scholarly journals Resurgent Na+ currents promote ultrafast spiking in projection neurons that drive fine motor control

2021 ◽  
Author(s):  
Benjamin M. Zemel ◽  
Alexander A. Nevue ◽  
Andre Dagostin ◽  
Peter V. Lovell ◽  
Claudio V. Mello ◽  
...  
Keyword(s):  
Motor Neurons ◽  
High Frequency ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Vocal Learning ◽  
Temporal Coding ◽  
Fine Motor ◽  
Inactivation Kinetics ◽  
Projection Neurons ◽  
Upper Motor Neurons

AbstractThe underlying mechanisms that promote precise spiking in upper motor neurons controlling fine motor skills are not well understood. Here we report that projection neurons in the adult zebra finch song nucleus RA display: 1) robust high-frequency firing, 2) ultra-short half-width spike waveforms, 3) superfast Na+ current inactivation kinetics and 4) large resurgent Na+ currents (INaR). These spiking properties closely resemble those of specialized pyramidal neurons in mammalian motor cortex and are well suited for precise temporal coding. They emerge during the critical period for vocal learning in males but not females, coinciding with a complete switch of modulatory Na+ channel subunit expression from Navβ3 to Navβ4. Dynamic clamping and dialysis of Navβ4’s C-terminal peptide into juvenile RA neurons provide evidence that this subunit, and its associated INaR, promote neuronal excitability. We propose that Navβ4 underpins INaR that facilitates precise, prolonged, and reliable high-frequency firing in upper motor neurons.

scholarly journals Resurgent Na+ currents promote ultrafast spiking in projection neurons that drive fine motor control

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benjamin M. Zemel ◽  
Alexander A. Nevue ◽  
Andre Dagostin ◽  
Peter V. Lovell ◽  
Claudio V. Mello ◽  
...  
Keyword(s):  
Motor Skills ◽  
Motor Neurons ◽  
Primary Motor Cortex ◽  
Neuronal Excitability ◽  
Fine Motor ◽  
Inactivation Kinetics ◽  
Na Channel ◽  
Projection Neurons ◽  
Fine Motor Skills ◽  
Upper Motor Neurons

AbstractThe underlying mechanisms that promote precise spiking in upper motor neurons controlling fine motor skills are not well understood. Here we report that projection neurons in the adult zebra finch song nucleus RA display robust high-frequency firing, ultra-narrow spike waveforms, superfast Na+ current inactivation kinetics, and large resurgent Na+ currents (INaR). These properties of songbird pallial motor neurons closely resemble those of specialized large pyramidal neurons in mammalian primary motor cortex. They emerge during the early phases of song development in males, but not females, coinciding with a complete switch of Na+ channel subunit expression from Navβ3 to Navβ4. Dynamic clamping and dialysis of Navβ4’s C-terminal peptide into juvenile RA neurons provide evidence that Navβ4, and its associated INaR, promote neuronal excitability. We thus propose that INaR modulates the excitability of upper motor neurons that are required for the execution of fine motor skills.

scholarly journals Slowly inactivating component of Na+ current in peri-somatic region of hippocampal CA1 pyramidal neurons

2013 ◽  
Vol 109 (5) ◽  
pp. 1378-1390 ◽  
Author(s):  
Yul Young Park ◽  
Daniel Johnston ◽  
Richard Gray
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Peak Amplitude ◽  
Neuronal Membrane ◽  
Inactivation Kinetics ◽  
Channel Blockers ◽  
Hippocampal Ca1 ◽  
Ramp Voltage ◽  
Dendritic Spikes ◽  
Voltage Gated Ion Channels

The properties of voltage-gated ion channels on the neuronal membrane shape electrical activity such as generation and backpropagation of action potentials, initiation of dendritic spikes, and integration of synaptic inputs. Subthreshold currents mediated by sodium channels are of interest because of their activation near rest, slow inactivation kinetics, and consequent effects on excitability. Modulation of these currents can also perturb physiological responses of a neuron that might underlie pathological states such as epilepsy. Using nucleated patches from the peri-somatic region of hippocampal CA1 neurons, we recorded a slowly inactivating component of the macroscopic Na+ current (which we have called INaS) that shared many biophysical properties with the persistent Na+ current, INaP, but showed distinctively faster inactivating kinetics. Ramp voltage commands with a velocity of 400 mV/s were found to elicit this component of Na+ current reliably. INaS also showed a more hyperpolarized I-V relationship and slower inactivation than those of the fast transient Na+ current ( INaT) recorded in the same patches. The peak amplitude of INaS was proportional to the peak amplitude of INaT but was much smaller in amplitude. Hexanol, riluzole, and ranolazine, known Na+ channel blockers, were tested to compare their effects on both INaS and INaT. The peak conductance of INaS was preferentially blocked by hexanol and riluzole, but the shift of half-inactivation voltage ( V1/2) was only observed in the presence of riluzole. Current-clamp measurements with hexanol suggested that INaS was involved in generation of an action potential and in upregulation of neuronal excitability.

