A hypothesis is presented that non-separability of degrees of freedom is the fundamental property underlying consciousness in physical systems. The amount of consciousness in a system is determined ...by the extent of non-separability and the number of degrees of freedom involved. Non-interacting and feedforward systems have zero consciousness, whereas most systems of interacting particles appear to have low non-separability and consciousness. By contrast, brain circuits exhibit high complexity and weak but tightly coordinated interactions, which appear to support high non-separability and therefore high amount of consciousness. The hypothesis applies to both classical and quantum cases, and we highlight the formalism employing the Wigner function (which in the classical limit becomes the Liouville density function) as a potentially fruitful framework for characterizing non-separability and, thus, the amount of consciousness in a system. The hypothesis appears to be consistent with both the Integrated Information Theory and the Orchestrated Objective Reduction Theory and may help reconcile the two. It offers a natural explanation for the physical properties underlying the amount of consciousness and points to methods of estimating the amount of non-separability as promising ways of characterizing the amount of consciousness.
The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically
. However, direct observation of cellular-level functional interactions across this hierarchy ...is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory
-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas
. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.
Neurons are frequently classified into distinct types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the ...transcriptomes and intrinsic physiological properties of over 4,200 mouse visual cortical GABAergic interneurons and reconstructed the local morphologies of 517 of those neurons. We find that most transcriptomic types (t-types) occupy specific laminar positions within visual cortex, and, for most types, the cells mapping to a t-type exhibit consistent electrophysiological and morphological properties. These properties display both discrete and continuous variation among t-types. Through multimodal integrated analysis, we define 28 met-types that have congruent morphological, electrophysiological, and transcriptomic properties and robust mutual predictability. We identify layer-specific axon innervation pattern as a defining feature distinguishing different met-types. These met-types represent a unified definition of cortical GABAergic interneuron types, providing a systematic framework to capture existing knowledge and bridge future analyses across different modalities.
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•Patch-seq data obtained from >4,200 GABAergic interneurons with >500 morphologies•Comprehensive characterization of morphoelectric features of transcriptomic types•28 interneuron met-types with congruent properties across data modalities•Different Sst met-types preferentially innervate different cortical layers
GABAergic cortical interneurons of the mouse visual cortex can be defined into 28 types based on their morphological, electrophysiological, and transcriptomic properties and are distinguished by their layer-specific axon innervation patterns.
Understanding the diversity of cell types in the brain has been an enduring challenge and requires detailed characterization of individual neurons in multiple dimensions. To systematically profile ...morpho-electric properties of mammalian neurons, we established a single-cell characterization pipeline using standardized patch-clamp recordings in brain slices and biocytin-based neuronal reconstructions. We built a publicly accessible online database, the Allen Cell Types Database, to display these datasets. Intrinsic physiological properties were measured from 1,938 neurons from the adult laboratory mouse visual cortex, morphological properties were measured from 461 reconstructed neurons, and 452 neurons had both measurements available. Quantitative features were used to classify neurons into distinct types using unsupervised methods. We established a taxonomy of morphologically and electrophysiologically defined cell types for this region of the cortex, with 17 electrophysiological types, 38 morphological types and 46 morpho-electric types. There was good correspondence with previously defined transcriptomic cell types and subclasses using the same transgenic mouse lines.
Dimerization-driven activation of the intracellular kinase domains of the epidermal growth factor receptor (EGFR) upon extracellular ligand binding is crucial to cellular pathways regulating ...proliferation, migration, and differentiation. Inactive EGFR can exist as both monomers and dimers, suggesting that the mechanism regulating EGFR activity may be subtle. The membrane itself may play a role but creates substantial difficulties for structural studies. Our molecular dynamics simulations of membrane-embedded EGFR suggest that, in ligand-bound dimers, the extracellular domains assume conformations favoring dimerization of the transmembrane helices near their N termini, dimerization of the juxtamembrane segments, and formation of asymmetric (active) kinase dimers. In ligand-free dimers, by holding apart the N termini of the transmembrane helices, the extracellular domains instead favor C-terminal dimerization of the transmembrane helices, juxtamembrane segment dissociation and membrane burial, and formation of symmetric (inactive) kinase dimers. Electrostatic interactions of EGFR’s intracellular module with the membrane are critical in maintaining this coupling.
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► Full-length EGFRs are modeled in a realistic membrane environment ► The models show how EGF binding controls the extracellular domains in EGFR dimers ► The trans- and juxtamembrane segments alternate between two dimer forms as a result ► Anionic lipids in the membrane are critical to the regulation of the kinase domains
Atomistic models of full-length EGFR based on computer simulations illustrate the conformational coupling between the extra- and intracellular components and show that the receptor’s interactions with the anionic lipids in the inner leaflet of the cell membrane are critical to its regulation.
