RESUMO
In many parts of the nervous system, neuronal somata display orderly spatial arrangements. In the retina, neurons of numerous individual subtypes form regular arrays called mosaics: they are less likely to be near neighbours of the same subtype than would occur by chance, resulting in 'exclusion zones' that separate them. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements. Remarkably, mosaics are independent of each other: although a neuron of one subtype is unlikely to be adjacent to another of the same subtype, there is no restriction on its spatial relationship to neighbouring neurons of other subtypes. This independence has led to the hypothesis that molecular cues expressed by specific subtypes pattern mosaics by mediating homotypic (within-subtype) short-range repulsive interactions. So far, however, no molecules have been identified that show such activity, so this hypothesis remains untested. Here we demonstrate in mouse that two related transmembrane proteins, MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells. MEGF10 and 11 and their invertebrate relatives Caenorhabditis elegans CED-1 and Drosophila Draper have hitherto been studied primarily as receptors necessary for engulfment of debris following apoptosis or axonal injury. Our results demonstrate that members of this gene family can also serve as subtype-specific ligands that pattern neuronal arrays.
Assuntos
Células Amácrinas/citologia , Proteínas de Membrana/metabolismo , Células Horizontais da Retina/citologia , Células Amácrinas/metabolismo , Animais , Adesão Celular , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligantes , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Células Fotorreceptoras de Vertebrados/metabolismo , Células Horizontais da Retina/metabolismoRESUMO
The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXVα1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations.
Assuntos
Percepção de Movimento/fisiologia , Estimulação Luminosa/métodos , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Vias Visuais/citologia , Vias Visuais/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Caderinas/biossíntese , Dendritos/metabolismo , Dendritos/ultraestrutura , Metaloproteinases da Matriz Associadas à Membrana/biossíntese , Camundongos , Camundongos Transgênicos , Retina/citologia , Retina/metabolismoRESUMO
The rodent olfactory bulb incorporates thousands of newly generated inhibitory neurons daily throughout adulthood, but the role of adult neurogenesis in olfactory processing is not fully understood. Here we adopted a genetic method to inducibly suppress adult neurogenesis and investigated its effect on behavior and bulbar activity. Mice without young adult-born neurons (ABNs) showed normal ability in discriminating very different odorants but were impaired in fine discrimination. Furthermore, two-photon calcium imaging of mitral cells (MCs) revealed that the ensemble odor representations of similar odorants were more ambiguous in the ablation animals. This increased ambiguity was primarily due to a decrease in MC suppressive responses. Intriguingly, these deficits in MC encoding were only observed during task engagement but not passive exposure. Our results indicate that young olfactory ABNs are essential for the enhancement of MC pattern separation in a task engagement-dependent manner, potentially functioning as a gateway for top-down modulation.
Assuntos
Comportamento Animal/fisiologia , Neurogênese/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Olfato/genética , Animais , Proteína Glial Fibrilar Ácida/genética , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese/genética , Neurônios/metabolismo , Neurônios/fisiologia , Odorantes , Bulbo Olfatório/fisiologia , Olfato/fisiologiaRESUMO
Recent studies revealed changes in odor representations in the olfactory bulb during active olfactory learning (Chu et al., 2016; Yamada et al., 2017). Specifically, mitral cell ensemble responses to very similar odorant mixtures sparsened and became more distinguishable as mice learned to discriminate the odorants over days (Chu et al., 2016). In this study, we explored whether changes in the sensory inputs to the bulb underlie the observed changes in mitral cell responses. Using two-photon calcium imaging to monitor the odor responses of the olfactory sensory neuron (OSN) axon terminals in the glomeruli of the olfactory bulb during a discrimination task, we found that OSN inputs to the bulb are stable during discrimination learning. During one week of training to discriminate between very similar odorant mixtures in a Go/No-go task, OSN responses did not show significant sparsening, and the responses to the trained similar odorants did not diverge throughout training. These results suggest that the adaptive changes of mitral cell responses during perceptual learning are ensured by mechanisms downstream of OSN input, possibly in local circuits within olfactory bulb.
Assuntos
Aprendizagem por Discriminação/fisiologia , Odorantes , Bulbo Olfatório/citologia , Percepção Olfatória/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Animais , Comportamento de Escolha/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Percepção Olfatória/efeitos dos fármacos , Neurônios Receptores Olfatórios/efeitos dos fármacos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
For reliable stimulus identification, sensory codes have to be robust by including redundancy to combat noise, but redundancy sacrifices coding efficiency. To address how experience affects the balance between the robustness and efficiency of sensory codes, we probed odor representations in the mouse olfactory bulb during learning over a week, using longitudinal two-photon calcium imaging. When mice learned to discriminate between two dissimilar odorants, responses of mitral cell ensembles to the two odorants gradually became less discrete, increasing the efficiency. In contrast, when mice learned to discriminate between two very similar odorants, the initially overlapping representations of the two odorants became progressively decorrelated, enhancing the robustness. Qualitatively similar changes were observed when the same odorants were experienced passively, a condition that would induce implicit perceptual learning. These results suggest that experience adjusts odor representations to balance the robustness and efficiency depending on the similarity of the experienced odorants.
Assuntos
Aprendizagem/fisiologia , Odorantes , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Animais , Caderinas/genética , Discriminação Psicológica/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologiaRESUMO
How are sensory representations in the brain influenced by the state of an animal? Here we use chronic two-photon calcium imaging to explore how wakefulness and experience shape odor representations in the mouse olfactory bulb. Comparing the awake and anesthetized state, we show that wakefulness greatly enhances the activity of inhibitory granule cells and makes principal mitral cell odor responses more sparse and temporally dynamic. In awake mice, brief repeated odor experience leads to a gradual and long-lasting (months) weakening of mitral cell odor representations. This mitral cell plasticity is odor specific, recovers gradually over months, and can be repeated with different odors. Furthermore, the expression of this experience-dependent plasticity is prevented by anesthesia. Together, our results demonstrate the dynamic nature of mitral cell odor representations in awake animals, which is constantly shaped by recent odor experience.
Assuntos
Dinâmica não Linear , Odorantes , Bulbo Olfatório/fisiologia , Olfato/fisiologia , Vigília/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Animais Recém-Nascidos , Proteínas Relacionadas a Caderinas , Caderinas/genética , Calmodulina/genética , Calmodulina/metabolismo , Glutamato Descarboxilase/genética , Proteínas de Fluorescência Verde/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/citologia , Proteína de Marcador Olfatório/genética , Condutos Olfatórios/fisiologia , Fatores de TempoRESUMO
Most regions of the CNS contain many subtypes of inhibitory interneurons with specialized roles in circuit function. In the mammalian retina, the â¼30 subtypes of inhibitory interneurons called amacrine cells (ACs) are generally divided into two groups: wide/medium-field GABAergic ACs and narrow-field glycinergic ACs, which mediate lateral and vertical interactions, respectively, within the inner plexiform layer. We used expression profiling and mouse transgenic lines to identify and characterize two closely related narrow-field AC subtypes. Both arise postnatally and one is neither glycinergic nor GABAergic (nGnG). Two transcription factors selectively expressed by these subtypes, Neurod6 and special AT-rich-sequence-binding protein 2 (Satb2), regulate a postmitotic cell fate choice between these subtypes. Satb2 induces Neurod6, which persists in nGnG ACs and promotes their fate but is downregulated in the related glycinergic AC subtype. Our results support the view that cell fate decisions made in progenitors and their progeny act together to diversify ACs.