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Temporal Lobe Epilepsy (TLE) is the most common form of epilepsy in adults. In TLE, recurrent mossy fiber (rMF) sprouting from dentate gyrus granule cells (DGCs) forms an aberrant epileptogenic network between dentate granule cells (DGCs) that operates via ectopically expressed kainate receptors (KARs). It was previously shown that KARs expressed at the rMF-DGC synapses play a prominent role in epileptiform network events in TLE. However, it is not well understood how KARs influence neuronal network dynamics and contribute to the generation of epileptiform network activity in the dentate gyrus. To address this question, we monitored the activity of DGCs using single-cell resolution calcium imaging performed in a reliable in vitro model of TLE. Under our experimental conditions, the most prominent DGC activity patterns were interictal-like epileptiform network events, which were correlated with high levels of neuronal synchronization. The pharmacological blockade of KARs reduced the frequency as well as the number of neurons involved in these events, without altering their spatiotemporal dynamics. Analysis of the microstructure of synchrony showed that blockade of KARs diminished the fraction of neurons forming the main functional cluster. Therefore, we propose that KARs act as modulators in the epileptic network by facilitating the recruitment of neurons into coactive cell assemblies, thereby contributing to the occurrence of epileptiform network events.
Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Humanos , Receptores de Ácido Caínico , Neurônios/metabolismo , Giro Denteado/metabolismoRESUMO
Rodents perceive pheromones via vomeronasal receptors encoded by highly evolutionarily dynamic Vr and Fpr gene superfamilies. We report here that high numbers of V1r pseudogenes are scattered in mammalian genomes, contrasting with the clustered organization of functional V1r and Fpr genes. We also found that V1r pseudogenes are more likely to be expressed when located in a functional V1r gene cluster than when isolated. To explore the potential regulatory role played by the association of functional vomeronasal receptor genes with their clusters, we dissociated the mouse Fpr-rs3 from its native cluster via transgenesis. Singular and specific transgenic Fpr-rs3 transcription was observed in young vomeronasal neurons but was only transient. Our study of natural and artificial dispersed gene duplications uncovers the existence of transcription-stabilizing elements not coupled to vomeronasal gene units but rather associated with vomeronasal gene clusters and thus explains the evolutionary conserved clustered organization of functional vomeronasal genes.
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The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.
Assuntos
Hipogonadismo , Óxido Nítrico , Animais , Cognição , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/complicações , Hipogonadismo/congênito , Hipogonadismo/genética , Camundongos , Proteínas Mutantes , Mutação/genética , Óxido Nítrico Sintase Tipo I/genética , NitritosRESUMO
In mammals, chemoperception relies on a diverse set of neuronal sensors able to detect chemicals present in the environment, and to adapt to various levels of stimulation. The contribution of endogenous and external factors to these neuronal identities remains to be determined. Taking advantage of the parallel coding lines present in the olfactory system, we explored the potential variations of neuronal identities before and after olfactory experience. We found that at rest, the transcriptomic profiles of mouse olfactory sensory neuron populations are already divergent, specific to the olfactory receptor they express, and are associated with the sequence of these latter. These divergent profiles further evolve in response to the environment, as odorant exposure leads to reprogramming via the modulation of transcription. These findings highlight a broad range of sensory neuron identities that are present at rest and that adapt to the experience of the individual, thus adding to the complexity and flexibility of sensory coding.
Assuntos
Neurônios Receptores Olfatórios , Receptores Odorantes , Animais , Mamíferos , Camundongos , Odorantes , Neurônios Receptores Olfatórios/fisiologia , Receptores Odorantes/genética , Células Receptoras Sensoriais , OlfatoRESUMO
Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.
