scholarly journals Bayesian modeling of BAC firing as a mechanism for apical amplification in neocortical pyramidal neurons

2019 ◽  
Author(s):  
Jim W. Kay ◽  
W. A. Phillips ◽  
Jaan Aru ◽  
Bruce P. Graham ◽  
Matthew E. Larkum
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Single Site ◽  
Biophysical Model ◽  
Cellular Mechanisms ◽  
Context Sensitive ◽  
Dendritic Shaft ◽  
Current Task ◽  
Integration Sites

AbstractPyramidal cells in layer 5 of the neocortex have two distinct integration sites. These cells integrate inputs to basal dendrites in the soma while integrating inputs to the tuft in a site at the top of the apical trunk. The two sites communicate by action potentials that backpropagate to the apical site and by backpropagation-activated calcium spikes (BAC firing) that travel from the apical to the somatic site. Six key messages arise from the probabilistic information-theoretic analyses of BAC firing presented here. First, we suggest that pyramidal neurons with BAC firing could convert the odds in favour of the presence of a feature given the basal data into the odds in favour of the presence of a feature given the basal data and the apical input, by a simple Bayesian calculation. Second, the strength of the cell’s response to basal input can be amplified when relevant to the current context, as specified by the apical input, without corrupting the message that it sends. Third, these analyses show rigorously how this apical amplification depends upon communication between the sites. Fourth, we use data on action potentials from a very detailed multi-compartmental biophysical model to study our general model in a more realistic setting, and demonstrate that it describes the data well. Fifth, this form of BAC firing meets criteria for distinguishing modulatory from driving interactions that have been specified using recent definitions of multivariate mutual information. Sixth, our general decomposition can be extended to cases where, instead of being purely driving or purely amplifying, apical and basal inputs can be partly driving and partly amplifying to various extents. These conclusions imply that an advance beyond the assumption of a single site of integration within pyramidal cells is needed, and suggest that the evolutionary success of neocortex may depend upon the cellular mechanisms of context-sensitive selective amplification hypothesized here.Author summaryThe cerebral cortex has a key role in conscious perception, thought, and action, and is predominantly composed of a particular kind of neuron: the pyramidal cells. The distinct shape of the pyramidal neuron with a long dendritic shaft separating two regions of profuse dendrites allows them to integrate inputs to the two regions separately and combine the results non-linearly to produce output. Here we show how inputs to this more distant site strengthen the cell’s output when it is relevant to the current task and environment. By showing that such neurons have capabilities that transcend those of neurons with the single site of integration assumed by many neuroscientists, this ‘splitting of the neuronal atom’ offers a radically new viewpoint from which to understand the evolution of the cortex and some of its many pathologies. This also suggests that approaches to artificial intelligence using neural networks might come closer to something analogous to real intelligence, if, instead of basing them on processing elements with a single site of integration, they were based on elements with two sites, as in cortex.

Axon terminal hyperexcitability associated with epileptogenesis in vitro. I. Origin of ectopic spikes

1993 ◽  
Vol 70 (3) ◽  
pp. 961-975 ◽  
Author(s):  
S. F. Stasheff ◽  
M. Hines ◽  
W. A. Wilson
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Model Neuron ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Initiation Site ◽  
Electrographic Seizures ◽  
Ca3 Pyramidal Cells

1. Intracellular and extracellular recording techniques were used to study the increase in ectopic (i.e., nonsomatic) action-potential generation occurring among CA3 pyramidal cells during the kindling-like induction of electrographic seizures (EGSs) in this subpopulation of the hippocampal slice. Kindling-like stimulus trains (60 Hz, 2 s) were delivered to s. radiatum of CA3 at 10-min intervals. As EGSs developed, the frequency of ectopic firing increased markedly (by 10.33 +/- 3.29 spikes/min, mean +/- SE, P << 0.01). Several methods were applied to determine the initiation site for these action potentials within the cell (axons vs. dendrites). 2. Collision tests were conducted between known antidromic and orthodromic action potentials in CA3 cells to determine the critical period, c, for collision. Attempts were then made to collide ectopic spikes with known antidromic action potentials. At intervals less than c, ectopic spikes failed to collide with antidromic ones, in 5 of 10 cases. In these cells, this clearly indicates that the ectopic spikes were themselves of axonal origin. In the remaining five cases, ectopic spikes collided with antidromic action potentials at intervals approximately equal to c, most likely because of interactions within the complex system of recurrent axon collaterals in CA3. 3. Action potentials of CA3 pyramidal cells were simulated with the use of a compartmental computer model, NEURON. These simulations were based on prior models of CA3 pyramidal neurons and of the motoneuron action potential. Simulated action potentials generated in axonal compartments possessed a prominent inflection on their rising phase (IS-SD break), which was difficult to appreciate in those spikes generated in somatic or dendritic compartments. 4. An analysis of action potentials recorded experimentally from CA3 pyramidal cells also showed that antidromic spikes possess a prominent IS-SD break that is not present in orthodromic spikes. In addition to identified antidromic action potentials, ectopic spikes also possess such an inflection. Together with the predictions of computer simulations, this analysis also indicates that ectopic spikes originate in the axons of CA3 cells. 5. Tetrodotoxin (TTX, 50 microM) was locally applied by pressure injection while monitoring ectopic spike activity. Localized application of TTX to regions of the slice that could include the axons but not the dendrites of recorded cells abolished or markedly reduced the frequency of ectopic spikes (n = 5), further confirming the hypothesis that these action potentials arise from CA3 axons.(ABSTRACT TRUNCATED AT 400 WORDS)

