Slow oscillations and sleep spindles are hallmarks of the EEG during slow-wave sleep (SWS). Both oscillatory events, especially when co-occurring in the constellation of spindles nesting in the slow oscillation upstate, are considered to support memory formation and underlying synaptic plasticity. The regulatory mechanisms of this function at the circuit level are poorly understood. Here, using two-photon imaging in mice, we relate EEG-recorded slow oscillations and spindles to calcium signals recorded from the soma of cortical putative pyramidal-like (Pyr) cells and neighboring parvalbumin-positive interneurons (PV-Ins) or somatostatin-positive interneurons (SOM-Ins). Pyr calcium activity was increased more than threefold when spindles co-occurred with slow oscillation upstates compared with slow oscillations or spindles occurring in isolation. Independent of whether or not a spindle was nested in the slow oscillation upstate, the slow oscillation downstate was preceded by enhanced calcium signal in SOM-Ins that vanished during the upstate, whereas spindles were associated with strongly increased PV-In calcium activity. Additional wide-field calcium imaging of Pyr cells confirmed the enhanced calcium activity and its widespread topography associated with spindles nested in slow oscillation upstates. In conclusion, when spindles are nested in slow oscillation upstates, maximum Pyr activity appears to concur with strong perisomatic inhibition of Pyr cells via PV-Ins and low dendritic inhibition via SOM-Ins (i.e., conditions that might optimize synaptic plasticity within local cortical circuits).

https://www.pnas.org/content/pnas/115/39/E9220.full.pdf

Cortical circuit activity underlying sleep slow oscillations and spindles.

Inhibitory Interneurons Regulate Temporal Precision and Correlations in Cortical Circuits.

We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3. 

Local connectivity and synaptic dynamics in mouse and human neocortex

Sensory perception depends on neocortical computations that contextually adjust sensory signals in different internal and environmental contexts. Neocortical layer 1 (L1) is the main target of cortical and subcortical inputs that provide "top-down" information for context-dependent sensory processing. Although L1 is devoid of excitatory cells, it contains the distal "tuft" dendrites of pyramidal cells (PCs) located in deeper layers. L1 also contains a poorly characterized population of GABAergic interneurons (INs), which regulate the impact that different top-down inputs have on PCs. A poor comprehension of L1 IN subtypes and how they affect PC activity has hampered our understanding of the mechanisms that underlie contextual modulation of sensory processing. We used novel genetic strategies in male and female mice combined with electrophysiological and morphological methods to help resolve differences that were unclear when using only electrophysiological and/or morphological approaches. We discovered that L1 contains four distinct populations of INs, each with a unique molecular profile, morphology, and electrophysiology, including a previously overlooked IN population (named here "canopy cells") representing 40% of L1 INs. In contrast to what is observed in other layers, most L1 neurons appear to be unique to the layer, highlighting the specialized character of the signal processing that takes place in L1. This new understanding of INs in L1, as well as the application of genetic methods based on the markers described here, will enable investigation of the cellular and circuit mechanisms of top-down processing in L1 with unprecedented detail.SIGNIFICANCE STATEMENT Neocortical layer 1 (L1) is the main target of corticocortical and subcortical projections that mediate top-down or context-dependent sensory perception. However, this unique layer is often referred to as "enigmatic" because its neuronal composition has been difficult to determine. Using a combination of genetic, electrophysiological, and morphological approaches that helped to resolve differences that were unclear when using a single approach, we were able to decipher the neuronal composition of L1. We identified markers that distinguish L1 neurons and found that the layer contains four populations of GABAergic interneurons, each with unique molecular profiles, morphologies, and electrophysiological properties. These findings provide a new framework for studying the circuit mechanisms underlying the processing of top-down inputs in neocortical L1.

https://www.jneurosci.org/content/jneuro/39/1/125.full.pdf

Four Unique Interneuron Populations Reside in Neocortical Layer 1.

Functions of the neocortex depend on its bidirectional communication with the thalamus, via cortico-thalamo-cortical (CTC) loops. Recent work dissecting the synaptic connectivity in these loops is generating a clearer picture of their cellular organization. Here, we review findings across sensory, motor and cognitive areas, focusing on patterns of cell type-specific synaptic connections between the major types of cortical and thalamic neurons. We outline simple and complex CTC loops, and note features of these loops that appear to be general versus specialized. CTC loops are tightly interlinked with local cortical and corticocortical (CC) circuits, forming extended chains of loops that are probably critical for communication across hierarchically organized cerebral networks. Such CTC-CC loop chains appear to constitute a modular unit of organization, serving as scaffolding for area-specific structural and functional modifications. Inhibitory neurons and circuits are embedded throughout CTC loops, shaping the flow of excitation. We consider recent findings in the context of established CTC and CC circuit models, and highlight current efforts to pinpoint cell type-specific mechanisms in CTC loops involved in consciousness and perception. As pieces of the connectivity puzzle fall increasingly into place, this knowledge can guide further efforts to understand structure-function relationships in CTC loops.

Untangling the cortico-thalamo-cortical loop: cellular pieces of a knotty circuit puzzle.

Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs.

Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex.

Author response: Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex

Disinhibition of cortical excitatory cell gate information flow through and between cortical columns. The major contribution of Martinotti cells (MC) is providing dendritic inhibition to excitatory neurons and therefore they are a main component of disinhibitory connections. Here we show by means of optogenetics that MC in layers II/III of the mouse primary somatosensory cortex are inhibited by both parvalbumin (PV)- and vasoactive intestinal polypeptide (VIP)-expressing cells. Paired recordings revealed stronger synaptic input onto MC from PV cells than from VIP cells. Moreover, PV cell input showed frequency-independent depression, whereas VIP cell input facilitated at high frequencies. These differences in the properties of the two unitary connections enable disinhibition with distinct temporal features.

Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells.

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Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex.

Author response: Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex

Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells.