Layer 6A pyramidal cells subtypes form synaptic microcircuits with distinct functional and structural properties

Neocortical layer 6 plays a crucial role in sensorimotor coordination and integration through functionally segregated circuits linking intracortical and subcortical areas. However, because of the high neuronal heterogeneity and sparse intralaminar connectivity data on the cell-type specific synaptic microcircuits in layer 6 remain few and far between. To address this issue, whole-cell recordings combined with morphological reconstructions have been used to identify morphoelectric types of layer 6A pyramidal cells (PCs) in rat barrel cortex. Cortico-thalamic (CT), corticocortical (CC) and cortico-claustral (CCla) pyramidal cells have been distinguished based on to their distinct dendritic and axonal morphologies as well as their different electrophysiological properties. Here we demonstrate that these three types of layer 6A pyramidal cells innervate neighboring excitatory neurons with distinct synaptic properties: CT PCs establish weak facilitating synapses to other L6A PCs; CC PCs form synapses of moderate efficacy; while synapses made by putative CCla PCs display the highest release probability and a marked short-term depression. Furthermore, for excitatory-inhibitory synaptic connections in layer 6 we were able to show that both the presynaptic PC type and the postsynaptic interneuron type govern the dynamic properties of the of the respective synaptic connections. We have identified a functional division of local layer 6A excitatory microcircuits which may be responsible of the differential temporal engagement of layer 6 feed-forward and feedback networks. Our results provides a basis for further investigations on the long-range cortico-cortical, cortico-thalamic and cortico-claustral pathways.

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Cell Type-Specific Modulation of Layer 6A Excitatory Microcircuits by Acetylcholine in Rat Barrel Cortex

10.1101/701318 ◽

2019 ◽

Cited By ~ 2

Author(s):

Danqing Yang ◽

Robert Günter ◽

Guanxiao Qi ◽

Gabriele Radnikow ◽

Dirk Feldmeyer

Keyword(s):

Pyramidal Cell ◽

Barrel Cortex ◽

Glutamate Release ◽

Synaptic Connections ◽

Cell Type ◽

Presynaptic Neuron ◽

Synaptic Release ◽

Low Concentrations ◽

Cell Type Specific ◽

Behavioral States

AbstractAcetylcholine (ACh) is known to regulate cortical activity during different behavioral states, e.g. wakefulness and attention. Here we show a differential expression of muscarinic ACh receptors (mAChRs) and nicotinic AChRs (nAChRs) in different layer 6A (L6A) pyramidal cell (PC) types of somatosensory cortex. At low concentrations, ACh induced a persistent hyperpolarization in corticocortical (CC) but a depolarization in corticothalamic (CT) L6A PCs via M4 and M1 mAChRs, respectively. At ∼1 mM ACh depolarized exclusively CT PCs via α4β2 subunit-containing nAChRs without affecting CC PCs. Miniature EPSC frequency in CC PCs was decreased by ACh but increased in CT PCs. In synaptic connections with a presynaptic CC PC, glutamate release was suppressed via M4 mAChR activation but enhanced by nAChRs via α4β2 nAChRs when the presynaptic neuron was a CT PC. Thus, in layer 6A the interaction of mAChRs and nAChRs results in an altered excitability and synaptic release, effectively strengthening corticothalamic output while weakening corticocortical synaptic signaling.

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Cell type-specific effects of isoflurane on two distinct afferent inputs to cortical layer 1

10.1101/2020.05.18.102913 ◽

2020 ◽

Author(s):

Caitlin A. Murphy ◽

Matthew I. Banks

Keyword(s):

Ex Vivo ◽

Brain Slices ◽

Pyramidal Cells ◽

Cellular Level ◽

Cortical Layer ◽

Cell Type ◽

Specific Effects ◽

Primary Mouse ◽

Cell Type Specific ◽

Synaptic Responses

ABSTRACTBackgroundWhile their behavioral effects are well-characterized, the mechanisms by which anaesthetics induce loss of consciousness are largely unknown. Anaesthetics may disrupt integration and propagation of information in corticothalamic networks. Recent studies have shown that isoflurane diminishes synaptic responses of thalamocortical (TC) and corticocortical (CC) afferents in a pathway-specific manner. However, whether the synaptic effects of isoflurane observed in extracellular recordings persist at the cellular level has yet to be explored.MethodsHere, we activate TC and CC layer 1 inputs in non-primary mouse neocortex in ex vivo brain slices and explore the degree to which isoflurane modulates synaptic responses in pyramidal cells and in two inhibitory cell populations, somatostatin-positive (SOM+) and parvalbumin-positive (PV+) interneurons.ResultsWe show that the effects of isoflurane on synaptic responses and intrinsic properties of these cells varies among cell type and by cortical layer. Layer 1 inputs to L4 pyramidal cells were suppressed by isoflurane at both TC and CC synapses, while those to L2/3 pyramidal cells and PV+ interneurons were not. TC inputs to SOM+ cells were rarely observed at all, while CC inputs to SOM+ interneurons were robustly suppressed by isoflurane.ConclusionsThese results suggest a mechanism by which isoflurane disrupts integration and propagation of thalamocortical and intracortical signals.

