Calcium Dynamics in Basal Dendrites of Layer 5A and 5B Pyramidal Neurons Is Tuned to the Cell-Type Specific Physiological Action Potential Discharge

Layer 5 (L5) is a major neocortical output layer containing L5A slender-tufted (L5A-st) and L5B thick-tufted (L5B-tt) pyramidal neurons. These neuron types differ in their in vivo firing patterns, connectivity and dendritic morphology amongst other features, reflecting their specific functional role within the neocortical circuits. Here, we asked whether the active properties of the basal dendrites that receive the great majority of synaptic inputs within L5 differ between these two pyramidal neuron classes. To quantify their active properties, we measured the efficacy with which action potential (AP) firing patterns backpropagate along the basal dendrites by measuring the accompanying calcium transients using two-photon laser scanning microscopy in rat somatosensory cortex slices. For these measurements we used both “artificial” three-AP patterns and more complex physiological AP patterns that were previously recorded in anesthetized rats in L5A-st and L5B-tt neurons in response to whisker stimulation. We show that AP patterns with relatively few APs (3APs) evoke a calcium response in L5B-tt, but not L5A-st, that is dependent on the temporal pattern of the three APs. With more complex in vivo recorded AP patterns, the average calcium response was similar in the proximal dendrites but with a decay along dendrites (measured up to 100 μm) of L5B-tt but not L5A-st neurons. Interestingly however, the whisker evoked AP patterns—although very different for the two cell types—evoke similar calcium responses. In conclusion, although the effectiveness with which different AP patterns evoke calcium transients vary between L5A-st and L5B-tt cell, the calcium influx appears to be tuned such that whisker-evoked calcium transients are within the same dynamic range for both cell types

Shared and divergent principles of synaptic transmission between cortical excitatory neurons in rodent and human brain

Information transfer between principal neurons in neocortex occurs through (glutamatergic) synaptic transmission. In this focussed review, we provide a detailed overview on the strength of synaptic neurotransmission between pairs of excitatory neurons in human and laboratory animals with a specific focus on data obtained using patch clamp electrophysiology. We reach two major conclusions: (1) the synaptic strength, measured as unitary excitatory postsynaptic potential (or uEPSP), is remarkably consistent across species, cortical regions, layers and/or cell-types (median 0.5 mV, interquartile range 0.4–1.0 mV) with most variability associated with the cell-type specific connection studied (min 0.1–max 1.4 mV), (2) synaptic function cannot be generalized across human and rodent, which we exemplify by discussing the differences in anatomical and functional properties of pyramidal-to-pyramidal connections within human and rodent cortical layers 2 and 3. With only a handful of studies available on synaptic transmission in human, it is obvious that much remains unknown to date. Uncovering the shared and divergent principles of synaptic transmission across species however, will almost certainly be a pivotal step toward understanding human cognitive ability and brain function in health and disease

Human Synapses Show a Wide Temporal Window for Spike-Timing-Dependent Plasticity

Throughout our lifetime, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. Synapses can bi-directionally alter strength and the magnitude and sign depend on the millisecond timing of presynaptic and postsynaptic action potential firing. Recent findings on laboratory animals have shown that neurons can show a variety of temporal windows for spike-timing-dependent plasticity (STDP). It is unknown what synaptic learning rules exist in human synapses and whether similar temporal windows for STDP at synapses hold true for the human brain. Here, we directly tested in human slices cut from hippocampal tissue removed for surgical treatment of deeper brain structures in drug-resistant epilepsy patients, whether adult human synapses can change strength in response to millisecond timing of pre- and postsynaptic firing. We find that adult human hippocampal synapses can alter synapse strength in response to timed pre- and postsynaptic activity. In contrast to rodent hippocampal synapses, the sign of plasticity does not sharply switch around 0-ms timing. Instead, both positive timing intervals, in which presynaptic firing preceded the postsynaptic action potential, and negative timing intervals, in which postsynaptic firing preceded presynaptic activity down to −80 ms, increase synapse strength (tLTP). Negative timing intervals between −80 to −130 ms induce a lasting reduction of synapse strength (tLTD). Thus, similar to rodent synapses, adult human synapses can show spike-timing-dependent changes in strength. The timing rules of STDP in human hippocampus, however, seem to differ from rodent hippocampus, and suggest a less strict interpretation of Hebb's predictions

Neural Representation of Motor Output, Context and Behavioral Adaptation in Rat Medial Prefrontal Cortex During Learned Behavior

Selecting behavioral outputs in a dynamic environment is the outcome of integrating multiple information streams and weighing possible action outcomes with their value. Integration depends on the medial prefrontal cortex (mPFC), but how mPFC neurons encode information necessary for appropriate behavioral adaptation is poorly understood. To identify spiking patterns of mPFC during learned behavior, we extracellularly recorded neuronal action potential firing in the mPFC of rats performing a whisker-based “Go”/“No-go” object localization task. First, we identify three functional groups of neurons, which show different degrees of spiking modulation during task performance. One group increased spiking activity during correct “Go” behavior (positively modulated), the second group decreased spiking (negatively modulated) and one group did not change spiking. Second, the relative change in spiking was context-dependent and largest when motor output had contextual value. Third, the negatively modulated population spiked more when rats updated behavior following an error compared to trials without integration of error information. Finally, insufficient spiking in the positively modulated population predicted erroneous behavior under dynamic “No-go” conditions. Thus, mPFC neuronal populations with opposite spike modulation characteristics differentially encode context and behavioral updating and enable flexible integration of error corrections in future actions