Assuntos
Proteínas de Transporte de Ânions/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Ácido Pirúvico/metabolismo , Ácido 3-Hidroxibutírico/farmacologia , Animais , Proteínas de Transporte de Ânions/genética , Transporte Biológico , Cálcio/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Corpos Cetônicos , Camundongos , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/genética , Transportadores de Ácidos Monocarboxílicos/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxirredução , Pentilenotetrazol/toxicidade , Fosforilação , Convulsões/induzido quimicamente , Tamoxifeno/farmacologiaRESUMO
Social behaviours characterize cooperative, mutualistic, aggressive or parental interactions that occur among conspecifics. Although the Ventral Tegmental Area (VTA) has been identified as a key substrate for social behaviours, the input and output pathways dedicated to specific aspects of conspecific interaction remain understudied. Here, in male mice, we investigated the activity and function of two distinct VTA inputs from superior colliculus (SC-VTA) and medial prefrontal cortex (mPFC-VTA). We observed that SC-VTA neurons display social interaction anticipatory calcium activity, which correlates with orienting responses towards an unfamiliar conspecific. In contrast, mPFC-VTA neuron population activity increases after initiation of the social contact. While protracted phasic stimulation of SC-VTA pathway promotes head/body movements and decreases social interaction, inhibition of this pathway increases social interaction. Here, we found that SC afferents mainly target a subpopulation of dorsolateral striatum (DLS)-projecting VTA dopamine (DA) neurons (VTADA-DLS). While, VTADA-DLS pathway stimulation decreases social interaction, VTADA-Nucleus Accumbens stimulation promotes it. Altogether, these data support a model by which at least two largely anatomically distinct VTA sub-circuits oppositely control distinct aspects of social behaviour.
Assuntos
Vias Neurais/fisiologia , Orientação Espacial/fisiologia , Interação Social , Colículos Superiores/patologia , Área Tegmentar Ventral/fisiologia , Animais , Neurônios Dopaminérgicos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Comportamento SocialRESUMO
Variations in gene expression patterns represent a powerful source of evolutionary innovation. In a rodent living about 70 million years ago, a genomic accident led an immune formyl peptide receptor (FPR) gene to hijack a vomeronasal receptor regulatory sequence. This gene shuffling event forced an immune pathogen sensor to transition into an olfactory chemoreceptor, which thus moved from sensing the internal world to probing the outside world. We here discuss the evolution of the FPR gene family, the events that led to their neofunctionalization in the vomeronasal organ and the functions of immune and vomeronasal FPRs.
Assuntos
Receptores Odorantes/metabolismo , Animais , Receptores de Formil PeptídeoRESUMO
Reports indicate an association between COVID-19 and anosmia, as well as the presence of SARS-CoV-2 virions in the olfactory bulb. To test whether the olfactory neuroepithelium may represent a target of the virus, we generated RNA-seq libraries from human olfactory neuroepithelia, in which we found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2) and for the virus internalization enhancer TMPRSS2. We analyzed a human olfactory single-cell RNA-seq dataset and determined that sustentacular cells, which maintain the integrity of olfactory sensory neurons, express ACE2 and TMPRSS2. ACE2 protein was highly expressed in a subset of sustentacular cells in human and mouse olfactory tissues. Finally, we found ACE2 transcripts in specific brain cell types, both in mice and humans. Sustentacular cells thus represent a potential entry door for SARS-CoV-2 in a neuronal sensory system that is in direct connection with the brain.
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Neurons in primary sensory cortex encode a variety of stimulus features upon perceptual learning. However, it is unclear whether the acquired stimulus selectivity remains stable when the same input is perceived in a different context. Here, we monitor the activity of individual neurons in the mouse primary somatosensory cortex during reward-based texture discrimination. We track their stimulus selectivity before and after changing reward contingencies, which allows us to identify various classes of neurons. We find neurons that stably represented a texture or the upcoming behavioral choice, but the majority is dynamic. Among those, a subpopulation of neurons regains texture selectivity contingent on the associated reward value. These value-sensitive neurons forecast the onset of learning by displaying a distinct and transient increase in activity, depending on past behavioral experience. Thus, stimulus selectivity of excitatory neurons during perceptual learning is dynamic and largely relies on behavioral contingencies, even in primary sensory cortex.
