Double-μPeriscope, a tool for multilayer optical recordings, optogenetic stimulations or both

Intelligent behavior and cognitive functions in mammals depend on cortical microcircuits made up of a variety of excitatory and inhibitory cells that form a forest-like complex across six layers. Mechanistic understanding of cortical microcircuits requires both manipulation and monitoring of multiple layers and interactions between them. However, existing techniques are limited as to simultaneous monitoring and stimulation at different depths without damaging a large volume of cortical tissue. Here, we present a relatively simple and versatile method for delivering light to any two cortical layers simultaneously. The method uses a tiny optical probe consisting of two microprisms mounted on a single shaft. We demonstrate the versatility of the probe in three sets of experiments: first, two distinct cortical layers were optogenetically and independently manipulated; second, one layer was stimulated while the activity of another layer was monitored; third, the activity of thalamic axons distributed in two distinct cortical layers was simultaneously monitored in awake mice. Its simple-design, versatility, small-size, and low-cost allow the probe to be applied widely to address important biological questions.

Analysis of visual processing capabilities and neural coding strategies of a detailed model for laminar cortical microcircuits in mouse V1

The neocortex is a network of rather stereotypical cortical microcircuits that share an exquisite genetically encoded architecture: Neurons of a fairly large number of different types are distributed over several layers (laminae), with specific probabilities of synaptic connections that depend on the neuron types involved and their spatial locations. Most available knowledge about this structure has been compiled into a detailed model [Billeh et al., 2020] for a generic cortical microcircuit in the primary visual cortex, consisting of 51,978 neurons of 111 different types. We add a noise model to the network that is based on experimental data, and analyze the results of network computations that can be extracted by projection neurons on layer 5. We show that the resulting model acquires through alignment of its synaptic weights via gradient descent training the capability to carry out a number of demanding visual processing tasks. Furthermore, this weight-alignment induces specific neural coding features in the microcircuit model that match those found in the living brain: High dimensional neural codes with an arguably close to optimal power-law decay of explained variance of PCA components, specific relations between signal- and noise-coding dimensions, and network dynamics in a critical regime. Hence these important features of neural coding and dynamics of cortical microcircuits in the brain are likely to emerge from aspects of their genetically encoded architecture that are captured by this data-based model in combination with learning processes. In addition, the model throws new light on the relation between visual processing capabilities and details of neural coding.

EEG Biomarkers of reduced inhibition in human cortical microcircuits in depression

Major depressive disorder (depression) is a complex condition that involves multiple physiological mechanisms, spanning a range of spatial scales. Altered cortical inhibition is associated with treatment-resistant depression, and reduced dendritic inhibition by somatostatin-expressing (SST) interneurons has been strongly implicated in this aspect of the pathology. However, whether the effects of reduced SST inhibition on microcircuit activity have signatures detectible in electroencephalography (EEG) signals remains unknown. We used detailed models of human cortical layer 2/3 microcircuits with normal or reduced SST inhibition to simulate resting-state activity together with EEG signals in health and depression. We first show that the healthy microcircuit models exhibit emergent key features of resting-state EEG. We then simulated EEG from depression microcircuits and found a significant power increase in theta, alpha and low beta frequencies (4 - 15 Hz). Following spectral decomposition, we show that the power increase involved a combination of aperiodic broadband component, and a periodic theta and low beta components. Neuronal spiking showed a spike preference for the phase preceding the EEG trough, which did not differ between conditions. Our study thus used detailed computational models to identify EEG biomarkers of reduced SST inhibition in human cortical microcircuits in depression, which may serve to improve the diagnosis and stratification of depression subtypes, and in monitoring the effects of pharmacological modulation of inhibition for treating depression.

Double-μPeriscope: a tool for multi-layer optical recordings, optogenetic stimulations or both

Intelligent behavior and cognitive functions in mammals depend on cortical microcircuits made up of a variety of excitatory and inhibitory cells that form a forest-like complex across six layers. Mechanistic understanding of cortical microcircuits requires both manipulation and monitoring of multiple layers and interactions between them. However, existing techniques are limited as to simultaneous monitoring and stimulation at different depths without damaging a large volume of cortical tissue. Here, we present a relatively simple and versatile method for delivering light to any two cortical layers simultaneously. The method uses a tiny optical probe consisting of two micro-prisms mounted on a single shaft. We demonstrate the versatility of the probe in three sets of experiments: first, two distinct cortical layers were optogenetically and independently manipulated; second, one layer was stimulated while the activity of another layer was monitored; third, the activity of thalamic axons distributed in two distinct cortical layers were simultaneously monitored in awake mice. Its simple-design, versatility, small-size and low-cost allow the probe to be applied widely to address important biological questions.

Interneuronal dynamics facilitate the initiation of cortical spreading depression

Cortical spreading depression (CSD) is thought to precede migraine attacks with aura and is characterized by a slowly traveling wave of inactivity through cortical pyramidal cells. During CSD, pyramidal cells experience hyperexcitation with rapidly increasing firing rates, major changes in electrochemistry, and ultimately spike block that propagates slowly across the cortex. While the identifying characteristic of CSD is the pyramidal cell hyperexcitation and subsequent spike block, it is currently unknown how the dynamics of the cortical microcircuits and inhibitory interneurons affect the initiation of CSD.We tested the contribution of cortical inhibitory interneurons to the initiation of spike block using a cortical microcircuit model that takes into account changes in ion concentrations that result from neuronal firing. Our results show that interneuronal inhibition provides a wider dynamic range to the circuit and generally improves stability against spike block.Despite these beneficial effects, strong interneuronal firing contributed to rapidly changing extracellular ion concentrations, which facilitated hyperexcitation and led to spike block first in the interneuron and then in the pyramidal cell. In all cases, a loss of interneuronal firing triggered pyramidal cell spike block. However, preventing interneuronal spike block was insufficient to rescue the pyramidal cell from spike block. Our data thus demonstrate that while the role of interneurons in cortical microcircuits is complex, they are critical to the initiation of pyramidal cell spike block and CSD. We discuss the implications that localized effects on cortical interneurons have beyond the isolated microcircuit.

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories

SummaryDisinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory and excitatory neurons suggests that each circuit motif is controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a newly-developed genetically-encoded GRP sensor and trans-synaptic tracing we reveal that GRP regulates VIP cells via extrasynaptic diffusion from several putative local and long-range sources. In vivo photometry and CRISPR/Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and that GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

Neuron Geometry Underlies Universal Network Features in Cortical Microcircuits

ABSTRACTWhy do cortical microcircuits in a variety of brain regions express similar, highly nonrandom, network motifs? To what extent this structure is innate and how much of it is molded by plasticity and learning processes? To address these questions, we developed a general network science framework to quantify the contribution of neurons’ geometry and their embedding in cortical volume to the emergence of three-neuron network motifs. Applying this framework to a dense in silico reconstructed cortical microcircuits showed that the innate asymmetric neuron’s geometry underlies the universally recurring motif architecture. It also predicted the spatial alignment of cells composing the different triplets-motifs. These predictions were directly validated via in vitro 12-patch whole-cell recordings (7,309 triplets) from rat somatosensory cortex. We conclude that the local geometry of neurons imposes an innate, already structured, global network architecture, which serves as a skeleton upon which fine-grained structural and functional plasticity processes take place.