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Cell-type specific innervation of cortical pyramidal cells at their apical dendrites

eLife ◽

10.7554/elife.46876 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Ali Karimi ◽

Jan Odenthal ◽

Florian Drawitsch ◽

Kevin M Boergens ◽

Moritz Helmstaedter

Keyword(s):

Electron Microscopy ◽

Pyramidal Cells ◽

Inhibitory Input ◽

Cell Type ◽

Cell Type Specific ◽

Cortical Regions ◽

Apical Dendrites ◽

Computational Properties

We investigated the synaptic innervation of apical dendrites of cortical pyramidal cells in a region between layers (L) 1 and 2 using 3-D electron microscopy applied to four cortical regions in mouse. We found the relative inhibitory input at the apical dendrite’s main bifurcation to be more than 2-fold larger for L2 than L3 and L5 thick-tufted pyramidal cells. Towards the distal tuft dendrites in upper L1, the relative inhibitory input was at least about 2-fold larger for L5 pyramidal cells than for all others. Only L3 pyramidal cells showed homogeneous inhibitory input fraction. The inhibitory-to-excitatory synaptic ratio is thus specific for the types of pyramidal cells. Inhibitory axons preferentially innervated either L2 or L3/5 apical dendrites, but not both. These findings describe connectomic principles for the control of pyramidal cells at their apical dendrites and support differential computational properties of L2, L3 and subtypes of L5 pyramidal cells in cortex.

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Distinct Electrophysiological Properties in Subtypes of Nonspiking Olfactory Local Interneurons Correlate With Their Cell Type–Specific Ca2+ Current Profiles

Journal of Neurophysiology ◽

10.1152/jn.00627.2009 ◽

2009 ◽

Vol 102 (5) ◽

pp. 2834-2845 ◽

Cited By ~ 24

Author(s):

Andreas Husch ◽

Moritz Paehler ◽

Debora Fusca ◽

Lars Paeger ◽

Peter Kloppenburg

Keyword(s):

Periplaneta Americana ◽

Membrane Properties ◽

Type Ii ◽

Diverse Population ◽

Cell Type ◽

Cellular Mechanisms ◽

Electrophysiological Properties ◽

Local Interneurons ◽

Cell Type Specific ◽

Process Structure

A diverse population of local interneurons (LNs) helps to process, structure, and spatially represent olfactory information in the insect antennal lobe. In Periplaneta americana, we identified two subtypes of nonspiking local interneurons (type II LNs) by their distinct morphological and intrinsic electrophysiological properties. As an important step toward a better understanding of the cellular mechanisms that mediate odor information processing, we present a detailed analysis of their distinct voltage-activated Ca2+ currents, which clearly correlated with their distinct intrinsic electrophysiological properties. Both type II LNs did not posses voltage-activated Na+ currents and apparently innervated all glomeruli including the macroglomerulus. Type IIa LNs had significant longer and thicker low-order neurites and innervated each glomerulus entirely and homogeneously, whereas type IIb LNs innervated only parts of each glomerulus. All type II LNs were broadly tuned and responded to odorants of many chemical classes with graded changes in the membrane potential. Type IIa LNs responded with odor-specific elaborate patterns of excitation that could also include “spikelets” riding on the depolarizations and periods of inhibition. In contrast, type IIb LNs responded mostly with sustained, relatively smooth depolarizations. Consistent with the strong active membrane properties of type IIa LNs versus type IIb LNs, the voltage-activated Ca2+ current of type IIa LNs activated at more hyperpolarized membrane potentials and had a larger transient component.

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Neuronal Circuits in Barrel Cortex for Whisker Sensory Perception

Physiological Reviews ◽

10.1152/physrev.00019.2019 ◽

2021 ◽

Vol 101 (1) ◽

pp. 353-415

Author(s):

Jochen F. Staiger ◽

Carl C. H. Petersen

Keyword(s):