Fiberoptic System for Recording Dendritic Calcium Signals in Layer 5 Neocortical Pyramidal Cells in Freely Moving Rats

2007 ◽  
Vol 98 (3) ◽  
pp. 1791-1805 ◽  
Author(s):  
Masanori Murayama ◽  
Enrique Pérez-Garci ◽  
Hans-Rudolf Lüscher ◽  
Matthew E. Larkum
Keyword(s):  
Pyramidal Neurons ◽  
Calcium Influx ◽  
Signal To Noise Ratio ◽  
Pyramidal Cells ◽  
Cellular Mechanisms ◽  
Novel Approach ◽  
Specific Loading ◽  
Apical Dendrites

Calcium influx into the dendritic tufts of layer 5 neocortical pyramidal neurons modifies a number of important cellular mechanisms. It can trigger local synaptic plasticity and switch the firing properties from regular to burst firing. Due to methodological limitations, our knowledge about Ca2+ spikes in the dendritic tuft stems mostly from in vitro experiments. However, it has been speculated that regenerative Ca2+ events in the distal dendrites correlate with distinct behavioral states. Therefore it would be most desirable to be able to record these Ca2+ events in vivo, preferably in the behaving animal. Here, we present a novel approach for recording Ca2+ signals in the dendrites of populations of layer 5 pyramidal neurons in vivo, which ensures that all recorded fluorescence changes are due to intracellular Ca2+ signals in the apical dendrites. The method has two main features: 1) bolus loading of layer 5 with a membrane-permeant Ca2+ dye resulting in specific loading of pyramidal cell dendrites in the upper layers and 2) a fiberoptic cable attached to a gradient index lens and a prism reflecting light horizontally at 90° to the angle of the apical dendrites. We demonstrate that the in vivo signal-to-noise ratio recorded with this relatively inexpensive and easy-to-implement fiberoptic-based device is comparable to conventional camera-based imaging systems used in vitro. In addition, the device is flexible and lightweight and can be used for recording Ca2+ signals in the distal dendritic tuft of freely behaving animals.

scholarly journals A Multi-Scale Computational Model of the effects of TMS on Motor Cortex

2016 ◽  
Author(s):  
Hyeon Seo ◽  
Natalie Schaworonkow ◽  
Sung Chan Jun ◽  
Jochen Triesch
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Computational Model ◽  
Electric Fields ◽  
Action Potentials ◽  
Magnetic Stimulation ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Cell Types ◽  
Cortical Layer ◽  
Multi Scale

AbstractThe detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different cell types in motor cortex due to transcranial magnetic stimulation. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict detailed neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to predict activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also predicts differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of corctial pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.

scholarly journals Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

2021 ◽  
Author(s):  
Perry W.E. Spratt ◽  
Roy Ben-Shalom ◽  
Atehsa Sahagun ◽  
Caroline M. Keeshen ◽  
Stephan J. Sanders ◽  
...  
Keyword(s):  
Sodium Channel ◽  
High Frequency ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Autism Spectrum ◽  
Dynamic Clamp ◽  
Loss Of Function ◽  
Intrinsic Mechanism ◽  
Channel Loss

Loss-of-function variants in the gene SCN2A, which encodes the sodium channel NaV1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20-30% of children with these variants are co-morbid for epilepsy, with altered neuronal activity originating in neocortex, a region where NaV1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking NaV1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic clamp recordings revealed that NaV1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may therefore account for why SCN2A loss-of-function can paradoxically promote seizure.

scholarly journals Calcium dynamics in single spines during coincident pre- and postsynaptic activity depend on relative timing of back-propagating action potentials and subthreshold excitatory postsynaptic potentials

