Jon Cafaro

Atoh1 expression defines activated progenitors and differentiating hair cells during avian hair cell regeneration

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. Developmental Dynamics 236:156–170, 2007.

Noise correlations improve response fidelity and stimulus encoding

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.

Regulation of Spatial Selectivity by Crossover Inhibition

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 cells 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.

Multiple sites of adaptation lead to contrast encoding in the Drosophila olfactory system.

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 the ORNs 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 accessible Drosophila olfactory system. The responses of the ORNs are compared to the responses of the second order, projection neurons (PNs), directly connected to them. Adaptation in PN spike rate was found to be much greater than adaptation in the ORN spike rate. This greater adaptation allows PNs 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 both ORNs and PNs, 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.

Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact

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.

Gap Junctions Contribute to Differential Light Adaptation across Direction-Selective Retinal Ganglion Cells

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.