Human Cortical Pyramidal Neurons: From Spines to Spikes via Models

We present detailed models of pyramidal cells from human neocortex, including models on their excitatory synapses, dendritic spines, dendritic NMDA- and somatic/axonal Na+ spikes that provided new insights into signal processing and computational capabilities of these principal cells. Six human layer 2 and layer 3 pyramidal cells (HL2/L3 PCs) were modeled, integrating detailed anatomical and physiological data from both fresh and postmortem tissues from human temporal cortex. The models predicted particularly large AMPA- and NMDA-conductances per synaptic contact (0.88 and 1.31 nS, respectively) and a steep dependence of the NMDA-conductance on voltage. These estimates were based on intracellular recordings from synaptically-connected HL2/L3 pairs, combined with extra-cellular current injections and use of synaptic blockers, and the assumption of five contacts per synaptic connection. A large dataset of high-resolution reconstructed HL2/L3 dendritic spines provided estimates for the EPSPs at the spine head (12.7 ± 4.6 mV), spine base (9.7 ± 5.0 mV), and soma (0.3 ± 0.1 mV), and for the spine neck resistance (50–80 MΩ). Matching the shape and firing pattern of experimental somatic Na+-spikes provided estimates for the density of the somatic/axonal excitable membrane ion channels, predicting that 134 ± 28 simultaneously activated HL2/L3-HL2/L3 synapses are required for generating (with 50% probability) a somatic Na+ spike. Dendritic NMDA spikes were triggered in the model when 20 ± 10 excitatory spinous synapses were simultaneously activated on individual dendritic branches. The particularly large number of basal dendrites in HL2/L3 PCs and the distinctive cable elongation of their terminals imply that ~25 NMDA-spikes could be generated independently and simultaneously in these cells, as compared to ~14 in L2/3 PCs from the rat somatosensory cortex. These multi-sites non-linear signals, together with the large (~30,000) excitatory synapses/cell, equip human L2/L3 PCs with enhanced computational capabilities. Our study provides the most comprehensive model of any human neuron to-date demonstrating the biophysical and computational distinctiveness of human cortical neurons

Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons

High Bandwidth Synaptic Communication and Frequency Tracking in Human Neocortex

Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Calcium Dynamics in Basal Dendrites of Layer 5A and 5B Pyramidal Neurons Is Tuned to the Cell-Type Specific Physiological Action Potential Discharge

Layer 5 (L5) is a major neocortical output layer containing L5A slender-tufted (L5A-st) and L5B thick-tufted (L5B-tt) pyramidal neurons. These neuron types differ in their in vivo firing patterns, connectivity and dendritic morphology amongst other features, reflecting their specific functional role within the neocortical circuits. Here, we asked whether the active properties of the basal dendrites that receive the great majority of synaptic inputs within L5 differ between these two pyramidal neuron classes. To quantify their active properties, we measured the efficacy with which action potential (AP) firing patterns backpropagate along the basal dendrites by measuring the accompanying calcium transients using two-photon laser scanning microscopy in rat somatosensory cortex slices. For these measurements we used both "artificial" three-AP patterns and more complex physiological AP patterns that were previously recorded in anesthetized rats in L5A-st and L5B-tt neurons in response to whisker stimulation. We show that AP patterns with relatively few APs (3APs) evoke a calcium response in L5B-tt, but not L5A-st, that is dependent on the temporal pattern of the three APs. With more complex in vivo recorded AP patterns, the average calcium response was similar in the proximal dendrites but with a decay along dendrites (measured up to 100 μm) of L5B-tt but not L5A-st neurons. Interestingly however, the whisker evoked AP patterns-although very different for the two cell types-evoke similar calcium responses. In conclusion, although the effectiveness with which different AP patterns evoke calcium transients vary between L5A-st and L5B-tt cell, the calcium influx appears to be tuned such that whisker-evoked calcium transients are within the same dynamic range for both cell types

Network-neuron interactions underlying sensory responses of layer 5 pyramidal tract neurons in barrel cortex.

Neurons in the cerebral cortex receive thousands of synaptic inputs per second from thousands of presynaptic neurons. How the dendritic location of inputs, their timing, strength, and presynaptic origin, in conjunction with complex dendritic physiology, impact the transformation of synaptic input into action potential (AP) output remains generally unknown for in vivo conditions. Here, we introduce a computational approach to reveal which properties of the input causally underlie AP output, and how this neuronal input-output computation is influenced by the morphology and biophysical properties of the dendrites. We demonstrate that this approach allows dissecting of how different input populations drive in vivo observed APs. For this purpose, we focus on fast and broadly tuned responses that pyramidal tract neurons in layer 5 (L5PTs) of the rat barrel cortex elicit upon passive single whisker deflections. By reducing a multi-scale model that we reported previously, we show that three features are sufficient to predict with high accuracy the sensory responses and receptive fields of L5PTs under these specific in vivo conditions: the count of active excitatory versus inhibitory synapses preceding the response, their spatial distribution on the dendrites, and the AP history. Based on these three features, we derive an analytically tractable description of the input-output computation of L5PTs, which enabled us to dissect how synaptic input from thalamus and different cell types in barrel cortex contribute to these responses. We show that the input-output computation is preserved across L5PTs despite morphological and biophysical diversity of their dendrites. We found that trial-to-trial variability in L5PT responses, and cell-to-cell variability in their receptive fields, are sufficiently explained by variability in synaptic input from the network, whereas variability in biophysical and morphological properties have minor contributions. Our approach to derive analytically tractable models of input-output computations in L5PTs provides a roadmap to dissect network-neuron interactions underlying L5PT responses across different in vivo conditions and for other cell types