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1.
J Neurosci ; 40(30): 5807-5819, 2020 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-32561674

RESUMEN

Simple stimuli have been critical to understanding neural population codes in sensory systems. Yet it remains necessary to determine the extent to which this understanding generalizes to more complex conditions. To examine this problem, we measured how populations of direction-selective ganglion cells (DSGCs) from the retinas of male and female mice respond to a global motion stimulus with its direction and speed changing dynamically. We then examined the encoding and decoding of motion direction in both individual and populations of DSGCs. Individual cells integrated global motion over ∼200 ms, and responses were tuned to direction. However, responses were sparse and broadly tuned, which severely limited decoding performance from small DSGC populations. In contrast, larger populations compensated for response sparsity, enabling decoding with high temporal precision (<100 ms). At these timescales, correlated spiking was minimal and had little impact on decoding performance, unlike results obtained using simpler local motion stimuli decoded over longer timescales. We use these data to define different DSGC population decoding regimes that use or mitigate correlated spiking to achieve high-spatial versus high-temporal resolution.SIGNIFICANCE STATEMENT ON-OFF direction-selective ganglion cells (ooDSGCs) in the mammalian retina are typically thought to signal local motion to the brain. However, several recent studies suggest they may signal global motion. Here we analyze the fidelity of encoding and decoding global motion in a natural scene across large populations of ooDSGCs. We show that large populations of DSGCs are capable of signaling rapid changes in global motion.


Asunto(s)
Percepción de Movimiento/fisiología , Orientación/fisiología , Estimulación Luminosa/métodos , Células Ganglionares de la Retina/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA
2.
J Neurosci ; 39(34): 6798-6810, 2019 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-31285302

RESUMEN

A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells disappear and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and are thought to occur in response to deafferentation. How the remodeled retinal circuit affects visual processing following rod rescue is not known. To address this question, we generated male and female transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channels exhibit a resting membrane potential that was ~10 mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.SIGNIFICANCE STATEMENT Current strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neurons function within a complex neural circuitry, which also becomes degraded during disease. It is not known whether rescued neurons and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward dendrites of rod bipolar cells re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.


Asunto(s)
Retina/patología , Degeneración Retiniana/patología , Células Fotorreceptoras Retinianas Bastones , Transducción de Señal/fisiología , Sinapsis/fisiología , Animales , Canales Catiónicos Regulados por Nucleótidos Cíclicos/fisiología , Electrorretinografía , Humanos , Ratones , Ratones Transgénicos , Plasticidad Neuronal/fisiología , Estimulación Luminosa , Células Fotorreceptoras de Vertebrados/fisiología , Células Bipolares de la Retina/fisiología , Degeneración Retiniana/inducido químicamente , Transmisión Sináptica , Tamoxifeno
3.
Neuron ; 100(1): 216-228.e6, 2018 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-30220512

RESUMEN

Direction-selective ganglion cells (DSGCs) deliver signals from the retina to multiple brain areas to indicate the presence and direction of motion. Delivering reliable signals in response to motion is critical across light levels. Here we determine how populations of DSGCs adapt to changes in light level, from moonlight to daylight. Using large-scale measurements of neural activity, we demonstrate that the population of DSGCs switches encoding strategies across light levels. Specifically, the direction tuning of superior (upward)-preferring ON-OFF DSGCs becomes broader at low light levels, whereas other DSGCs exhibit stable tuning. Using a conditional knockout of gap junctions, we show that this differential adaptation among superior-preferring ON-OFF DSGCs is caused by connexin36-mediated electrical coupling and differences in effective GABAergic inhibition. Furthermore, this adaptation strategy is beneficial for balancing motion detection and direction estimation at the lower signal-to-noise ratio encountered at night. These results provide insights into how light adaptation impacts motion encoding in the retina.


Asunto(s)
Adaptación Ocular/fisiología , Uniones Comunicantes/fisiología , Percepción de Movimiento/fisiología , Células Ganglionares de la Retina/fisiología , Animales , Conexinas/metabolismo , Ratones , Ratones Noqueados , Proteína delta-6 de Union Comunicante
4.
Elife ; 72018 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-29611808

RESUMEN

A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here, we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism's importance in forming circuit-specific sublayers.


