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1.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437090

RESUMO

The ability to perceive and respond to environmental stimuli emerges in the absence of sensory experience. Spontaneous retinal activity prior to eye opening guides the refinement of retinotopy and eye-specific segregation in mammals, but its role in the development of higher-order visual response properties remains unclear. Here, we describe a transient window in neonatal mouse development during which the spatial propagation of spontaneous retinal waves resembles the optic flow pattern generated by forward self-motion. We show that wave directionality requires the same circuit components that form the adult direction-selective retinal circuit and that chronic disruption of wave directionality alters the development of direction-selective responses of superior colliculus neurons. These data demonstrate how the developing visual system patterns spontaneous activity to simulate ethologically relevant features of the external world and thereby instruct self-organization.


Assuntos
Fluxo Óptico , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Visão Ocular/fisiologia , Vias Visuais , Potenciais de Ação , Células Amácrinas/fisiologia , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Proteínas do Citoesqueleto/genética , Camundongos , Movimento (Física) , Mutação , Piridazinas/farmacologia , Receptores de GABA-A/metabolismo , Retina/crescimento & desenvolvimento , Análise Espaço-Temporal , Colículos Superiores/fisiologia
2.
Cell ; 184(16): 4299-4314.e12, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34297923

RESUMO

Retinal ganglion cells (RGCs) are the sole output neurons that transmit visual information from the retina to the brain. Diverse insults and pathological states cause degeneration of RGC somas and axons leading to irreversible vision loss. A fundamental question is whether manipulation of a key regulator of RGC survival can protect RGCs from diverse insults and pathological states, and ultimately preserve vision. Here, we report that CaMKII-CREB signaling is compromised after excitotoxic injury to RGC somas or optic nerve injury to RGC axons, and reactivation of this pathway robustly protects RGCs from both injuries. CaMKII activity also promotes RGC survival in the normal retina. Further, reactivation of CaMKII protects RGCs in two glaucoma models where RGCs degenerate from elevated intraocular pressure or genetic deficiency. Last, CaMKII reactivation protects long-distance RGC axon projections in vivo and preserves visual function, from the retina to the visual cortex, and visually guided behavior.

4.
Neuron ; 109(3): 502-515.e7, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33290732

RESUMO

In mammals with binocular vision, integration of the left and right visual scene relies on information in the center visual field, which are relayed from each retina in parallel and merge in the primary visual cortex (V1) through the convergence of ipsi- and contralateral geniculocortical inputs as well as transcallosal projections between two visual cortices. The developmental assembly of this binocular circuit, especially the transcallosal pathway, remains incompletely understood. Using genetic methods in mice, we found that several days before eye-opening, retinal and callosal activities drive massive apoptosis of GABAergic chandelier cells (ChCs) in the binocular region of V1. Blockade of ChC elimination resulted in a contralateral eye-dominated V1 and deficient binocular vision. As pre-vision retinal activities convey the left-right organization of the visual field, their regulation of ChC density through the transcallosal pathway may prime a nascent binocular territory for subsequent experience-driven tuning during the post-vision critical period.


Assuntos
Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Retina/fisiologia , Visão Binocular/fisiologia , Córtex Visual/fisiologia , Animais , Apoptose/fisiologia , Período Crítico Psicológico , Camundongos , Camundongos Transgênicos , Córtex Visual/crescimento & desenvolvimento , Campos Visuais/fisiologia , Vias Visuais/crescimento & desenvolvimento , Vias Visuais/fisiologia
5.
Nat Methods ; 17(12): 1262-1271, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33139894

RESUMO

Achieving a comprehensive understanding of brain function requires multiple imaging modalities with complementary strengths. We present an approach for concurrent widefield optical and functional magnetic resonance imaging. By merging these modalities, we can simultaneously acquire whole-brain blood-oxygen-level-dependent (BOLD) and whole-cortex calcium-sensitive fluorescent measures of brain activity. In a transgenic murine model, we show that calcium predicts the BOLD signal, using a model that optimizes a gamma-variant transfer function. We find consistent predictions across the cortex, which are best at low frequency (0.009-0.08 Hz). Furthermore, we show that the relationship between modality connectivity strengths varies by region. Our approach links cell-type-specific optical measurements of activity to the most widely used method for assessing human brain function.