Barrel Cortex ◽

Specific Activity ◽

Sensory Information ◽

Inhibitory Neurons ◽

Future Research ◽

Cell Type ◽

Molecular Features ◽

Somatotopic Map ◽

Cell Type Specific ◽

The Impact

The array of whiskers on the snout provides rodents with tactile sensory information relating to the size, shape and texture of objects in their immediate environment. Rodents can use their whiskers to detect stimuli, distinguish textures, locate objects and navigate. Important aspects of whisker sensation are thought to result from neuronal computations in the whisker somatosensory cortex (wS1). Each whisker is individually represented in the somatotopic map of wS1 by an anatomical unit named a ‘barrel’ (hence also called barrel cortex). This allows precise investigation of sensory processing in the context of a well-defined map. Here, we first review the signaling pathways from the whiskers to wS1, and then discuss current understanding of the various types of excitatory and inhibitory neurons present within wS1. Different classes of cells can be defined according to anatomical, electrophysiological and molecular features. The synaptic connectivity of neurons within local wS1 microcircuits, as well as their long-range interactions and the impact of neuromodulators, are beginning to be understood. Recent technological progress has allowed cell-type-specific connectivity to be related to cell-type-specific activity during whisker-related behaviors. An important goal for future research is to obtain a causal and mechanistic understanding of how selected aspects of tactile sensory information are processed by specific types of neurons in the synaptically connected neuronal networks of wS1 and signaled to downstream brain areas, thus contributing to sensory-guided decision-making.

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Two Dynamically Distinct Inhibitory Networks in Layer 4 of the Neocortex

Journal of Neurophysiology ◽

10.1152/jn.00283.2003 ◽

2003 ◽

Vol 90 (5) ◽

pp. 2987-3000 ◽

Cited By ~ 343

Author(s):

Michael Beierlein ◽

Jay R. Gibson ◽

Barry W. Connors

Keyword(s):

Barrel Cortex ◽

Dynamic Properties ◽

Inhibitory Synapses ◽

Projection Neurons ◽

Inhibitory Interneurons ◽

Short Term ◽

Layer 4 ◽

Recurrent Collaterals ◽

Chemical Synapses ◽

Excitatory And Inhibitory Synapses

Normal operations of the neocortex depend critically on several types of inhibitory interneurons, but the specific function of each type is unknown. One possibility is that interneurons are differentially engaged by patterns of activity that vary in frequency and timing. To explore this, we studied the strength and short-term dynamics of chemical synapses interconnecting local excitatory neurons (regular-spiking, or RS, cells) with two types of inhibitory interneurons: fast-spiking (FS) cells, and low-threshold spiking (LTS) cells of layer 4 in the rat barrel cortex. We also tested two other pathways onto the interneurons: thalamocortical connections and recurrent collaterals from corticothalamic projection neurons of layer 6. The excitatory and inhibitory synapses interconnecting RS cells and FS cells were highly reliable in response to single stimuli and displayed strong short-term depression. In contrast, excitatory and inhibitory synapses interconnecting the RS and LTS cells were less reliable when initially activated. Excitatory synapses from RS cells onto LTS cells showed dramatic short-term facilitation, whereas inhibitory synapses made by LTS cells onto RS cells facilitated modestly or slightly depressed. Thalamocortical inputs strongly excited both RS and FS cells but rarely and only weakly contacted LTS cells. Both types of interneurons were strongly excited by facilitating synapses from axon collaterals of corticothalamic neurons. We conclude that there are two parallel but dynamically distinct systems of synaptic inhibition in layer 4 of neocortex, each defined by its intrinsic spiking properties, the short-term plasticity of its chemical synapses, and (as shown previously) an exclusive set of electrical synapses. Because of their unique dynamic properties, each inhibitory network will be recruited by different temporal patterns of cortical activity.

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Development of Intrinsic Properties and Excitability of Layer 2/3 Pyramidal Neurons During a Critical Period for Sensory Maps in Rat Barrel Cortex

Journal of Neurophysiology ◽

10.1152/jn.00598.2003 ◽

2004 ◽

Vol 92 (1) ◽

pp. 144-156 ◽

Cited By ~ 53

Author(s):

Miguel Maravall ◽

Edward A. Stern ◽

Karel Svoboda

Keyword(s):

Critical Period ◽

Pyramidal Neurons ◽

Barrel Cortex ◽

Pyramidal Cells ◽

Membrane Properties ◽

Sensory Maps ◽

Layer 2 ◽

Whole Cell Recordings ◽

Passive Membrane Properties

The development of layer 2/3 sensory maps in rat barrel cortex (BC) is experience dependent with a critical period around postnatal days (PND) 10–14. The role of intrinsic response properties of neurons in this plasticity has not been investigated. Here we characterize the development of BC layer 2/3 intrinsic responses to identify possible sites of plasticity. Whole cell recordings were performed on pyramidal cells in acute BC slices from control and deprived rats, over ages spanning the critical period (PND 12, 14, and 17). Vibrissa trimming began at PND 9. Spiking behavior changed from phasic (more spike frequency adaptation) to regular (less adaptation) with age, such that the number of action potentials per stimulus increased. Changes in spiking properties were related to the strength of a slow Ca2+-dependent afterhyperpolarization. Maturation of the spiking properties of layer 2/3 pyramidal neurons coincided with the close of the critical period and was delayed by deprivation. Other measures of excitability, including I-f curves and passive membrane properties, were affected by development but unaffected by whisker deprivation.

