Disruption of Cholinergic Retinal Waves Alters Visual Cortex Development and Function.

Retinal waves represent an early form of patterned spontaneous neural activity in the visual system. These waves originate in the retina before eye-opening and propagate throughout the visual system, influencing the assembly and maturation of subcortical visual brain regions. However, because it is technically challenging to ablate retina-derived cortical waves without inducing compensatory activity, the role these waves play in the development of the visual cortex remains unclear. To address this question, we used targeted conditional genetics to disrupt cholinergic retinal waves and their propagation to select regions of primary visual cortex, which largely prevented compensatory patterned activity. We find that loss of cholinergic retinal waves without compensation impaired the molecular and synaptic maturation of excitatory neurons located in the input layers of visual cortex, as well as layer 1 interneurons. These perinatal molecular and synaptic deficits also relate to functional changes observed at later ages. We find that the loss of perinatal cholinergic retinal waves causes abnormal visual cortex retinotopy, mirroring changes in the retinotopic organization of gene expression, and additionally impairs the processing of visual information. We further show that retinal waves are necessary for higher order processing of sensory information by impacting the state-dependent activity of layer 1 interneurons, a neuronal type that shapes neocortical state-modulation, as well as for state-dependent gain modulation of visual responses of excitatory neurons. Together, these results demonstrate that a brief targeted perinatal disruption of patterned spontaneous activity alters early cortical gene expression as well as synaptic and physiological development, and compromises both fundamental and, notably, higher-order functions of visual cortex after eye-opening.

Neuronal oscillator robustness to multiple global perturbations.

Neuronal activity depends on ion channels and biophysical processes that are strongly and differentially sensitive to physical variables such as temperature and pH. Nonetheless, neuronal oscillators can be surprisingly resilient to perturbations in these variables. We study a three-neuron pacemaker ensemble that drives the pyloric rhythm of the crab, Cancer borealis. These crabs routinely experience a number of global perturbations, including changes in temperature and pH. Although pyloric oscillations are robust to such changes, for sufficiently large deviations the rhythm reversibly breaks down. As temperature increases beyond a tipping point, oscillators transition to silence. Acidic pH deviations also show tipping points, with a reliable transition first to tonic spiking, then to silence. Surprisingly, robustness to perturbations in pH only moderately affects temperature robustness. Consistent with high animal-to-animal variability in biophysical circuit parameters, tipping points in temperature and pH vary across animals. However, the ordering and discrete classes of transitions at critical points are conserved. This implies that qualitative oscillator dynamics are preserved across animals despite high quantitative parameter variability. A universal model of bursting dynamics predicts the existence of these transition types and the order in which they occur.

The Interneuron Class Struggle.

In this issue of Cell, Gouwens et al. establish the state of the art for defining inhibitory cell types in the mouse neocortex. By combining morphological, electrophysiological, and transcriptomic features to classify interneurons in the mouse visual cortex, this work provides a roadmap for understanding the diversity of cell types and their functional role in cortical computations.

Modulation of cortical circuits by top-down processing and arousal state in health and disease.

In this review, we explore how contextual modulations of sensory processing are implemented within the local cortical circuit. We focus on contextual influences of global arousal state (e.g. how alert am I?), sensory predictions (e.g. which stimuli do I expect?), and top-down attention (what is relevant to me?). We review recent literature suggesting that these operations are implemented throughout sensory cortices, and are mediated by excitatory and inhibitory local circuits. By focusing on the circuit mechanisms of contextual modulation operations, we may begin to understand how mutations in GABAergic interneurons and alterations in neuromodulatory signaling lead to specific deficits of information processing in neuropsychiatric disease.