balance is disturbed by the accumulation of neuropathological biomarkers such as amyloid-beta peptide (Aß42). Failure of Aß42 clearance mechanisms as well as desynchronization of crucial neuronal classes such as fast-spiking interneurons (FSN) are root causes for the disruption of the cognition-relevant gamma brain rhythm (30-80 Hz) and consequent cognitive impairment observed in AD. Here we show that recombinant BRICHOS molecular chaperone domains from ProSP-C or Bri2, which interfere with Aß42 aggregation, can rescue the gamma rhythm. We demonstrate that Aß42 progressively decreases gamma oscillation power and rhythmicity, disrupts the inhibition/excitation balance in pyramidal cells, and desynchronizes FSN firing during gamma oscillations in the hippocampal CA3 network of mice. Application of the more efficacious Bri2 BRICHOS chaperone rescued the cellular and neuronal network performance from all ongoing Aß42-induced functional impairments. Collectively, our findings offer critical missing data to explain the importance of FSN for normal network function and underscore the therapeutic potential of Bri2 BRICHOS to rescue the disruption of cognition-relevant brain rhythms in AD.


Sujet(s)
Potentiels d'action/effets des médicaments et des substances chimiques , Protéines adaptatrices de la transduction du signal/pharmacologie , Hippocampe/effets des médicaments et des substances chimiques , Interneurones/effets des médicaments et des substances chimiques , Chaperons moléculaires/pharmacologie , Cellules pyramidales/effets des médicaments et des substances chimiques , Potentiels d'action/physiologie , Protéines adaptatrices de la transduction du signal/métabolisme , Peptides bêta-amyloïdes , Animaux , Modèles animaux de maladie humaine , Rythme gamma , Hippocampe/physiopathologie , Techniques in vitro , Interneurones/physiologie , Souris , Voies nerveuses/effets des médicaments et des substances chimiques , Voies nerveuses/physiopathologie , Fragments peptidiques , Domaines protéiques , Protéine C associée au surfactant pulmonaire/métabolisme , Protéine C associée au surfactant pulmonaire/pharmacologie , Cellules pyramidales/métabolisme , Cellules pyramidales/physiologie , Protéines recombinantes
19.
Toxicology ; 462: 152958, 2021 10.
Article de Anglais | MEDLINE | ID: mdl-34547370

RÉSUMÉ

Drinking alcohol during pregnancy may cause fetal alcohol spectrum disorder. The present study investigated the effects of maternal oral ethanol (EtOH) exposure (0, 10, or 12.5 % in drinking water) from gestational day 6 until day 21 post-delivery (weaning) on postnatal hippocampal neurogenesis at weaning and in adulthood on postnatal day 77 in rat offspring. At weaning, type-3 neural progenitor cells (NPCs) were decreased in the subgranular zone (SGZ), accompanied by Chrnb2 downregulation and Grin2b upregulation in the dentate gyrus (DG). These results suggested suppression of CHRNB2-mediated cholinergic signaling in γ-aminobutyric acid (GABA)ergic interneurons in the DG hilus and increased glutamatergic signaling through the NR2B subtype of N-methyl-d-aspartate (NMDA) receptors, resulting in NPC reduction. In contrast, upregulation of Chrna7 may increase CHRNA7-mediated cholinergic signaling in immature granule cells, and upregulation of Ntrk2 may cause an increase in somatostatin-immunoreactive (+) GABAergic interneurons, suggesting a compensatory response against NPC reduction. Promotion of SGZ cell proliferation increased type-2a NPCs. Moreover, an increase in calbindin-d-29 K+ interneurons and upregulation of Reln, Drd2, Tgfb2, Il18, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunit genes might participate in this compensatory response. In adulthood, reduction of FOS+ cells and downregulation of Fos and Arc suggested suppression of granule cell synaptic plasticity, reflecting upregulation of Tnf and downregulation of Cntf, Ntrk2, and AMPA-type glutamate receptor genes. In the DG hilus, gliosis and hyper-ramified microglia, accompanying upregulation of C3, appeared at weaning, suggesting contribution to suppressed synaptic plasticity in adulthood. M1 microglia increased throughout adulthood, suggesting sustained neuroinflammation. These results indicate that maternal EtOH exposure temporarily disrupts hippocampal neurogenesis and later suppresses synaptic plasticity. Induction of neuroinflammation might initially ameliorate neurogenesis (as evident by upregulation of Tgfb2 and Il18) but later suppress synaptic plasticity (as evident by upregulation of C3 at weaning and Tnf in adulthood).


Sujet(s)
Éthanol/toxicité , Neurogenèse/effets des médicaments et des substances chimiques , Maladies neuro-inflammatoires/étiologie , Effets différés de l'exposition prénatale à des facteurs de risque/physiopathologie , Animaux , Prolifération cellulaire/effets des médicaments et des substances chimiques , Gyrus denté/effets des médicaments et des substances chimiques , Gyrus denté/anatomopathologie , Femelle , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/anatomopathologie , Interneurones/effets des médicaments et des substances chimiques , Mâle , Exposition maternelle/effets indésirables , Maladies neuro-inflammatoires/anatomopathologie , Plasticité neuronale/effets des médicaments et des substances chimiques , Grossesse , Rats , Rat Sprague-Dawley
20.
Mol Brain ; 14(1): 139, 2021 09 10.
Article de Anglais | MEDLINE | ID: mdl-34507588

RÉSUMÉ

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.


Sujet(s)
Anxiété/physiopathologie , Douleur chronique/physiopathologie , Neurones GABAergiques/physiologie , Gyrus du cingulum/physiopathologie , Inflammation/psychologie , Cellules pyramidales/physiologie , Animaux , Anxiolytiques/administration et posologie , Anxiolytiques/pharmacologie , Anxiolytiques/usage thérapeutique , Anxiété/traitement médicamenteux , Anxiété/étiologie , Sensibilisation du système nerveux central/effets des médicaments et des substances chimiques , Douleur chronique/psychologie , Clozapine/usage thérapeutique , Adjuvant Freund/toxicité , Agonistes du récepteur GABA-A/administration et posologie , Agonistes du récepteur GABA-A/pharmacologie , Agonistes du récepteur GABA-A/usage thérapeutique , Antagonistes du récepteur GABA-A/administration et posologie , Antagonistes du récepteur GABA-A/pharmacologie , Antagonistes du récepteur GABA-A/toxicité , Neurones GABAergiques/enzymologie , Vecteurs génétiques/pharmacologie , Inflammation/induit chimiquement , Inflammation/physiopathologie , Injections , Interneurones/effets des médicaments et des substances chimiques , Mâle , Muscimol/administration et posologie , Muscimol/pharmacologie , Muscimol/usage thérapeutique , Test en champ ouvert , Seuil nociceptif/effets des médicaments et des substances chimiques , Techniques de patch-clamp , Picrotoxine/toxicité , Terminaisons présynaptiques/effets des médicaments et des substances chimiques , Terminaisons présynaptiques/physiologie , Cellules pyramidales/enzymologie , Rats , Rat Sprague-Dawley
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