Assuntos
Mapeamento Encefálico/métodos , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Animais , Gasometria , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Fluorescência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Transgênicos , Oxigênio/análise
6.
Neuron ; 108(1): 33-43, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058764

RESUMO

Optical imaging has revolutionized our ability to monitor brain activity, spanning spatial scales from synapses to cells to circuits. Here, we summarize the rapid development and application of mesoscopic imaging, a widefield fluorescence-based approach that balances high spatiotemporal resolution with extraordinarily large fields of view. By leveraging the continued expansion of fluorescent reporters for neuronal activity and novel strategies for indicator expression, mesoscopic analysis enables measurement and correlation of network dynamics with behavioral state and task performance. Moreover, the combination of widefield imaging with cellular resolution methods such as two-photon microscopy and electrophysiology is bridging boundaries between cellular and network analyses. Overall, mesoscopic imaging provides a powerful option in the optical toolbox for investigation of brain function.


Assuntos
Encéfalo/patologia , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Neurônios/patologia , Imagem Óptica/métodos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiologia , Cálcio/metabolismo , Humanos , Microscopia Intravital , Neurônios/metabolismo , Neurônios/fisiologia
7.
Elife ; 92020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32420870

RESUMO

Convenient, efficient and fast whole-brain delivery of transgenes presents a persistent experimental challenge in neuroscience. Recent advances demonstrate whole-brain gene delivery by retro-orbital injection of virus, but slow and sparse expression and the large injection volumes required make this approach cumbersome, especially for developmental studies. We developed a novel method for efficient gene delivery across the central nervous system in neonatal mice and rats starting as early as P1 and persisting into adulthood. The method employs transverse sinus injections of 2-4 µL of AAV9 at P0. Here, we describe how to use this method to label and/or genetically manipulate cells in the neonatal rat and mouse brain. The protocol is fast, simple, can be readily adopted by any laboratory, and utilizes the widely available AAV9 capsid. The procedure is adaptable for diverse experimental applications ranging from biochemistry, anatomical and functional mapping, gene expression, silencing, and editing.


Assuntos
Encéfalo/metabolismo , Dependovirus/genética , Técnicas de Transferência de Genes , Infusões Intraventriculares , Transgenes/genética , Animais , Animais Geneticamente Modificados , Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-Evans
8.
Nat Methods ; 17(1): 107-113, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31686040

RESUMO

Spontaneous and sensory-evoked activity propagates across varying spatial scales in the mammalian cortex, but technical challenges have limited conceptual links between the function of local neuronal circuits and brain-wide network dynamics. We present a method for simultaneous cellular-resolution two-photon calcium imaging of a local microcircuit and mesoscopic widefield calcium imaging of the entire cortical mantle in awake mice. Our multi-scale approach involves a microscope with an orthogonal axis design where the mesoscopic objective is oriented above the brain and the two-photon objective is oriented horizontally, with imaging performed through a microprism. We also introduce a viral transduction method for robust and widespread gene delivery in the mouse brain. These approaches allow us to identify the behavioral state-dependent functional connectivity of pyramidal neurons and vasoactive intestinal peptide-expressing interneurons with long-range cortical networks. Our imaging system provides a powerful strategy for investigating cortical architecture across a wide range of spatial scales.


Assuntos
Encéfalo/fisiologia , Cálcio/metabolismo , Córtex Cerebral/fisiologia , Rede Nervosa/fisiologia , Neuroimagem/métodos , Neurônios/fisiologia , Fótons , Animais , Comportamento Animal , Encéfalo/citologia , Córtex Cerebral/citologia , Interneurônios/citologia , Interneurônios/fisiologia , Camundongos , Neurônios/citologia , Células Piramidais/citologia , Células Piramidais/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo
9.
Neuron ; 104(4): 711-723.e3, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31561919

RESUMO

Visual spatial perception in the mammalian brain occurs through two parallel pathways: one reaches the primary visual cortex (V1) through the thalamus and another the superior colliculus (SC) via direct projections from the retina. The origin, development, and relative function of these two evolutionarily distinct pathways remain obscure. We examined the early functional development of both pathways by simultaneously imaging pre- and post-synaptic spontaneous neuronal activity. We observed that the quality of retinal activity transfer to the thalamus and superior colliculus does not change across the first two postnatal weeks. However, beginning in the second postnatal week, retinal activity does not drive V1 as strongly as earlier wave activity, suggesting that intrinsic cortical activity competes with signals from the sensory periphery as the cortex matures. Together, these findings bring new insight into the function of the SC and V1 and the role of peripheral activity in driving both circuits across development.