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Cell-type–specific neuromodulation guides synaptic credit assignment in a spiking neural network

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111821118 ◽

2021 ◽

Vol 118 (51) ◽

pp. e2111821118

Author(s):

Yuhan Helena Liu ◽

Stephen Smith ◽

Stefan Mihalas ◽

Eric Shea-Brown ◽

Uygar Sümbül

Keyword(s):

Neural Network ◽

Normative Theory ◽

Synaptic Connections ◽

Neuron Type ◽

Cell Type ◽

Credit Assignment ◽

Neural Network Learning ◽

Network Learning ◽

Cell Type Specific ◽

Synaptic Learning

Brains learn tasks via experience-driven differential adjustment of their myriad individual synaptic connections, but the mechanisms that target appropriate adjustment to particular connections remain deeply enigmatic. While Hebbian synaptic plasticity, synaptic eligibility traces, and top-down feedback signals surely contribute to solving this synaptic credit-assignment problem, alone, they appear to be insufficient. Inspired by new genetic perspectives on neuronal signaling architectures, here, we present a normative theory for synaptic learning, where we predict that neurons communicate their contribution to the learning outcome to nearby neurons via cell-type–specific local neuromodulation. Computational tests suggest that neuron-type diversity and neuron-type–specific local neuromodulation may be critical pieces of the biological credit-assignment puzzle. They also suggest algorithms for improved artificial neural network learning efficiency.

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Cell-type specific innervation of cortical pyramidal cells at their apical tufts

10.1101/571695 ◽

2019 ◽

Author(s):

Ali Karimi ◽

Jan Odenthal ◽

Florian Drawitsch ◽

Kevin M. Boergens ◽

Moritz Helmstaedter

Keyword(s):

Electron Microscopy ◽

Pyramidal Cells ◽

Inhibitory Input ◽

Cell Type ◽

Layer 2 ◽

Cell Type Specific ◽

Cortical Regions ◽

3D Em ◽

Apical Dendrites ◽

Computational Properties

ABSTRACTWe investigated the synaptic innervation of apical tufts of cortical pyramidal cells in a region between layers 1 and 2 using 3-D electron microscopy (3D-EM) applied to four cortical regions in mouse. Across all cortices, we found the relative inhibitory input at the apical dendrite’s main bifurcation to be more than 3-fold stronger for layer 2 pyramidal cells than for all other pyramidal cells. Towards the distal tuft dendrites in upper layer 1, however, the relative inhibitory input was about 2-fold stronger for L5 pyramidal cells than for all others. Only L3 pyramidal cells showed homogeneous inhibitory input density. The inhibitory to excitatory synaptic balance is thus specific for the types of pyramidal cells. Inhibitory axons preferentially innervated either layer 2 or L3/5 apical dendrites, but not both. These findings describe connectomic principles for the control of pyramidal cells at their apical dendrites in the upper layers of the cerebral cortex and point to differential computational properties of layer 2, layer 3 and layer 5 pyramidal cells in cortex.

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State-dependent cell-type-specific membrane potential dynamics and unitary synaptic inputs in awake mice

eLife ◽

10.7554/elife.35869 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 16

Author(s):

Aurélie Pala ◽

Carl CH Petersen

Keyword(s):

Membrane Potential ◽

Barrel Cortex ◽

Field Potential ◽

Low Frequency ◽

Inhibitory Neuron ◽

Single Layer ◽

Cell Type ◽

State Dependent ◽

Layer 2 ◽

Cell Type Specific

The cellular and synaptic mechanisms driving cell-type-specific function during various cortical network activities and behaviors are poorly understood. Here, we targeted whole-cell recordings to two classes of inhibitory GABAergic neurons in layer 2/3 of the barrel cortex of awake head-restrained mice and correlated spontaneous membrane potential dynamics with cortical state and whisking behavior. Using optogenetic stimulation of single layer 2/3 excitatory neurons we measured unitary excitatory postsynaptic potentials (uEPSPs) across states. During active states, characterized by whisking and reduced low-frequency activity in the local field potential, parvalbumin-expressing neurons depolarized and, albeit in a small number of recordings, received uEPSPs with increased amplitude. In contrast, somatostatin-expressing neurons hyperpolarized and reduced firing rates during active states without consistent change in uEPSP amplitude. These results further our understanding of neocortical inhibitory neuron function in awake mice and are consistent with the hypothesis that distinct genetically-defined cell classes have different state-dependent patterns of activity.

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