Asunto(s)
Células Amacrinas/fisiología , Neurópilo/fisiología , Retina/embriología , Células Ganglionares de la Retina/fisiología , Animales , Proteínas de la Membrana/metabolismo , Ratones
5.
Physiol Rep ; 4(7)2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27053295

RESUMEN

Animals often encounter large increases in odor intensity that can persist for many seconds. These increases in the background odor are often accompanied by increases in the variance of the odor stimulus. Previous studies have shown that a persistent odor stimulus (odor background) results in a decrease in the response to brief odor pulses in the olfactory receptor neurons (ORNs). However, the contribution of adapting mechanisms beyond theORNs is not clear. Thus, it is unclear how adaptive mechanisms are distributed within the olfactory circuit and what impact downstream adaptation may have on the encoding of odor stimuli. In this study, adaptation to the same odor stimulus is examined at multiple levels in the well studied and accessibleDrosophilaolfactory system. The responses of theORNs are compared to the responses of the second order, projection neurons (PNs), directly connected to them. Adaptation inPNspike rate was found to be much greater than adaptation in theORNspike rate. This greater adaptation allowsPNs to encode odor contrast (ratio of pulse intensity to background intensity) with little ambiguity. Moreover, distinct neural mechanisms contribute to different aspects of adaptation; adaptation to the background odor is dominated by adaptation in spike generation in bothORNs andPNs, while adaptation to the odor pulse is dominated by changes within olfactory transduction and the glomerulus. These observations suggest that the olfactory system adapts at multiple sites to better match its response gain to stimulus statistics.


Asunto(s)
Antenas de Artrópodos/fisiología , Drosophila/fisiología , Odorantes , Neuronas Receptoras Olfatorias/fisiología , Olfato , Potenciales de Acción , Adaptación Fisiológica , Animales , Antenas de Artrópodos/citología , Drosophila/citología , Transmisión Sináptica , Factores de Tiempo
6.
Neuron ; 89(2): 369-383, 2016 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-26796691

RESUMEN

Neural responses are noisy, and circuit structure can correlate this noise across neurons. Theoretical studies show that noise correlations can have diverse effects on population coding, but these studies rarely explore stimulus dependence of noise correlations. Here, we show that noise correlations in responses of ON-OFF direction-selective retinal ganglion cells are strongly stimulus dependent, and we uncover the circuit mechanisms producing this stimulus dependence. A population model based on these mechanistic studies shows that stimulus-dependent noise correlations improve the encoding of motion direction 2-fold compared to independent noise. This work demonstrates a mechanism by which a neural circuit effectively shapes its signal and noise in concert, minimizing corruption of signal by noise. Finally, we generalize our findings beyond direction coding in the retina and show that stimulus-dependent correlations will generally enhance information coding in populations of diversely tuned neurons.


Asunto(s)
Potenciales de Acción/fisiología , Red Nerviosa/fisiología , Estimulación Luminosa/métodos , Células Ganglionares de la Retina/fisiología , Sinapsis/fisiología , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/citología
7.
J Neurosci ; 33(15): 6310-20, 2013 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-23575830

RESUMEN

Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.


Asunto(s)
Inhibición Neural/fisiología , Células Ganglionares de la Retina/fisiología , Sinapsis/fisiología , Potenciales Sinápticos/fisiología , Potenciales de Acción/fisiología , Animales , Femenino , Macaca , Masculino , Estimulación Luminosa/métodos , Factores de Tiempo , Visión Ocular/fisiología , Campos Visuales/fisiología
9.
Nature ; 468(7326): 964-7, 2010 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-21131948

RESUMEN

Computation in the nervous system often relies on the integration of signals from parallel circuits with different functional properties. Correlated noise in these inputs can, in principle, have diverse and dramatic effects on the reliability of the resulting computations. Such theoretical predictions have rarely been tested experimentally because of a scarcity of preparations that permit measurement of both the covariation of a neuron's input signals and the effect on a cell's output of manipulating such covariation. Here we introduce a method to measure covariation of the excitatory and inhibitory inputs a cell receives. This method revealed strong correlated noise in the inputs to two types of retinal ganglion cell. Eliminating correlated noise without changing other input properties substantially decreased the accuracy with which a cell's spike outputs encoded light inputs. Thus, covariation of excitatory and inhibitory inputs can be a critical determinant of the reliability of neural coding and computation.


