MeCP2 and non-CG DNA methylation stabilize the expression of long genes that distinguish closely related neuron types.

The diversity of mammalian neurons is delineated by subtle gene expression differences that may require specialized mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and use non-CG DNA methylation (mCA), together with the Rett syndrome protein methyl-CpG-binding protein 2 (MeCP2), to control gene expression. However, whether these distinctive gene structures and molecular machinery regulate neuronal diversity remains unexplored.

Modular horizontal network within mouse primary visual cortex.

Interactions between feedback connections from higher cortical areas and local horizontal connections within primary visual cortex (V1) were shown to play a role in contextual processing in different behavioral states. Layer 1 (L1) is an important part of the underlying network. This cell-sparse layer is a target of feedback and local inputs, and nexus for contacts onto apical dendrites of projection neurons in the layers below.

Non-CG DNA methylation and MeCP2 stabilize repeated tuning of long genes that distinguish closely related neuron types.

The extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require specialized molecular mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and utilize neuron-enriched non-CG DNA methylation (mCA) together with the Rett syndrome protein, MeCP2, to control gene expression, but the function of these unique gene structures and machinery in regulating finely resolved neuron type-specific gene programs has not been explored. Here, we employ epigenomic and spatial transcriptomic analyses to discover a major role for mCA and MeCP2 in maintaining neuron type-specific gene programs at the finest scale of cellular resolution.

Integration of Feedforward and Feedback Information Streams in the Modular Architecture of Mouse Visual Cortex.

Radial cell columns are a hallmark feature of cortical architecture in many mammalian species. It has long been held, based on the lack of orientation columns, that such functional units are absent in rodent primary visual cortex (V1). These observations led to the view that rodent visual cortex has a fundamentally different network architecture than that of carnivores and primates.

Hierarchical and nonhierarchical features of the mouse visual cortical network.

Neocortical computations underlying vision are performed by a distributed network of functionally specialized areas. Mouse visual cortex, a dense interareal network that exhibits hierarchical properties, comprises subnetworks interconnecting distinct processing streams. To determine the layout of the mouse visual hierarchy, we have evaluated the laminar patterns formed by interareal axonal projections originating in each of ten areas.

Spatial Clustering of Inhibition in Mouse Primary Visual Cortex.

Whether mouse visual cortex contains orderly feature maps is debated. The overlapping pattern of geniculocortical inputs with M2 muscarinic acetylcholine receptor-rich patches in layer 1 (L1) suggests a non-random architecture. Here, we found that L1 inputs from the lateral posterior thalamus (LP) avoid patches and target interpatches.

A dominant role for the beta 4 nicotinic receptor subunit in nicotinic modulation of glomerular microcircuits in the mouse olfactory bulb.

Nicotinic acetylcholine receptors (nAChRs) regulate information transfer across the main olfactory bulb by instituting a high-pass intensity filter allowing for the filtering out of weak inputs. Excitation-driven inhibition of the glomerular microcircuit via GABA release from periglomerular cells appears to underlie this effect of nAChR activation. The multiplicity of nAChR subtypes and cellular locations raises questions about their respective roles in mediating their effects on the glomerular output.

A Laminar Organization for Selective Cortico-Cortical Communication.

The neocortex is central to mammalian cognitive ability, playing critical roles in sensory perception, motor skills and executive function. This thin, layered structure comprises distinct, functionally specialized areas that communicate with each other through the axons of pyramidal neurons. For the hundreds of such cortico-cortical pathways to underlie diverse functions, their cellular and synaptic architectures must differ so that they result in distinct computations at the target projection neurons.

Recruitment of inhibition and excitation across mouse visual cortex depends on the hierarchy of interconnecting areas.

Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relative recruitment of inhibitory and excitatory neurons within an area controls the gain of neurons for appropriate stimulus coding. We examined how such a balance of inhibition and excitation is differentially recruited across multiple levels of a cortical hierarchy by mapping the locations and strengths of synaptic inputs to pyramidal and parvalbumin (PV)-expressing neurons in feedforward and feedback pathways interconnecting primary (V1) and two higher visual areas.

Modularity in the Organization of Mouse Primary Visual Cortex.

Layer 1 (L1) of primary visual cortex (V1) is the target of projections from many brain regions outside of V1. We found that inputs to the non-columnar mouse V1 from the dorsal lateral geniculate nucleus and feedback projections from multiple higher cortical areas to L1 are patchy. The patches are matched to a pattern of M2 muscarinic acetylcholine receptor expression at fixed locations of mouse, rat, and monkey V1.

Paying attention to smell: cholinergic signaling in the olfactory bulb.

The tractable, layered architecture of the olfactory bulb (OB), and its function as a relay between odor input and higher cortical processing, makes it an attractive model to study how sensory information is processed at a synaptic and circuit level. The OB is also the recipient of strong neuromodulatory inputs, chief among them being the central cholinergic system. Cholinergic axons from the basal forebrain modulate the activity of various cells and synapses within the OB, particularly the numerous dendrodendritic synapses, resulting in highly variable responses of OB neurons to odor input that is dependent upon the behavioral state of the animal.

Nicotinic receptors modulate olfactory bulb external tufted cells via an excitation-dependent inhibitory mechanism.

Olfactory bulb (OB) glomeruli, the initial sites of synaptic processing of odor information, exhibit high levels of nicotinic acetylcholine receptor (nAChR) expression and receive strong cholinergic input from the basal forebrain. The role of glomerular nAChRs in olfactory processing, however, remains to be elucidated. External tufted (ET) cells are a major source of excitation in the glomerulus and an important component of OB physiology.

Nicotinic receptor-mediated filtering of mitral cell responses to olfactory nerve inputs involves the α3β4 subtype.

Acetylcholine (ACh) plays a major role in the processing of sensory inputs. Cholinergic input to the mammalian olfactory bulb modulates odor discrimination and perceptual learning by mechanisms that have yet to be elucidated. We have used the mouse olfactory bulb to examine the role of nicotinic ACh receptors (nAChRs) in regulating the responses of mitral cells (MCs), the output neurons of the olfactory bulb, to olfactory nerve input.