The epidermal growth factor receptor (EGFR) is a key protein in cellular signaling, and its kinase domain (EGFR kinase) is an intensely pursued target of small-molecule drugs. Although both ...catalytically active and inactive conformations of EGFR kinase have been resolved crystallographically, experimental characterization of the transitions between these conformations remains difficult. Using unbiased, all-atom molecular dynamics simulations, we observed EGFR kinase spontaneously transition from the active to the socalled "Src-like inactive" conformation by way of two sets of intermediate conformations: One corresponds to a previously identified locally disordered state and the other to previously undescribed "extended" conformations, marked by the opening of the ATP-binding site between the two lobes of the kinase domain. We also simulated the protonation-dependent transition of EGFR kinase to another "Asp-Phe-Gly-out" ("DFG-out") inactive conformation and observed similar intermediate conformations. A key element observed in the simulated transitions is local unfolding, or "cracking," which supports a prediction of energy landscape theory. We used hydrogen-deuterium (H/D) exchange measurements to corroborate our simulations and found that the simulated intermediate conformations correlate better with the H/D exchange data than existing active or inactive EGFR kinase crystal structures. The intermediate conformations revealed by our simulations of the transition process differ significantly from the existing crystal structures and may provide unique possibilities for structure-based drug discovery.
How the epidermal growth factor receptor (EGFR) activates is incompletely understood. The intracellular portion of the receptor is intrinsically active in solution, and to study its regulation, we ...measured autophosphorylation as a function of EGFR surface density in cells. Without EGF, intact EGFR escapes inhibition only at high surface densities. Although the transmembrane helix and the intracellular module together suffice for constitutive activity even at low densities, the intracellular module is inactivated when tethered on its own to the plasma membrane, and fluorescence cross-correlation shows that it fails to dimerize. NMR and functional data indicate that activation requires an N-terminal interaction between the transmembrane helices, which promotes an antiparallel interaction between juxtamembrane segments and release of inhibition by the membrane. We conclude that EGF binding removes steric constraints in the extracellular module, promoting activation through N-terminal association of the transmembrane helices.
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► Interactions with the membrane help suppress ligand-independent EGFR activation ► Dependence of EGFR activation on cell surface density reveals control mechanisms ► Intrinsic dimerization of the cytoplasmic module is suppressed at the membrane ► Activation requires structural coupling of transmembrane and juxtamembrane segments
NMR and functional analyses of EGFR indicate that EGF binding removes steric constraints in the extracellular module, promoting activation through a specific configuration of the transmembrane helices and the release of inhibition by the plasma membrane.
The cellular components of mammalian neocortical circuits are diverse, and capturing this diversity in computational models is challenging. Here we report an approach for generating biophysically ...detailed models of 170 individual neurons in the Allen Cell Types Database to link the systematic experimental characterization of cell types to the construction of cortical models. We build models from 3D morphologies and somatic electrophysiological responses measured in the same cells. Densities of active somatic conductances and additional parameters are optimized with a genetic algorithm to match electrophysiological features. We evaluate the models by applying additional stimuli and comparing model responses to experimental data. Applying this technique across a diverse set of neurons from adult mouse primary visual cortex, we verify that models preserve the distinctiveness of intrinsic properties between subsets of cells observed in experiments. The optimized models are accessible online alongside the experimental data. Code for optimization and simulation is also openly distributed.
This work presents an all-atom molecular dynamics simulation of a complete virus, the satellite tobacco mosaic virus. Simulations with up to 1 million atoms for over 50 ns demonstrate the stability ...of the entire virion and of the RNA core alone, while the capsid without RNA exhibits a pronounced instability. Physical properties of the simulated virus particle including electrostatic potential, radial distribution of viral components, and patterns of correlated motion are analyzed, and the implications for the assembly and infection mechanism of the virus are discussed.
The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor ...tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.
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► EGFR kinase is intrinsically disordered in the dimerization interface ► Cancer mutations stabilize the interface, promoting EGFR dimerization ► High activity of EGFR cancer mutants is due primarily to enhanced dimerization ► Phosphorylation similarly promotes dimerization and allows autonomous signaling
A prevalent EGFR mutation linked to lung cancer was previously thought to promote activation of the monomeric form of the receptor. A combination of biochemical and long-timescale molecular dynamics experiments now provides evidence that this mutation promotes ligand-independent dimerization by stabilizing receptors' dimerization interface.
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