Asunto(s)
Modelos Neurológicos , Células Ganglionares de la Retina/fisiología , Sinapsis/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Conductividad Eléctrica , Potenciales Postsinápticos Excitadores/efectos de la radiación , Potenciales Postsinápticos Inhibidores/efectos de la radiación , Ratones , Inhibición Neural/fisiología , Inhibición Neural/efectos de la radiación , Estimulación Luminosa , Primates , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de la radiación , Sinapsis/efectos de la radiación
10.
J Assoc Res Otolaryngol ; 11(2): 203-22, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20165896

RESUMEN

In chickens, nonsensory supporting cells divide and regenerate auditory hair cells after injury. Anatomical evidence suggests that supporting cells can also transdifferentiate into hair cells without dividing. In this study, we characterized an organ culture model to study auditory hair cell regeneration, and we used these cultures to test if direct transdifferentiation alone can lead to significant hair cell regeneration. Control cultures (organs from posthatch chickens maintained without streptomycin) showed complete hair cell loss in the proximal (high-frequency) region by 5 days. In contrast, a 2-day treatment with streptomycin induced loss of hair cells from all regions by 3 days. Hair cell regeneration proceeded in culture, with the time course of supporting cell division and hair cell differentiation generally resembling in vivo patterns. The degree of supporting cell division depended upon the presence of streptomycin, the epithelial region, the type of culture media, and serum concentration. On average, 87% of the regenerated hair cells lacked the cell division marker BrdU despite its continuous presence, suggesting that most hair cells were regenerated via direct transdifferentiation. Addition of the DNA polymerase inhibitor aphidicolin to culture media prevented supporting cell division, but numerous hair cells were regenerated nonetheless. These hair cells showed signs of functional maturation, including stereociliary bundles and rapid uptake of FM1-43. These observations demonstrate that direct transdifferentiation is a significant mechanism of hair cell regeneration in the chicken auditory after streptomycin damage in vitro.


Asunto(s)
Células Ciliadas Auditivas/citología , Órgano Espiral/patología , Regeneración/fisiología , Estreptomicina/toxicidad , Animales , Antimetabolitos/farmacocinética , Afidicolina/farmacología , Bromodesoxiuridina/farmacocinética , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Diferenciación Celular/fisiología , División Celular/efectos de los fármacos , División Celular/fisiología , Embrión de Pollo , Pollos , Medio de Cultivo Libre de Suero/farmacología , Inhibidores Enzimáticos/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/fisiología , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/fisiología , Técnicas de Cultivo de Órganos , Órgano Espiral/efectos de los fármacos , Órgano Espiral/fisiología , Inhibidores de la Síntesis de la Proteína/toxicidad , Regeneración/efectos de los fármacos
11.
Dev Dyn ; 236(1): 156-70, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17096404

RESUMEN

In the avian inner ear, nonsensory supporting cells give rise to new sensory hair cells through two distinct processes: mitosis and direct transdifferentiation. Regulation of supporting cell behavior and cell fate specification during avian hair cell regeneration is poorly characterized. Expression of Atoh1, a proneural transcription factor necessary and sufficient for developmental hair cell specification, was examined using immunofluorescence in quiescent and regenerating hair cell epithelia of mature chickens. In untreated birds, Atoh1 protein was not detected in the auditory epithelium, which is quiescent. In contrast, numerous Atoh1-positive nuclei were seen in the utricular macula, which undergoes continual hair cell turnover. Atoh1-positive nuclei emerged in the auditory epithelium by 15 hr post-ototoxin administration, before overt hair cell damage and supporting cell re-entry into the cell cycle. Subsequently, Atoh1 labeling was seen in 15% of dividing supporting cells. During cell division, Atoh1 was distributed symmetrically to daughter cells, but Atoh1 levels were dramatically regulated shortly thereafter. After cellular differentiation, Atoh1 labeling was confined to hair cells regenerated through either mitosis or direct transdifferentiation. However, Atoh1 expression in dividing progenitors did not necessarily predict hair cell fate specification in daughter cells. Finally, predominant modes of hair cell regeneration varied significantly across the radial axis of the auditory epithelium, with mitosis most frequent neurally and direct transdifferentiation most frequent abneurally. These observations suggest a role for Atoh1 in re-specifying supporting cells and in biasing postmitotic cells toward the hair cell fate during hair cell regeneration in the mature chicken ear.


Asunto(s)
Proteínas Aviares/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Ciliadas Auditivas/fisiología , Regeneración , Células Madre/fisiología , Animales , Proteínas Aviares/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Embrión de Pollo , Pollos/genética , Pollos/metabolismo , Pollos/fisiología , Células Ciliadas Auditivas/citología , Células Ciliadas Auditivas/metabolismo , Inmunohistoquímica , Mitosis , Células Madre/citología , Células Madre/metabolismo , Regulación hacia Arriba
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