1998 ◽  
Vol 95 (16) ◽  
pp. 9596-9601 ◽  
Author(s):  
Helmut J. Koester ◽  
Bert Sakmann
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Small Time ◽  
Time Interval ◽  
Relative Timing ◽  
Excitatory Postsynaptic Potentials ◽  
Postsynaptic Potentials ◽  
Postsynaptic Activity ◽  
Basal Dendrites ◽  
Dendritic Shaft

We compared the transient increase of Ca2+ in single spines on basal dendrites of rat neocortical layer 5 pyramidal neurons evoked by subthreshold excitatory postsynaptic potentials (EPSPs) and back-propagating action potentials (APs) by using calcium fluorescence imaging. AP-evoked Ca2+ transients were detected in both the spines and in the adjacent dendritic shaft, whereas Ca2+ transients evoked by single EPSPs were largely restricted to a single active spine head. Calcium transients elicited in the active spines by a single AP or EPSP, in spines up to 80 μm for the soma, were of comparable amplitude. The Ca2+ transient in an active spine evoked by pairing an EPSP and a back-propagating AP separated by a time interval of 50 ms was larger if the AP followed the EPSP than if it preceded it. This difference reflected supra- and sublinear summation of Ca2+ transients, respectively. A comparable dependence of spinous Ca2+ transients on relative timing was observed also when short bursts of APs and EPSPs were paired. These results indicate that the amplitude of the spinous Ca2+ transients during coincident pre- and postsynaptic activity depended critically on the relative order of subthreshold EPSPs and back-propagating APs. Thus, in neocortical neurons the amplitude of spinous Ca2+ transients could encode small time differences between pre- and postsynaptic activity.

scholarly journals Somadendritic Backpropagation of Action Potentials in Cortical Pyramidal Cells of the Awake Rat

1998 ◽  
Vol 79 (3) ◽  
pp. 1587-1591 ◽  
Author(s):  
György Buzsáki ◽  
Adam Kandel
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Current Source ◽  
Pyramidal Cells ◽  
Apical Dendrite ◽  
Individual Layer ◽  
Awake Rat ◽  
Density Analysis ◽  
Freely Behaving ◽  
Layer V

Buzsáki, György and Adam Kandel. Somadendritic backpropagation of action potentials in cortical pyramidal cells of the awake rat. J. Neurophysiol. 79: 1587–1591, 1998. The invasion of fast (Na+) spikes from the soma into dendrites was studied in single pyramidal cells of the sensorimotor cortex by simultaneous extracellular recordings of the somatic and dendritic action potentials in freely behaving rats. Field potentials and unit activity were monitored with multiple-site silicon probes along trajectories perpendicular to the cortical layers at spatial intervals of 100 μm. Dendritic action potentials of individual layer V pyramidal neurons could be recorded up to 400 μm from the cell body. Action potentials were initiated at the somatic recording site and traveled back to the apical dendrite at a velocity of 0.67 m/s. Current source density analysis of the action potential revealed time shifted dipoles, supporting the view of active spike propagation in dendrites. The presented method is suitable for exploring the conditions affecting the somadendritic propagation action of potentials in the behaving animal.

scholarly journals Dopamine Increases Excitability of Pyramidal Neurons in Primate Prefrontal Cortex

2000 ◽  
Vol 84 (6) ◽  
pp. 2799-2809 ◽  
Author(s):  
Darrell A. Henze ◽  
Guillermo R. González-Burgos ◽  
Nathaniel N. Urban ◽  
David A. Lewis ◽  
German Barrionuevo
Keyword(s):  
Prefrontal Cortex ◽  
Action Potential ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Initiation Site ◽  
D1 Receptor ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms

Dopaminergic modulation of neuronal networks in the dorsolateral prefrontal cortex (PFC) is believed to play an important role in information processing during working memory tasks in both humans and nonhuman primates. To understand the basic cellular mechanisms that underlie these actions of dopamine (DA), we have investigated the influence of DA on the cellular properties of layer 3 pyramidal cells in area 46 of the macaque monkey PFC. Intracellular voltage recordings were obtained with sharp and whole cell patch-clamp electrodes in a PFC brain-slice preparation. All of the recorded neurons in layer 3 ( n = 86) exhibited regular spiking firing properties consistent with those of pyramidal neurons. We found that DA had no significant effects on resting membrane potential or input resistance of these cells. However DA, at concentrations as low as 0.5 μM, increased the excitability of PFC cells in response to depolarizing current steps injected at the soma. Enhanced excitability was associated with a hyperpolarizing shift in action potential threshold and a decreased first interspike interval. These effects required activation of D1-like but not D2-like receptors since they were inhibited by the D1 receptor antagonist SCH23390 (3 μM) but not significantly altered by the D2 antagonist sulpiride (2.5 μM). These results show, for the first time, that DA modulates the activity of layer 3 pyramidal neurons in area 46 of monkey dorsolateral PFC in vitro. Furthermore the results suggest that, by means of these effects alone, DA modulation would generally enhance the response of PFC pyramidal neurons to excitatory currents that reach the action potential initiation site.