Assuntos
Neurogênese/fisiologia , Colículos Superiores/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Colículos Superiores/crescimento & desenvolvimento , Córtex Visual/crescimento & desenvolvimento , Vias Visuais/crescimento & desenvolvimento
10.
Cell Rep ; 26(2): 381-393.e6, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30625321

RESUMO

Cortical plasticity peaks early in life and tapers in adulthood, as exemplified in the primary visual cortex (V1), wherein brief loss of vision in one eye reduces cortical responses to inputs from that eye during the critical period but not in adulthood. The synaptic locus of cortical plasticity and the cell-autonomous synaptic factors determining critical periods remain unclear. We here demonstrate that the immunoglobulin protein Synaptic Cell Adhesion Molecule 1 (SynCAM 1/Cadm1) is regulated by visual experience and limits V1 plasticity. Loss of SynCAM 1 selectively reduces the number of thalamocortical inputs onto parvalbumin (PV+) interneurons, impairing the maturation of feedforward inhibition in V1. SynCAM 1 acts in PV+ interneurons to actively restrict cortical plasticity, and brief PV+-specific knockdown of SynCAM 1 in adult visual cortex restores juvenile-like plasticity. These results identify a synapse-specific, cell-autonomous mechanism for thalamocortical visual circuit maturation and closure of the visual critical period.


Assuntos
Molécula 1 de Adesão Celular/metabolismo , Plasticidade Neuronal , Sinapses/metabolismo , Córtex Visual/metabolismo , Animais , Células Cultivadas , Feminino , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Parvalbuminas/genética , Parvalbuminas/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia , Tálamo/crescimento & desenvolvimento , Tálamo/metabolismo , Tálamo/fisiologia , Córtex Visual/citologia , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/fisiologia
11.
Nature ; 560(7719): 484-488, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30111842

RESUMO

In zebrafish, Müller glia (MG) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision1. In mammals, however, MG do not spontaneously re-enter the cell cycle to generate a population of stem or progenitor cells that differentiate into retinal neurons. Nevertheless, the regenerative machinery may exist in the mammalian retina, as retinal injury can stimulate MG proliferation followed by limited neurogenesis2-7. Therefore, there is still a fundamental question regarding whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Gene transfer of ß-catenin stimulates MG proliferation in the absence of injury in mouse retinas8. Here we report that following gene transfer of ß-catenin, cell-cycle-reactivated MG can be reprogrammed to generate rod photoreceptors by subsequent gene transfer of transcription factors essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1rd17Gnat2cpfl3 double mutant mice, a model of congenital blindness9,10, throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.


Assuntos
Reprogramação Celular/genética , Neurogênese , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células-Tronco/citologia , Animais , Cegueira/congênito , Cegueira/genética , Cegueira/terapia , Ciclo Celular , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Masculino , Camundongos , Neuroglia/citologia , Neuroglia/metabolismo , Medicina Regenerativa , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transducina/genética , Córtex Visual/citologia , Vias Visuais , beta Catenina/genética , beta Catenina/metabolismo
12.
Neuron ; 99(3): 511-524.e5, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30077356

RESUMO

Neurons in the developing auditory system exhibit spontaneous bursts of activity before hearing onset. How this intrinsically generated activity influences development remains uncertain, because few mechanistic studies have been performed in vivo. We show using macroscopic calcium imaging in unanesthetized mice that neurons responsible for processing similar frequencies of sound exhibit highly synchronized activity throughout the auditory system during this critical phase of development. Spontaneous activity normally requires synaptic excitation of spiral ganglion neurons (SGNs). Unexpectedly, tonotopic spontaneous activity was preserved in a mouse model of deafness in which glutamate release from hair cells is abolished. SGNs in these mice exhibited enhanced excitability, enabling direct neuronal excitation by supporting cell-induced potassium transients. These results indicate that homeostatic mechanisms maintain spontaneous activity in the pre-hearing period, with significant implications for both circuit development and therapeutic approaches aimed at treating congenital forms of deafness arising through mutations in key sensory transduction components.