Assuntos
Percepção/fisiologia , Reversão de Aprendizagem/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Comportamento Animal , Sinalização do Cálcio , Comportamento de Escolha , Discriminação Psicológica , Masculino , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Recompensa , Sensação , Fatores de TempoRESUMO
The olfactory environment is first represented by glomerular activity patterns in the olfactory bulb. It remains unclear how these representations intersect with sampling behavior to account for the time required to discriminate odors. Using different chemical classes, we investigate glomerular representations and sniffing behavior during olfactory decision-making. Mice rapidly discriminate odorants and learn to increase sniffing frequency at a fixed latency after trial initiation, independent of odor identity. Relative to the increase in sniffing frequency, monomolecular odorants are discriminated within 10-40 ms, while binary mixtures require an additional 60-70 ms. Intrinsic imaging of glomerular activity in anesthetized and awake mice reveals that Euclidean distance between activity patterns and the time needed for discriminations are anti-correlated. Therefore, the similarity of glomerular patterns and their activation strengths, rather than sampling behavior, define the extent of neuronal processing required for odor discrimination, establishing a neural metric to predict olfactory discrimination time.
Assuntos
Comportamento Animal/fisiologia , Discriminação Psicológica/fisiologia , Bulbo Olfatório/fisiologia , Condutos Olfatórios/fisiologia , Olfato/fisiologia , Potenciais de Ação/fisiologia , Animais , Discriminação Psicológica/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Bulbo Olfatório/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Tempo de Reação/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
During development, the precise implementation of molecular programs is a key determinant of proper dendritic development. Here, we demonstrate that canonical Wnt signaling is active in dendritic bundle-forming layer II pyramidal neurons of the rat retrosplenial cortex during dendritic branching and spine formation. Transient downregulation of canonical Wnt transcriptional activity during the early postnatal period irreversibly reduces dendritic arbor architecture, leading to long-lasting deficits in spatial exploration and/or navigation and spatial memory in the adult. During the late phase of dendritogenesis, canonical Wnt-dependent transcription regulates spine formation and maturation. We identify neurotrophin-3 as canonical Wnt target gene in regulating dendritogenesis. Our findings demonstrate how temporary imbalance in canonical Wnt signaling during specific time windows can result in irreversible dendritic defects, leading to abnormal behavior in the adult.
Assuntos
Dendritos/metabolismo , Neurogênese , Células Piramidais/metabolismo , Memória Espacial , Via de Sinalização Wnt , Animais , Células Cultivadas , Feminino , Células HEK293 , Humanos , Masculino , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Células Piramidais/citologia , Células Piramidais/fisiologia , Ratos , Ratos WistarRESUMO
Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioral traits that are relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. We studied an animal model of the human 22q11 deletion syndrome, the mutation that represents the highest genetic risk of developing schizophrenia. We observed a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches was sufficient to restore wild-type-like CA1 network dynamics and hippocampal-dependent behavior during adulthood. In conclusion, our data provide insights into the network dysfunction underlying schizophrenia and highlight the use of reverse engineering to restore physiological and behavioral phenotypes in an animal model of neurodevelopmental disorder.
Assuntos
Região CA1 Hipocampal/patologia , Transtornos Mentais/etiologia , Rede Nervosa/patologia , Dinâmica não Linear , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Síndrome da Deleção 22q11/complicações , Síndrome da Deleção 22q11/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Clozapina/análogos & derivados , Clozapina/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/fisiopatologia , Neurregulinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Parvalbuminas/genética , Parvalbuminas/metabolismo , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologia , Esquizofrenia/etiologia , Esquizofrenia/genéticaRESUMO
Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose.