scholarly journals Genetic ablation of SOD1G37R selectively from corticofugal projection neurons protects corticospinal neurons from degeneration without affecting ALS onset and progression

2020 ◽  
Author(s):  
Jelena Scekic-Zahirovic ◽  
Mathieu Fischer ◽  
Geoffrey Stuart Lopez ◽  
Thibaut Burg ◽  
Marie-Christine Birling ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuronal Excitability ◽  
Disease Onset ◽  
Projection Neurons ◽  
Mutant Proteins ◽  
Genetic Ablation ◽  
Spinal Motor Neurons ◽  
Axonal Projections ◽  
Als Patients ◽  
Corticofugal Projection Neurons

AbstractWhile clinical evidence of combined degeneration of the bulbar and spinal motor neurons (MN) together with the corticospinal neurons (CSN) is required to diagnose Amyotrophic Lateral Sclerosis (ALS), preclinical studies have mostly concentrated on MN, leaving aside the CSN and their contribution to ALS onset and progression. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets, along the corticofugal axonal projections (including CSN), either via altered neuronal excitability and subsequent excitotoxicity, or via prion-like propagation of misfolded proteins. We recently provided first experimental arguments in favour of the corticofugal hypothesis of ALS, demonstrating that CSN and other subcerebral projection neurons were toxic in a context of ALS. Here, we aimed to determine how CSN may be detrimental to their downstream targets, and what governs their degeneration. To answer these questions, we took advantage of the FloxedSOD1G37R mouse model of ALS that allows genetic ablation of the mutant transgene in selected cells upon Cre-mediated recombination, and crossed it to the CrymCreERT2 mouse line that we purposely designed to genetically target CSN and other corticofugal projection neurons (CFuPN) populations. We demonstrate that excision of the mutant SOD1G37R transgene from the CSN is sufficient to prevent their death, suggesting that CSN degeneration mostly relies on cell-intrinsic mechanisms. However, genetic ablation of SOD1G37R transgene from the corticofugal neurons had no effect on disease onset and survival. The data thus indicate that the toxicity of CFuPN in the context of ALS, and corticofugal propagation of the disease, are not mediated by the presence of misfolded mutant proteins, but more likely by other aspects of the cortical pathology, possibly hyperexcitability.

scholarly journals Physiological noise optimizes multiplexed coding of vibrotactile-like signals in somatosensory cortex

2021 ◽  
Author(s):  
Mohammad Amin Kamaleddin ◽  
Aaron Shifman ◽  
Daniel MW Sigal ◽  
Steven A Prescott
Keyword(s):  
Somatosensory Cortex ◽  
Stimulus Intensity ◽  
High Frequency ◽  
Pyramidal Neurons ◽  
Phase Locking ◽  
Stimulus Frequency ◽  
Temporal Coding ◽  
Physiological Noise ◽  
Rate Coding

ABSTRACTNeurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to respectively encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100-600 Hz) inputs and instead must skip (i.e. not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase lock to the stimulus for spike times (intervals) to encode stimulus frequency but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations and in vitro experiments in which S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that physiological noise induces irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because the reliability and precision of spikes evoked by small- amplitude, fast-onset signals are differentially sensitive to noise. Simulations confirmed that differences in stimulus intensity and frequency can be well discriminated based on differences in spike rate or timing, respectively, but only in the presence of noise. Our results show that multiplexed coding by S1 pyramidal neurons is facilitated rather than degraded by physiological levels of noise. In fact, multiplexing is optimal under physiologically noisy conditions.

scholarly journals Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS

2021 ◽  
Vol 11 (5) ◽  
pp. 578
Author(s):  
Oge Gozutok ◽  
Benjamin Ryan Helmold ◽  
P. Hande Ozdinler
Keyword(s):  
Motor Neurons ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Cortical Neurons ◽  
Therapeutic Interventions ◽  
Functional Identification ◽  
Protein Protein Interaction ◽  
Cellular Events ◽  
Interaction Domains ◽  
Upper Motor Neurons

Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions.

scholarly journals Septohippocampal transmission from parvalbumin-positive neurons features rapid recovery from synaptic depression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Feng Yi ◽  
Tavita Garrett ◽  
Karl Deisseroth ◽  
Heikki Haario ◽  
Emily Stone ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Synaptic Depression ◽  
Medial Septum ◽  
Membrane Properties ◽  
Projection Neurons ◽  
Calcium Dependent ◽  
Light Pulses ◽  
Diagonal Band ◽  
Initial Release ◽  
Intrinsic Membrane Properties

