Brief Bursts Self-Inhibit and Correlate the Pyramidal Network

Inhibitory pathways are an essential component in the function of the neocortical microcircuitry. Despite the relatively small fraction of inhibitory neurons in the neocortex, these neurons are strongly activated due to their high connectivity rate and the intricate manner in which they interconnect with pyramidal cells (PCs). One prominent pathway is the frequency-dependent disynaptic inhibition (FDDI) formed between layer 5 PCs and mediated by Martinotti cells (MCs). Here, we show that simultaneous short bursts in four PCs are sufficient to exert FDDI in all neighboring PCs within the dimensions of a cortical column. This powerful inhibition is mediated by few interneurons, leading to strongly correlated membrane fluctuations and synchronous spiking between PCs simultaneously receiving FDDI. Somatic integration of such inhibition is independent and electrically isolated from monosynaptic excitation formed between the same PCs. FDDI is strongly shaped by I(h) in PC dendrites, which determines the effective integration time window for inhibitory and excitatory inputs. We propose a key disynaptic mechanism by which brief bursts generated by a few PCs can synchronize the activity in the pyramidal network.     

Electrical consequences of spine dimensions in a model of a cortical spiny stellate cell completely reconstructed from serial thin sections

We built a passive compartmental model of a cortical spiny stellate cell from the barrel cortex of the mouse that had been reconstructed in its entirety from electron microscopic analysis of serial thin sections (White and Rock, 1980). Morphological data included dimensions of soma and all five dendrites, neck lengths and head diameters of all 380 spines (a uniform neck diameter of 0.1 m was assumed), locations of all symmetrical and asymmetrical (axo-spinous) synapses, and locations of all 43 thalamocortical (TC) synapses (as identified from the consequences of a prior thalamic lesion). In the model, unitary excitatory synaptic inputs had a peak conductance change of 0.5 nS at 0.2 msec; conclusions were robust over a wide range of assumed passive-membrane parameters. When recorded at the soma, all unitary EPSPs, which were initiated at the spine heads, were relatively iso-efficient; each produced about 1 mV somatic depolarization regardless of spine location or geometry. However, in the spine heads there was a twentyfold variation in EPSP amplitudes, largely reflecting the variation in spine neck lengths. Synchronous activation of the TC synapses produced a somatic depolarization probably sufficient to fire the neuron; doubling or halving the TC spine neck diameters had only minimal effect on the amplitude of the composite TC-EPSP. As have others, we also conclude that from a somato-centric viewpoint, changes in spine geometry would have relatively little direct influence on amplitudes of EPSPs recorded at the soma, especially for a distributed, synchronously activated input such as the TC pathway. However, consideration of the detailed morphology of an entire neuron indicates that, from a dendro-centric point of view, changes in spine dimension can have a very significant electrical impact on local processing near the sites of input.     

Propagation of action potentials along complex axonal trees. Model and implementation.

Axonal trees are typically morphologically and physiologically complicated structures. Because of this complexity, axonal trees show a large repertoire of behavior: from transmission lines with delay, to frequency filtering devices in both temporal and spatial domains. Detailed theoretical exploration of the electrical behavior of realistically complex axonal trees is notably lacking, mainly because of the absence of a simple modeling tool. AXONTREE is an attempt to provide such a simulator. It is written in C for the SUN workstation and implements both a detailed compartmental modeling of Hodgkin and Huxley-like kinetics, and a more abstract, event-driven, modeling approach. The computing module of AXONTREE is introduced together with its input/output features. These features allow graphical construction of arbitrary trees directly on the computer screen, and superimposition of the results on the simulated structure. Several numerical improvements that increase the computational efficiency by a factor of 5-10 are presented; most notable is a novel method of dynamic lumping of the modeled tree into simpler representations ("equivalent cables"). AXONTREE's performance is examined using a reconstructed terminal of an axon from a Y cell in cat visual cortex. It is demonstrated that realistically complicated axonal trees can be handled efficiently. The application of AXONTREE for the study of propagation delays along axonal trees is presented in the companion paper (Manor et al., 1991).     

Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules

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Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model

The evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human (Homo sapiens) and six chimpanzee (Pan troglodytes) induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species.     