Assuntos
Córtex Auditivo/crescimento & desenvolvimento , Vias Auditivas/crescimento & desenvolvimento , Audição/fisiologia , Homeostase/fisiologia , Gânglio Espiral da Cóclea/crescimento & desenvolvimento , Estimulação Acústica/métodos , Animais , Córtex Auditivo/química , Vias Auditivas/química , Cóclea/química , Cóclea/crescimento & desenvolvimento , Feminino , Células Ciliadas Auditivas/química , Células Ciliadas Auditivas/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Gânglio Espiral da Cóclea/química
13.
Cereb Cortex ; 28(4): 1168-1182, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334242

RESUMO

The dorsal Lateral Geniculate Nucleus (dLGN) is the primary image-forming target of the retina and shares a reciprocal connection with primary visual cortex (V1). Previous studies showed that corticothalamic input is essential for the development of thalamocortical projections, but less is known about the potential role of this reciprocal connection in the development of retinal projections. Here, we show a deficit of retinal innervation in the dLGN around E18.5 in Tra2ß conditional knockout (cKO) "cortexless" mice, an age when apoptosis occurs along the thalamocortical tract and in some dLGN neurons. In vivo electrophysiology experiments in the dLGN further confirmed the loss of functional retinal input. Experiments with N-methyl-d-aspartic acid-induced V1 lesion as well as Fezf2 cKO mice confirmed that the disruption of connections between the dLGN and V1 lead to abnormal retinal projections to the dLGN. Interestingly, retinal projections to the ventral Lateral Geniculate Nucleus (vLGN) and Superior Colliculus (SC) were normal in all 3 mice models. Finally, we show that the cortexless mice had worse performance than control mice in a go-no go task with visual cues. Our results provide evidence that the wiring of visual circuit from the retina to the dLGN and V1 thereafter is coordinated at a surprisingly early stage of circuit development.


Assuntos
Axônios/fisiologia , Corpos Geniculados/fisiologia , Retina/citologia , Colículos Superiores/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/toxicidade , Toxina da Cólera/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos , Agonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de Serina-Arginina/deficiência , Fatores de Processamento de Serina-Arginina/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Córtex Visual/lesões
14.
Annu Rev Neurosci ; 40: 499-538, 2017 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-28772103

RESUMO

Vision is the sense humans rely on most to navigate the world, make decisions, and perform complex tasks. Understanding how humans see thus represents one of the most fundamental and important goals of neuroscience. The use of the mouse as a model for parsing how vision works at a fundamental level started approximately a decade ago, ushered in by the mouse's convenient size, relatively low cost, and, above all, amenability to genetic perturbations. In the course of that effort, a large cadre of new and powerful tools for in vivo labeling, monitoring, and manipulation of neurons were applied to this species. As a consequence, a significant body of work now exists on the architecture, function, and development of mouse central visual pathways. Excitingly, much of that work includes causal testing of the role of specific cell types and circuits in visual perception and behavior-something rare to find in studies of the visual system of other species. Indeed, one could argue that more information is now available about the mouse visual system than any other sensory system, in any species, including humans. As such, the mouse visual system has become a platform for multilevel analysis of the mammalian central nervous system generally. Here we review the mouse visual system structure, function, and development literature and comment on the similarities and differences between the visual system of this and other model species. We also make it a point to highlight the aspects of mouse visual circuitry that remain opaque and that are in need of additional experimentation to enrich our understanding of how vision works on a broad scale.


Assuntos
Neurônios/fisiologia , Retina/fisiologia , Visão Ocular/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Percepção Visual/fisiologia , Animais , Camundongos , Neurônios/citologia , Retina/citologia , Córtex Visual/citologia , Vias Visuais/citologia
15.
Curr Opin Neurobiol ; 42: 136-143, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28088066

RESUMO

It is widely appreciated that neuronal activity contributes to the development of brain representations of the external world. In the visual system, in particular, it is well known that activity cooperates with molecular cues to establish the topographic organization of visual maps on a macroscopic scale [1,2] (Huberman et al., 2008; Cang and Feldheim, 2013), mapping axons in a retinotopic and eye-specific manner. In recent years, significant progress has been made in elucidating the role of activity in driving the finer-scale circuit refinement that shapes the receptive fields of individual cells. In this review, we focus on these recent breakthroughs-primarily in mice, but also in other mammals where noted.