Assuntos
Células Quimiorreceptoras/metabolismo , Evolução Molecular , Sistema Imunitário , Receptores de Formil Peptídeo/metabolismo , Órgão Vomeronasal/metabolismo , Animais , Éxons , Perfilação da Expressão Gênica , Humanos , Inflamação , Camundongos , Família Multigênica , Neurônios/metabolismo , Filogenia , Regiões Promotoras Genéticas , Ratos , Células Receptoras Sensoriais/metabolismo , OlfatoRESUMO
Sensory information is translated into ensemble representations by various populations of projection neurons in brain circuits. The dynamics of ensemble representations formed by distinct channels of output neurons in diverse behavioral contexts remains largely unknown. We studied the two output neuron layers in the olfactory bulb (OB), mitral and tufted cells, using chronic two-photon calcium imaging in awake mice. Both output populations displayed similar odor response profiles. During passive sensory experience, both populations showed reorganization of ensemble odor representations yet stable pattern separation across days. Intriguingly, during active odor discrimination learning, mitral but not tufted cells exhibited improved pattern separation, although both populations showed reorganization of ensemble representations. An olfactory circuitry model suggests that cortical feedback on OB interneurons can trigger both forms of plasticity. In conclusion, we show that different OB output layers display unique context-dependent long-term ensemble plasticity, allowing parallel transfer of non-redundant sensory information to downstream centers. VIDEO ABSTRACT.
Assuntos
Plasticidade Neuronal/fisiologia , Odorantes , Bulbo Olfatório/citologia , Condutos Olfatórios/fisiologia , Olfato/fisiologia , Animais , Interneurônios/fisiologia , Camundongos , VigíliaRESUMO
Sensory information undergoes substantial transformation along sensory pathways, usually encompassing sparsening of activity. In the olfactory bulb, though natural odorants evoke dense glomerular input maps, mitral and tufted (M/T) cells tuning is considered to be sparse because of highly odor-specific firing rate change. However, experiments used to draw this conclusion were either based on recordings performed in anesthetized preparations or used monomolecular odorants presented at arbitrary concentrations. In this study, we evaluated the lifetime and population sparseness evoked by natural odorants by capturing spike temporal patterning of neuronal assemblies instead of individual M/T tonic activity. Using functional imaging and tetrode recordings in awake mice, we show that natural odorants at their native concentrations are encoded by broad assemblies of M/T cells. While reducing odorant concentrations, we observed a reduced number of activated glomeruli representations and consequently a narrowing of M/T tuning curves. We conclude that natural odorants at their native concentrations recruit M/T cells with phasic rather than tonic activity. When encoding odorants in assemblies, M/T cells carry information about a vast number of odorants (lifetime sparseness). In addition, each natural odorant activates a broad M/T cell assembly (population sparseness).
Assuntos
Potenciais Evocados/fisiologia , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Receptores Odorantes/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Masculino , Camundongos , Odorantes , Bulbo Olfatório/citologia , Células Receptoras Sensoriais/citologiaRESUMO
Building the topographic map in the mammalian olfactory bulb is explained by a model based on two axes along which sensory neurons are guided: one dorsoventral and one anteroposterior. This latter axis relies on specific expression levels of Nrp1. To evaluate the role of this receptor in this process, we used an in vivo genetic approach to decrease or suppress Nrp1 in specific neuronal populations and at different time points during axonal targeting. We observed, in neurons that express the M71 or M72 odorant receptors, that Nrp1 inactivation leads to two distinct wiring alterations, depending on the time at which Nrp1 expression is altered: first, a surprising dorsal shift of the M71 and M72 glomeruli, which often fuse with their contralateral counterparts, and second the formation of anteriorized glomeruli. The two phenotypes are partly recapitulated in mice lacking the Nrp1 ligand Sema3A and in mice whose sensory neurons express an Nrp1 mutant unable to bind Sema3A. Using a mosaic conditional approach, we show that M71 axonal fibers can bypass the Nrp1 signals that define their target area, since they are hijacked and coalesce with Nrp1-deficient M71-expressing axons that target elsewhere. Together, these findings show drastically different axonal targeting outcomes dependent on the timing at which Nrp1/Sema3A signaling is altered.