scholarly journals Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer’s Disease

2020 ◽  
Vol 78 (3) ◽  
pp. 951-964
Author(s):  
Marvin Ruiter ◽  
Lotte J. Herstel ◽  
Corette J. Wierenga
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Early Stage ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Excitatory Input ◽  
Aβ Oligomers ◽  
Ca1 Pyramidal Neurons

Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNL-F-G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent transmission after Aβ treatment. We observed a similar, although weaker, reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.

scholarly journals Contextual Modulation in Mammalian Neocortex is Asymmetric

Symmetry ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 815 ◽  
Author(s):  
Jim W. Kay ◽  
William A. Phillips
Keyword(s):  
Information Theory ◽  
Transfer Function ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Neural Systems ◽  
Intracellular Recordings ◽  
Simple Arithmetic ◽  
Contextual Modulation ◽  
Context Sensitive

Neural systems are composed of many local processors that generate an output given their many inputs as specified by a transfer function. This paper studies a transfer function that is fundamentally asymmetric and builds on multi-site intracellular recordings indicating that some neocortical pyramidal cells can function as context-sensitive two-point processors in which some inputs modulate the strength with which they transmit information about other inputs. Learning and processing at the level of the local processor can then be guided by the context of activity in the system as a whole without corrupting the message that the local processor transmits. We use a recent advance in the foundations of information theory to compare the properties of this modulatory transfer function with that of the simple arithmetic operators. This advance enables the information transmitted by processors with two distinct inputs to be decomposed into those components unique to each input, that shared between the two inputs, and that which depends on both though it is in neither, i.e., synergy. We show that contextual modulation is fundamentally asymmetric, contrasts with all four simple arithmetic operators, can take various forms, and can occur together with the anatomical asymmetry that defines pyramidal neurons in mammalian neocortex.

Mechanisms Underlying Burst and Regular Spiking Evoked by Dendritic Depolarization in Layer 5 Cortical Pyramidal Neurons

1999 ◽  
Vol 81 (3) ◽  
pp. 1341-1354 ◽  
Author(s):  
Peter Schwindt ◽  
Wayne Crill
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Critical Level ◽  
Pyramidal Cells ◽  
Burst Firing ◽  
Action Current ◽  
Constant Frequency ◽  
Functional Implications ◽  
Cortical Pyramidal Neurons ◽  
Apical Dendrites

Mechanisms underlying burst and regular spiking evoked by dendritic depolarization in layer 5 cortical pyramidal neurons. Apical dendrites of layer 5 pyramidal cells in a slice preparation of rat sensorimotor cortex were depolarized focally by long-lasting glutamate iontophoresis while recording intracellularly from their soma. In most cells the firing pattern evoked by the smallest dendritic depolarization that evoked spikes consisted of repetitive bursts of action potentials. During larger dendritic depolarizations initial burst firing was followed by regular spiking. As dendritic depolarization was increased further the duration (but not the firing rate) of the regular spiking increased, and the duration of burst firing decreased. Depolarization of the soma in most of the same cells evoked only regular spiking. When the dendrite was depolarized to a critical level below spike threshold, intrasomatic current pulses or excitatory postsynaptic potentials also triggered bursts instead of single spikes. The bursts were driven by a delayed depolarization (DD) that was triggered in an all-or-none manner along with the first Na+ spike of the burst. Somatic voltage-clamp experiments indicated that the action current underlying the DD was generated in the dendrite and was Ca2+ dependent. Thus the burst firing was caused by a Na+ spike-linked dendritic Ca2+spike, a mechanism that was available only when the dendrite was adequately depolarized. Larger dendritic depolarization that evoked late, constant-frequency regular spiking also evoked a long-lasting, Ca2+-dependent action potential (a “plateau”). The duration of the plateau but not its amplitude was increased by stronger dendritic depolarization. Burst-generating dendritic Ca2+spikes could not be elicited during this plateau. Thus plateau initiation was responsible for the termination of burst firing and the generation of the constant-frequency regular spiking. We conclude that somatic and dendritic depolarization can elicit quite different firing patterns in the same pyramidal neuron. The burst and regular spiking observed during dendritic depolarization are caused by two types of Ca2+-dependent dendritic action potentials. We discuss some functional implications of these observations.

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