Assuntos
Campos Visuais/fisiologia , Animais , Axônios/fisiologia , Sinais (Psicologia) , Retina/fisiologia , Campos Visuais/genética , Vias Visuais/fisiologia
16.
J Neurosci ; 36(42): 10707-10722, 2016 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-27798125

RESUMO

Although much is known about the regenerative capacity of retinal ganglion cells, very significant barriers remain in our ability to restore visual function following traumatic injury or disease-induced degeneration. Here we summarize our current understanding of the factors regulating axon guidance and target engagement in regenerating axons, and review the state of the field of neural regeneration, focusing on the visual system and highlighting studies using other model systems that can inform analysis of visual system regeneration. This overview is motivated by a Society for Neuroscience Satellite meeting, "Reconnecting Neurons in the Visual System," held in October 2015 sponsored by the National Eye Institute as part of their "Audacious Goals Initiative" and co-organized by Carol Mason (Columbia University) and Michael Crair (Yale University). The collective wisdom of the conference participants pointed to important gaps in our knowledge and barriers to progress in promoting the restoration of visual system function. This article is thus a summary of our existing understanding of visual system regeneration and provides a blueprint for future progress in the field.


Assuntos
Encéfalo/fisiologia , Fenômenos Fisiológicos Oculares , Vias Visuais/fisiologia , Animais , Axônios/fisiologia , Humanos , Nervo Óptico/fisiologia , Células Ganglionares da Retina/fisiologia , Vias Visuais/citologia
17.
J Neurosci ; 36(13): 3871-86, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-27030771

RESUMO

UNLABELLED: Retinal waves are correlated bursts of spontaneous activity whose spatiotemporal patterns are critical for early activity-dependent circuit elaboration and refinement in the mammalian visual system. Three separate developmental wave epochs or stages have been described, but the mechanism(s) of pattern generation of each and their distinct roles in visual circuit development remain incompletely understood. We used neuroanatomical,in vitroandin vivoelectrophysiological, and optical imaging techniques in genetically manipulated mice to examine the mechanisms of wave initiation and propagation and the role of wave patterns in visual circuit development. Through deletion of ß2 subunits of nicotinic acetylcholine receptors (ß2-nAChRs) selectively from starburst amacrine cells (SACs), we show that mutual excitation among SACs is critical for Stage II (cholinergic) retinal wave propagation, supporting models of wave initiation and pattern generation from within a single retinal cell type. We also demonstrate that ß2-nAChRs in SACs, and normal wave patterns, are necessary for eye-specific segregation. Finally, we show that Stage III (glutamatergic) retinal waves are not themselves necessary for normal eye-specific segregation, but elimination of both Stage II and Stage III retinal waves dramatically disrupts eye-specific segregation. This suggests that persistent Stage II retinal waves can adequately compensate for Stage III retinal wave loss during the development and refinement of eye-specific segregation. These experiments confirm key features of the "recurrent network" model for retinal wave propagation and clarify the roles of Stage II and Stage III retinal wave patterns in visual circuit development. SIGNIFICANCE STATEMENT: Spontaneous activity drives early mammalian circuit development, but the initiation and patterning of activity vary across development and among modalities. Cholinergic "retinal waves" are initiated in starburst amacrine cells and propagate to retinal ganglion cells and higher-order visual areas, but the mechanism responsible for creating their unique and critical activity pattern is incompletely understood. We demonstrate that cholinergic wave patterns are dictated by recurrent connectivity within starburst amacrine cells, and retinal ganglion cells act as "readouts" of patterned activity. We also show that eye-specific segregation occurs normally without glutamatergic waves, but elimination of both cholinergic and glutamatergic waves completely disrupts visual circuit development. These results suggest that each retinal wave pattern during development is optimized for concurrently refining multiple visual circuits.


Assuntos
Potenciais de Ação/fisiologia , Células Amácrinas/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Retina/citologia , Vias Visuais/fisiologia , Potenciais de Ação/efeitos dos fármacos , Fatores Etários , Células Amácrinas/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Toxina da Cólera/metabolismo , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Colinérgicos/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/genética , Retina/efeitos dos fármacos , Retina/crescimento & desenvolvimento , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/fisiologia , Proteína Vesicular 1 de Transporte de Glutamato/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Vias Visuais/efeitos dos fármacos
18.
Nat Commun ; 6: 8005, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26272629

RESUMO

Retinitis pigmentosa is a leading cause of inherited blindness, with no effective treatment currently available. Mutations primarily in genes expressed in rod photoreceptors lead to early rod death, followed by a slower phase of cone photoreceptor death. Rd1 mice provide an invaluable animal model to evaluate therapies for the disease. We previously reported that overexpression of histone deacetylase 4 (HDAC4) prolongs rod survival in rd1 mice. Here we report a key role of a short N-terminal domain of HDAC4 in photoreceptor protection. Expression of this domain suppresses multiple cell death pathways in photoreceptor degeneration, and preserves even more rd1 rods than the full-length HDAC4 protein. Expression of a short N-terminal domain of HDAC4 as a transgene in mice carrying the rd1 mutation also prolongs the survival of cone photoreceptors, and partially restores visual function. Our results may facilitate the design of a small protein therapy for some forms of retinitis pigmentosa.