Assuntos
Neuropilina-1/metabolismo , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Animais , Axônios/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Imuno-Histoquímica , Camundongos , Neuropilina-1/genética , Bulbo Olfatório/embriologia , Neurônios Receptores Olfatórios/citologia , Neurônios Receptores Olfatórios/metabolismo , Semaforina-3A/genética , Semaforina-3A/metabolismoRESUMO
Synaptic inhibition in the olfactory bulb (OB), the first relay station of olfactory information, is believed to be important for odour discrimination. We interfered with GABAergic inhibition of mitral and tufted cells (M/T cells), the principal neurons of the OB, by disrupting their potassium-chloride cotransporter 2 (Kcc2). Roughly, 70% of mice died around 3 weeks, but surviving mice appeared normal. In these mice, the resulting increase in the intracellular Cl(-) concentration nearly abolished GABA-induced hyperpolarization of mitral cells (MCs) and unexpectedly increased the number of perisomatic synapses on MCs. In vivo analysis of odorant-induced OB electrical activity revealed increased M/T cell firing rate, altered phasing of action potentials in the breath cycle and disrupted separation of odour-induced M/T cell activity patterns. Mice also demonstrated a severely impaired ability to discriminate chemically similar odorants or odorant mixtures. Our work suggests that precisely tuned GABAergic inhibition onto M/T cells is crucial for M/T cell spike pattern separation needed to distinguish closely similar odours.
Assuntos
Interneurônios/metabolismo , Bulbo Olfatório/metabolismo , Percepção Olfatória/fisiologia , Olfato/fisiologia , Simportadores/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Aldeídos/química , Aldeídos/farmacologia , Animais , Expressão Gênica , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microtomia , Odorantes/análise , Bulbo Olfatório/citologia , Bulbo Olfatório/efeitos dos fármacos , Condutos Olfatórios/citologia , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/metabolismo , Técnicas de Patch-Clamp , Simportadores/deficiência , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Técnicas de Cultura de Tecidos , Valeratos/química , Valeratos/farmacologia , Ácido gama-Aminobutírico/farmacologia , Cotransportadores de K e Cl-RESUMO
In mammals, olfactory perception is based on the combinatorial activation of G protein-coupled receptors. Identifying the full repertoire of receptors activated by a given odorant in vivo, a quest that has been hampered for over 20 years by technical difficulties, would represent an important step in deciphering the rules governing chemoperception. We found that odorants induced a fast and reversible concentration-dependent decrease in the transcription of genes corresponding to activated receptors in intact mice. On the basis of this finding, we developed a large-scale transcriptomic approach to uncover receptor-ligand pairs in vivo. We identified the mouse and rat odorant receptor signatures corresponding to specific odorants. Finally, we found that this approach, which can be used for species for which no genomic sequence is available, is also applicable to non-vertebrate species such as Drosophila.
Assuntos
Perfilação da Expressão Gênica/métodos , Neurônios Receptores Olfatórios/metabolismo , Receptores Odorantes/metabolismo , Olfato/fisiologia , Animais , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Neuronal pattern separation is thought to enable the brain to disambiguate sensory stimuli with overlapping features, thereby extracting valuable information. In the olfactory system, it remains unknown whether pattern separation acts as a driving force for sensory discrimination and the learning thereof. We found that overlapping odor-evoked input patterns to the mouse olfactory bulb (OB) were dynamically reformatted in the network on the timescale of a single breath, giving rise to separated patterns of activity in an ensemble of output neurons, mitral/tufted (M/T) cells. Notably, the extent of pattern separation in M/T assemblies predicted behavioral discrimination performance during the learning phase. Furthermore, exciting or inhibiting GABAergic OB interneurons, using optogenetics or pharmacogenetics, altered pattern separation and thereby odor discrimination learning in a bidirectional way. In conclusion, we propose that the OB network can act as a pattern separator facilitating olfactory stimulus distinction, a process that is sculpted by synaptic inhibition.