AbstractParvalbumin-containing projection neurons of the medial-septum-diagonal band of Broca ($$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB ) are essential for hippocampal rhythms and learning operations yet are poorly understood at cellular and synaptic levels. We combined electrophysiological, optogenetic, and modeling approaches to investigate $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB neuronal properties. $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB neurons had intrinsic membrane properties distinct from acetylcholine- and somatostatin-containing MS-DBB subtypes. Viral expression of the fast-kinetic channelrhodopsin ChETA-YFP elicited action potentials to brief (1–2 ms) 470 nm light pulses. To investigate $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB transmission, light pulses at 5–50 Hz frequencies generated trains of inhibitory postsynaptic currents (IPSCs) in CA1 stratum oriens interneurons. Using a similar approach, optogenetic activation of local hippocampal PV ($$\hbox {PV}_{\text{HC}}$$ PV HC ) neurons generated trains of $$\hbox {PV}_{\text{HC}}$$ PV HC -mediated IPSCs in CA1 pyramidal neurons. Both synapse types exhibited short-term depression (STD) of IPSCs. However, relative to $$\hbox {PV}_{\text{HC}}$$ PV HC synapses, $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB synapses possessed lower initial release probability, transiently resisted STD at gamma (20–50 Hz) frequencies, and recovered more rapidly from synaptic depression. Experimentally-constrained mathematical synapse models explored mechanistic differences. Relative to the $$\hbox {PV}_{\text{HC}}$$ PV HC model, the $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB model exhibited higher sensitivity to calcium accumulation, permitting a faster rate of calcium-dependent recovery from STD. In conclusion, resistance of $$\hbox {PV}_{\text{MS-DBB}}$$ PV MS-DBB synapses to STD during short gamma bursts enables robust long-range GABAergic transmission from MS-DBB to hippocampus.

Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher
Keyword(s):  
Working Memory ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
D1 Receptors ◽  
Input Output ◽  
Prefrontal Cortical ◽  
Noisy Input ◽  
Relationship Of

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

High-frequency submaximal stimulation over muscle evokes centrally generated forces in human upper limb skeletal muscles

2009 ◽  
Vol 106 (2) ◽  
pp. 370-377 ◽  
Author(s):  
Jean-Sébastien Blouin ◽  
Lee D. Walsh ◽  
Peter Nickolls ◽  
Simon C. Gandevia
Keyword(s):  
Upper Limb ◽  
High Frequency ◽  
Biceps Brachii ◽  
Fine Motor ◽  
Nerve Blocks ◽  
Ia Afferents ◽  
Lower Limb Muscles ◽  
Peripheral Mechanism ◽  
Central Origin ◽  
Motor Activities

Control of posture and movement requires control of the output from motoneurons. Motoneurons of human lower limb muscles exhibit sustained, submaximal activity to high-frequency electrical trains, which has been hypothesized to be partly triggered by monosynaptic Ia afferents. The possibility to trigger such behavior in upper limb motoneurons and the potential unique role of Ia afferents to trigger such behavior remain unclear. Subjects ( n = 9) received high-frequency trains of electrical stimuli over biceps brachii and flexor pollicis longus (FPL). We chose to study the FPL muscle because it has weak monosynaptic Ia afferent connectivity and it is involved in fine motor control of the thumb. Two types of stimulus trains (100-Hz bursts and triangular ramps) were tested at five intensities below painful levels. All subjects exhibited enhanced torque in biceps and FPL muscles after both types of high-frequency train. Torques also persisted after stimulation, particularly for the highest stimulus intensity. To separate the evoked torques that resulted from a peripheral mechanism (e.g., muscle potentiation) and that which resulted from a central origin, we studied FPL responses to high-frequency trains after complete combined nerve blocks of the median and radial nerves ( n = 2). During the blocks, high-frequency trains over the FPL did not yield torque enhancements or persisting torques. These results suggest that enhanced contractions of central origin can be elicited in motoneurons innervating the upper limb, despite weak monosynaptic Ia connections for FPL. Their presence in a recently evolved human muscle (FPL) indicates that these enhanced contractions may have a broad role in controlling tonic postural outputs of hand muscles and that they may be available even for fine motor activities involving the thumb.

Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons

2008 ◽  
Vol 99 (3) ◽  
pp. 1394-1407 ◽  
Author(s):  
Sarah Potez ◽  
Matthew E. Larkum
Keyword(s):  
High Frequency ◽  
Pyramidal Neurons ◽  
Animal Experiments ◽  
Apical Dendrite ◽  
Network Activity ◽  
Calcium Spikes ◽  
Firing Properties ◽  
The Impact

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

Sign in / Sign up

Export Citation Format

Share Document