Assuntos
Histona Desacetilases/metabolismo , Histona Desacetilases/farmacologia , Células Fotorreceptoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Proteínas Repressoras/farmacologia , Retinite Pigmentosa/tratamento farmacológico , Visão Ocular/efeitos dos fármacos , Animais , Eletrorretinografia , Deleção de Genes , Regulação da Expressão Gênica , Genótipo , Células HEK293 , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Transgênicos , Estrutura Terciária de Proteína , Proteínas Repressoras/genética
19.
Dev Neurobiol ; 75(6): 621-40, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25787992

RESUMO

Spontaneous activity during early development is necessary for the formation of precise neural connections, but it remains uncertain whether activity plays an instructive or permissive role in brain wiring. In the visual system, retinal ganglion cell (RGC) projections to the brain form two prominent sensory maps, one reflecting eye of origin and the other retinotopic location. Recent studies provide compelling evidence supporting an instructive role for spontaneous retinal activity in the development of eye-specific projections, but evidence for a similarly instructive role in the development of retinotopy is more equivocal. Here, we report on experiments in which we knocked down the expression of ß2-containing nicotinic acetylcholine receptors (ß2-nAChRs) specifically in the retina through a Cre-loxP recombination strategy. Overall levels of spontaneous retinal activity in retina-specific ß2-nAChR mutant mice (Rx-ß2cKO), examined in vitro and in vivo, were reduced to a degree comparable to that observed in whole animal ß2-nAChR mouse mutants (ß2KO). However, many residual spontaneous waves in Rx-ß2cKO mice displayed local propagating features with strong correlations between nearby but not distant RGCs typical of waves observed in wild-type (WT) but not ß2KO mice. We further observed that eye-specific segregation was disrupted in Rx-ß2cKO mice, but retinotopy was spared in a competition-dependent manner. These results suggest that propagating patterns of spontaneous retinal waves are essential for normal development of the retinotopic map, even while overall activity levels are significantly reduced, and support an instructive role for spontaneous retinal activity in both eye-specific segregation and retinotopic refinement.


Assuntos
Mapeamento Encefálico , Retina/citologia , Células Ganglionares da Retina/fisiologia , Vias Visuais , Potenciais de Ação/fisiologia , Aminoácidos/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Transgênicos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Colículos Superiores , Vias Visuais/citologia , Vias Visuais/embriologia , Vias Visuais/crescimento & desenvolvimento
20.
Neuron ; 84(5): 1049-64, 2014 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-25466916

RESUMO

The elaboration of nascent synaptic connections into highly ordered neural circuits is an integral feature of the developing vertebrate nervous system. In sensory systems, patterned spontaneous activity before the onset of sensation is thought to influence this process, but this conclusion remains controversial, largely due to the inherent difficulty recording neural activity in early development. Here, we describe genetic and pharmacological manipulations of spontaneous retinal activity, assayed in vivo, that demonstrate a causal link between retinal waves and visual circuit refinement. We also report a decoupling of downstream activity in retinorecipient regions of the developing brain after retinal wave disruption. Significantly, we show that the spatiotemporal characteristics of retinal waves affect the development of specific visual circuits. These results conclusively establish retinal waves as necessary and instructive for circuit refinement in the developing nervous system and reveal how neural circuits adjust to altered patterns of activity prior to experience.


Assuntos
Potenciais de Ação/fisiologia , Receptores Nicotínicos/metabolismo , Retina/fisiologia , Vias Visuais/crescimento & desenvolvimento , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , AMP Cíclico/farmacologia , GMP Cíclico/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Lateralidade Funcional , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Técnicas In Vitro , Ácido Meclofenâmico/farmacologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , RNA Mensageiro/metabolismo , Receptores Nicotínicos/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Retina/citologia , Células Ganglionares da Retina/fisiologia
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