Nonlinear cable properties of the giant axon of the cockroach Periplaneta americana

The steady state nonlinear properties of the giant axon membrane of the cockroach Periplaneta americana were studied by means of intracellular electrodes. The resistivity of this membrane markedly decreases in response to small subthreshold depolarizations. The specific slope resistance is reduced by twofold at 5 mV depolarization and by a factor of 14 at 20 mV depolarization. As a result, the spatial decay, V(X), of depolarizing potentials is enhanced when compared with the passive (exponential) decay. This enhancement is maximal at a distance of 1-1.5 mm from a point of subthreshold (0-20 mV) depolarizing perturbation. At that distance, the difference between the actual potential and the potential expected in the passive axon is approximately 30%. The effects of membrane rectification on V(X) were analyzed quantitatively with a novel derivation based on Cole's theorem, which enables one to calculate V(X) directly from the input current-voltage (I0-V) relation of a long axon. It is shown that when the experimental I0-V curve is replotted as (I0Rin)-1 against V (where Rin is the input resistance at the resting potential), the integral between any two potentials (V1 greater than V2) on this curve is the distance, in units of the resting space constant, over which V1 attenuates to V2. Excellent agreement was found between the experimental V(X) and the predicted value based solely on the input I0-V relation. The results demonstrate that the rectifying properties of the giant axon membrane must be taken into account when the electrotonic spread of even small subthreshold potentials is studied, and that, in the steady state, this behavior can be extracted from measurements at a single point. The effect of rectification on synaptic efficacy is also discussed.     

Membrane Properties of Striatal Direct and Indirect Pathway Neurons in Mouse and Rat Slices and Their Modulation by Dopamine

D1 and D2 receptor expressing striatal medium spiny neurons (MSNs) are ascribed to striatonigral (“direct”) and striatopallidal (“indirect”) pathways, respectively, that are believed to function antagonistically in motor control. Glutamatergic synaptic transmission onto the two types is differentially affected by Dopamine (DA), however, less is known about the effects on MSN intrinsic electrical properties. Using patch clamp recordings, we comprehensively characterized the two pathways in rats and mice, and investigated their DA modulation. We identified the direct pathway by retrograde labeling in rats, and in mice we used transgenic animals in which EGFP is expressed in D1 MSNs. MSNs were subjected to a series of current injections to pinpoint differences between the populations, and in mice also following bath application of DA. In both animal models, most electrical properties were similar, however, membrane excitability as measured by step and ramp current injections consistently differed, with direct pathway MSNs being less excitable than their counterparts. DA had opposite effects on excitability of D1 and D2 MSNs, counteracting the initial differences. Pronounced changes in AP shape were seen in D2 MSNs. In direct pathway MSNs, excitability increased across experimental conditions and parameters, and also when applying DA or the D1 agonist SKF-81297 in presence of blockers of cholinergic, GABAergic, and glutamatergic receptors. Thus, DA induced changes in excitability were D1 R mediated and intrinsic to direct pathway MSNs, and not a secondary network effect of altered synaptic transmission. DAergic modulation of intrinsic properties therefore acts in a synergistic manner with previously reported effects of DA on afferent synaptic transmission and dendritic processing, supporting the antagonistic model for direct vs. indirect striatal pathway function.     

Axons as computing devices: basic insights gained from models.

Detailed models of single neurons are typically focused on the dendritic tree and ignore the axonal tree, assuming that the axon is a simple transmission line. In the last 40 years, however, several theoretical and experimental studies have suggested that axons could implement information processing tasks by exploiting: 1) the time delay in action potential (AP) propagation along the axon; 2) the differential filtering of APs into the axonal subtrees; and 3) their activity-dependent excitability. Models for axonal trees have attempted to examine the feasibility of these ideas. However, because the physiological and anatomical data on axons are seriously limited, realistic models of axons have not been developed. The present paper summarizes the main insights that were gained from simplified models of axons; it also highlights the stochastic nature of axons, a topic that was largely neglected in classical models of axons. The advance of new experimental techniques makes it now possible to pay a very close experimental visit to axons. Theoretical tools and fast computers enable to go beyond the simplified models and to construct realistic models of axons. When tightly linked, experiments and theory will help to unravel how axons share the information processing tasks that single neurons implement.